FN Clarivate Analytics Web of Science
VR 1.0
PT J
AU Hu, DD
   Li, ZQ
   Zheng, B
   Lin, XX
   Pan, YH
   Gong, PR
   Zhuo, WY
   Hu, YJ
   Chen, C
   Chen, LN
   Zhou, JC
   Wang, LB
AF Hu, Dengdi
   Li, Zhaoqing
   Zheng, Bin
   Lin, Xixi
   Pan, Yuehong
   Gong, Peirong
   Zhuo, Wenying
   Hu, Yujie
   Chen, Cong
   Chen, Lini
   Zhou, Jichun
   Wang, Linbo
TI Cancer-associated fibroblasts in breast cancer: Challenges and
   opportunities
SO CANCER COMMUNICATIONS
LA English
DT Review
DE Cancer-associated fibroblasts; breast cancer; therapeutic target; tumor
   microenvironment; biomarker; tumor heterogeneity
ID NERVE GROWTH-FACTOR; EPITHELIAL-MESENCHYMAL TRANSITION; INVASIVE DUCTAL
   CARCINOMA; PANCREATIC STELLATE CELLS; PROMOTES TUMOR-GROWTH; PHASE-II
   TRIAL; ACTIVATION PROTEIN; TGF-BETA; STROMAL FIBROBLASTS; PODOPLANIN
   EXPRESSION
AB The tumor microenvironment is proposed to contribute substantially to the progression of cancers, including breast cancer. Cancer-associated fibroblasts (CAFs) are the most abundant components of the tumor microenvironment. Studies have revealed that CAFs in breast cancer originate from several types of cells and promote breast cancer malignancy by secreting factors, generating exosomes, releasing nutrients, reshaping the extracellular matrix, and suppressing the function of immune cells. CAFs are also becoming therapeutic targets for breast cancer due to their specific distribution in tumors and their unique biomarkers. Agents interrupting the effect of CAFs on surrounding cells have been developed and applied in clinical trials. Here, we reviewed studies examining the heterogeneity of CAFs in breast cancer and expression patterns of CAF markers in different subtypes of breast cancer. We hope that summarizing CAF-related studies from a historical perspective will help to accelerate the development of CAF-targeted therapeutic strategies for breast cancer.
C1 [Hu, Dengdi; Zheng, Bin; Pan, Yuehong; Gong, Peirong; Zhuo, Wenying; Hu, Yujie] Wenzhou Med Univ, Affiliated Cixi Hosp, Ningbo 315300, Zhejiang, Peoples R China.
   [Li, Zhaoqing; Lin, Xixi; Zhuo, Wenying; Chen, Cong; Chen, Lini; Zhou, Jichun; Wang, Linbo] Zhejiang Univ, Affiliated Sir Run Run Shaw Hosp, Sch Med, Key Lab Canc Prevent & Intervent,Minist Educ, Hangzhou 310016, Zhejiang, Peoples R China.
   [Li, Zhaoqing; Lin, Xixi; Zhuo, Wenying; Chen, Cong; Chen, Lini; Zhou, Jichun; Wang, Linbo] Biomed Res Ctr, Hangzhou 310016, Zhejiang, Peoples R China.
   [Li, Zhaoqing; Lin, Xixi; Zhuo, Wenying; Chen, Cong; Chen, Lini; Zhou, Jichun; Wang, Linbo] Key Lab Biotherapy Zhejiang Prov, 3 Eastern Qingchun Rd, Hangzhou 310016, Zhejiang, Peoples R China.
C3 Wenzhou Medical University; Zhejiang University
RP Zhou, JC; Wang, LB (corresponding author), Key Lab Biotherapy Zhejiang Prov, 3 Eastern Qingchun Rd, Hangzhou 310016, Zhejiang, Peoples R China.; Zhou, JC; Wang, LB (corresponding author), Zhejiang Univ, Affiliated Sir Run Run Shaw Hosp, Dept Surg Oncol,Biomed Res Ctr, Sch Med,Key Lab Canc Prevent & Intervent,Minist E, 3 Eastern Qingchun Rd, Hangzhou 310016, Zhejiang, Peoples R China.
EM jichun-zhou@zju.edu.cn; linbowang@zju.edu.cn
RI Zhou, Jichun/Q-8646-2019; xi, lin/JOK-1026-2023; Li,
   Zhaoqing/HGA-2068-2022
OI Zhou, Jichun/0000-0002-0727-4034
FU National Natural Science Foundation of China [81602471, 81672729,
   81972453, 81972597]; Natural Science Foundation of Zhejiang Province
   [LY19H160055, LY19H160059, LR22H160011]; Natural Science Foundation of
   Ningbo [2019A610315]; Cixi Agricultural and Social Development Science
   and Technology Project [CN2020006]; Zheng Shu Medical Elite Scholarship
   Fund
FX National Natural Science Foundation of China, Grant/Award Numbers:
   81602471, 81672729, 81972453, 81972597; Natural Science Foundation of
   Zhejiang Province, Grant/Award Numbers: LY19H160055, LY19H160059,
   LR22H160011; Natural Science Foundation of Ningbo, Grant/Award Number:
   2019A610315; Cixi Agricultural and Social Development Science and
   Technology Project, Grant/Award Number: CN2020006; Zheng Shu Medical
   Elite Scholarship Fund
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NR 365
TC 114
Z9 119
U1 30
U2 89
PU WILEY
PI HOBOKEN
PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA
EI 2523-3548
J9 CANCER COMMUN
JI Cancer Commun.
PD MAY
PY 2022
VL 42
IS 5
BP 401
EP 434
DI 10.1002/cac2.12291
EA APR 2022
PG 34
WC Oncology
WE Science Citation Index Expanded (SCI-EXPANDED)
SC Oncology
GA 1I8EY
UT WOS:000794179000001
PM 35481621
OA Green Published
HC Y
HP N
DA 2025-03-13
ER

PT J
AU Dong, HY
   Yang, CC
   Chen, X
   Sun, HN
   He, XH
   Wang, W
AF Dong, Huaying
   Yang, Changcheng
   Chen, Xiang
   Sun, Hening
   He, Xionghui
   Wang, Wei
TI Breast cancer-derived exosomal lncRNA SNHG14 induces normal fibroblast
   activation to cancer-associated fibroblasts via the EBF1/FAM171A1 axis
SO BREAST CANCER
LA English
DT Article
DE Breast cancer-derived exosomes; Normal fibroblasts; Cancer-associated
   fibroblasts; SNHG14; FAM171A1
ID PROGRESSION; EBF1
AB Background Exosomes released from cancer cells can activate normal fibroblasts (NFs) into cancer-associated fibroblasts (CAFs), which promotes cancer development. Our study aims to explore the role and potential mechanisms of breast cancer exosomes-delivered long non- coding RNA (lncRNA) SNHG14 in regulating CAFs transformation.
   Methods Adjacent normal tissues, cancerous and serum specimens were gathered in breast cancer patients. Exosomes and NFs were separated from breast cancer cells (SKBR-3) and normal tissues of patients, respectively. Cell viability and migration were measured with CCK-8 and Transwell assays. CAFs markers, fibroblast activation protein (FAP) and a-smooth muscle actin (alpha-SMA) were detected for assessing CAFs activation. The interactions between molecules were evaluated using dual luciferase reporter assay, RNA immunoprecipitation and chromatin immunoprecipitation.
   Results SNHG14 and FAM171A1 were upregulated in breast cancer. Exosomes secreted by SKBR-3 cells induced NFs activation in CAFs, as indicated by upregulating CAFs marker levels and facilitated cell viability and migration. Exosomal SNHG14 silencing in SKBR-3 cells inhibited CAFs activation. SNHG14 positively regulated FAM171A1 expression through EBF1. FAM171A1 overexpression eliminated the inhibition effect of exosomal SNHG14 silencing in CAFs transformation.
   Conclusion Breast cancer-derived exosomal SNHG14 contributed to NFs transformation into CAFs by the EBF1/FAM171A1 axis.
C1 [Dong, Huaying; Chen, Xiang; Sun, Hening; He, Xionghui; Wang, Wei] Hainan Med Univ, Hainan Gen Hosp, Dept Gen Surg, Hainan Affiliated Hosp, 19 Xiuhua Rd, Haikou 570311, Hainan, Peoples R China.
   [Yang, Changcheng] Hainan Med Univ, Dept Oncol, Affiliated Hosp 1, Haikou 570102, Hainan, Peoples R China.
C3 Hainan Medical University; Hainan Medical University
RP Wang, W (corresponding author), Hainan Med Univ, Hainan Gen Hosp, Dept Gen Surg, Hainan Affiliated Hosp, 19 Xiuhua Rd, Haikou 570311, Hainan, Peoples R China.
EM wangwei_haikou@126.com
OI Dong, Huaying/0000-0002-4905-6940
FU Key Research and Development Program of Hainan Province
   [ZDYF2021SHFZ055]; Hainan Provincial Natural Science Foundation of China
   [822CXTD535]; National Science Foundation of China [81960475]
FX This work was supported by The Key Research and Development Program of
   Hainan Province (ZDYF2021SHFZ055) and Hainan Provincial Natural Science
   Foundation of China (822CXTD535) and National Science Foundation of
   China (81960475).
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NR 46
TC 8
Z9 8
U1 2
U2 8
PU SPRINGER JAPAN KK
PI TOKYO
PA SHIROYAMA TRUST TOWER 5F, 4-3-1 TORANOMON, MINATO-KU, TOKYO, 105-6005,
   JAPAN
SN 1340-6868
EI 1880-4233
J9 BREAST CANCER-TOKYO
JI Breast Cancer
PD NOV
PY 2023
VL 30
IS 6
BP 1028
EP 1040
DI 10.1007/s12282-023-01496-9
PG 13
WC Oncology; Obstetrics & Gynecology
WE Science Citation Index Expanded (SCI-EXPANDED)
SC Oncology; Obstetrics & Gynecology
GA LS0W8
UT WOS:001188684700001
PM 37653187
DA 2025-03-13
ER

PT J
AU Donnarumma, E
   Fiore, D
   Nappa, M
   Roscigno, G
   Adamo, A
   Iaboni, M
   Russo, V
   Affinito, A
   Puoti, I
   Quintavalle, C
   Rienzo, A
   Piscuoglio, S
   Thomas, R
   Condorelli, G
AF Donnarumma, Elvira
   Fiore, Danilo
   Nappa, Martina
   Roscigno, Giuseppina
   Adamo, Assunta
   Iaboni, Margherita
   Russo, Valentina
   Affinito, Alessandra
   Puoti, Ilaria
   Quintavalle, Cristina
   Rienzo, Anna
   Piscuoglio, Salvatore
   Thomas, Renato
   Condorelli, Gerolama
TI Cancer-associated fibroblasts release exosomal microRNAs that dictate an
   aggressive phenotype in breast cancer
SO ONCOTARGET
LA English
DT Article
DE exosomes; breast cancer; microenvironment; cancer-associated
   fibroblasts; microRNAs
ID EPITHELIAL-MESENCHYMAL TRANSITION; STEM-CELLS; TUMOR MICROENVIRONMENT;
   POOR-PROGNOSIS; EXPRESSION; INVASION; TUMORIGENESIS; METASTASIS;
   RESISTANCE; FEATURES
AB Cancer-associated fibroblasts (CAFs) are the major components of the tumor microenvironment. They may drive tumor progression, although the mechanisms involved are still poorly understood. Exosomes have emerged as important mediators of intercellular communication in cancer. They mediate horizontal transfer of microRNAs (miRs), mRNAs and proteins, thus affecting breast cancer progression. Differential expression profile analysis identified three miRs (miRs -21, -378e, and -143) increased in exosomes from CAFs as compared from normal fibroblasts. Immunofluorescence indicated that exosomes may be transferred from CAFs to breast cancer cells, releasing their cargo miRs. Breast cancer cells (BT549, MDA-MB-231, and T47D lines) exposed to CAF exosomes or transfected with those miRs exhibited a significant increased capacity to form mammospheres, increased stem cell and epithelial-mesenchymal transition (EMT) markers, and anchorage-independent cell growth. These effects were reverted by transfection with anti-miRs. Similarly to CAF exosomes, normal fibroblast exosomes transfected with miRs -21, -378e, and -143 promoted the stemness and EMT phenotype of breast cancer cells. Thus, we provided evidence for the first time of the role of CAF exosomes and their miRs in the induction of the stemness and EMT phenotype in different breast cancer cell lines. Indeed, CAFs strongly promote the development of an aggressive breast cancer cell phenotype.
C1 [Donnarumma, Elvira] IRCCS SDN, Naples, Italy.
   [Fiore, Danilo; Nappa, Martina; Roscigno, Giuseppina; Adamo, Assunta; Iaboni, Margherita; Russo, Valentina; Affinito, Alessandra; Puoti, Ilaria; Condorelli, Gerolama] Univ Naples Federico II, Dept Mol Med & Med Biotechnol, Naples, Italy.
   [Rienzo, Anna; Condorelli, Gerolama] CNR, IEOS, Naples, Italy.
   [Quintavalle, Cristina; Piscuoglio, Salvatore] Univ Basel Hosp, Basel, Switzerland.
   [Thomas, Renato] Clin Mediterranea, Dept Surg & Oncol, Naples, Italy.
C3 IRCCS Istituto di Ricerca Diagnostica e Nucleare (SDN); University of
   Naples Federico II; Consiglio Nazionale delle Ricerche (CNR); Istituto
   per Endocrinologia e Oncologia "Gaetano Salvatore" (IEOS-CNR);
   University of Basel; Mediterranean Clinic
RP Condorelli, G (corresponding author), Univ Naples Federico II, Dept Mol Med & Med Biotechnol, Naples, Italy.; Condorelli, G (corresponding author), CNR, IEOS, Naples, Italy.
EM gecondor@unina.it
RI Puoti, Ilaria/HCI-8713-2022; Quintavalle, Cristina/AHH-9379-2022;
   Condorelli, Gerolama/AAC-3472-2022; Piscuoglio, Salvatore/F-9248-2014;
   Piscuoglio, Salvatore/AAB-4959-2022; Quintavalle, Cristina/O-1317-2015;
   Affinito, Alessandra/Q-7859-2018; Fiore, Danilo/A-6002-2019
OI Piscuoglio, Salvatore/0000-0003-2686-2939; Roscigno,
   Giuseppina/0000-0002-5359-6376; Quintavalle,
   Cristina/0000-0002-7432-9170; Adamo, Assunta/0000-0002-5050-0826;
   Affinito, Alessandra/0000-0002-3887-6513; Fiore,
   Danilo/0000-0003-3004-6862; Puoti, Ilaria/0000-0002-7779-4393
FU Associazione Italiana Ricerca sul Cancro (AIRC) [18473]; Fondazione
   Berlucchi
FX This work was partially supported by funds from Associazione Italiana
   Ricerca sul Cancro (AIRC grant number 18473) to G.C.; Fondazione
   Berlucchi to G.C.
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NR 44
TC 257
Z9 286
U1 0
U2 35
PU IMPACT JOURNALS LLC
PI ORCHARD PARK
PA 6666 E QUAKER ST, STE 1, ORCHARD PARK, NY 14127 USA
EI 1949-2553
J9 ONCOTARGET
JI Oncotarget
PD MAR 21
PY 2017
VL 8
IS 12
BP 19592
EP 19608
DI 10.18632/oncotarget.14752
PG 17
WC Oncology; Cell Biology
WE Science Citation Index Expanded (SCI-EXPANDED)
SC Oncology; Cell Biology
GA EO7OE
UT WOS:000396879200078
PM 28121625
OA Green Submitted, Green Accepted, Green Published, gold
DA 2025-03-13
ER

PT J
AU Xu, K
   Tian, XJ
   Oh, SY
   Movassaghi, M
   Naber, SP
   Kuperwasser, C
   Buchsbaum, RJ
AF Xu, Kun
   Tian, Xuejun
   Oh, Sun Y.
   Movassaghi, Mohammad
   Naber, Stephen P.
   Kuperwasser, Charlotte
   Buchsbaum, Rachel J.
TI The fibroblast Tiam1-osteopontin pathway modulates breast cancer
   invasion and metastasis
SO BREAST CANCER RESEARCH
LA English
DT Article
DE Tiam1; Osteopontin; Breast cancer; Cancer-associated fibroblast;
   Agelastatin; Metastasis
ID RAC ACTIVATOR TIAM1; MESENCHYMAL STEM-CELLS; TUMOR MICROENVIRONMENT;
   (-)-AGELASTATIN ALKALOIDS; MOLECULAR-MECHANISMS; COMPLEX-FORMATION;
   OSTEOPONTIN; EXPRESSION; GROWTH; PROGRESSION
AB Background: The tumor microenvironment has complex effects in cancer pathophysiology that are not fully understood. Most cancer therapies are directed against malignant cells specifically, leaving pro-malignant signals from the microenvironment unaddressed. Defining specific mechanisms by which the tumor microenvironment contributes to breast cancer metastasis may lead to new therapeutic approaches against advanced breast cancer.
   Methods: We use a novel method for manipulating three-dimensional mixed cell co-cultures, along with studies in mouse xenograft models of human breast cancer and a histologic study of human breast cancer samples, to investigate how breast cancer-associated fibroblasts affect the malignant behaviors of breast cancer cells.
   Results: Altering fibroblast Tiam1 expression induces changes in invasion, migration, epithelial-mesenchymal transition, and cancer stem cell characteristics in associated breast cancer cells. These changes are both dependent on fibroblast secretion of osteopontin and also long-lasting even after cancer cell dissociation from the fibroblasts, indicating a novel Tiam1-osteopontin pathway in breast cancer-associated fibroblasts. Notably, inhibition of fibroblast osteopontin with low doses of a novel small molecule prevents lung metastasis in a mouse model of human breast cancer metastasis. Moreover, fibroblast expression patterns of Tiam1 and osteopontin in human breast cancers show converse changes correlating with invasion, supporting the hypothesis that this pathway in tumor-associated fibroblasts regulates breast cancer invasiveness in human disease and is thus clinically relevant.
   Conclusions: These findings suggest a new therapeutic paradigm for preventing breast cancer metastasis. Pro-malignant signals from the tumor microenvironment with long-lasting effects on associated cancer cells may perpetuate the metastatic potential of developing cancers. Inhibition of these microenvironment signals represents a new therapeutic strategy against cancer metastasis that enables targeting of stromal cells with less genetic plasticity than associated cancer cells and opens new avenues for investigation of novel therapeutic targets and agents.
C1 [Xu, Kun; Oh, Sun Y.; Kuperwasser, Charlotte; Buchsbaum, Rachel J.] Tufts Med Ctr, Mol Oncol Res Inst, 75 Kneeland St, Boston, MA 02111 USA.
   [Tian, Xuejun; Naber, Stephen P.] Tufts Med Ctr, Dept Pathol, 800 Washington St, Boston, MA 02111 USA.
   [Oh, Sun Y.; Buchsbaum, Rachel J.] Tufts Med Ctr, Dept Med, 800 Washington St, Boston, MA 02111 USA.
   [Movassaghi, Mohammad] MIT, Dept Chem, 77 Massachusetts Ave, Cambridge, MA 02139 USA.
   [Kuperwasser, Charlotte] Tufts Univ, Sch Med, Dev Mol & Chem Biol Dept, 136 Harrison Ave, Boston, MA 02111 USA.
C3 Tufts Medical Center; Tufts Medical Center; Tufts Medical Center;
   Massachusetts Institute of Technology (MIT); Tufts University
RP Buchsbaum, RJ (corresponding author), Tufts Med Ctr, Mol Oncol Res Inst, 75 Kneeland St, Boston, MA 02111 USA.; Buchsbaum, RJ (corresponding author), Tufts Med Ctr, Dept Med, 800 Washington St, Boston, MA 02111 USA.
EM rbuchsbaum@tuftsmedicalcenter.org
FU Department of Defense; Diane Connolly-Zaniboni Research Scholarship in
   Breast Cancer; Russo Family Charitable Foundation; National Institutes
   of Health-National Cancer Institute [CA125554, CA170851]; Breast Cancer
   Research Foundation; NIH [T32 CA009429]; National Institutes of
   Health-National Institute of General Medical Services [GM074825]
FX This work was supported by the Department of Defense (RJB), the Diane
   Connolly-Zaniboni Research Scholarship in Breast Cancer (RJB), the Russo
   Family Charitable Foundation (RJB and CK), National Institutes of
   Health-National Cancer Institute CA125554 (CK) and CA170851 (CK), the
   Breast Cancer Research Foundation (CK), NIH-T32 CA009429 (SO), and
   National Institutes of Health-National Institute of General Medical
   Services GM074825 (MM). The authors would like to acknowledge Aaron
   Rosenberg for statistical assistance with this work.
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NR 58
TC 52
Z9 59
U1 0
U2 13
PU BMC
PI LONDON
PA CAMPUS, 4 CRINAN ST, LONDON N1 9XW, ENGLAND
SN 1465-542X
EI 1465-5411
J9 BREAST CANCER RES
JI Breast Cancer Res.
PD JAN 28
PY 2016
VL 18
AR 14
DI 10.1186/s13058-016-0674-8
PG 15
WC Oncology
WE Science Citation Index Expanded (SCI-EXPANDED)
SC Oncology
GA DC0CH
UT WOS:000368884000001
PM 26821678
OA Green Published, gold
DA 2025-03-13
ER

PT J
AU Deng, HF
   Wen, CX
   Jiang, SX
   Yu, YH
   Zhao, JG
   Zhang, B
AF Deng, Huifang
   Wen, Chengxu
   Jiang, Shangxuan
   Yu, Yuanhang
   Zhao, Jianguo
   Zhang, Bo
TI Single-cell analysis reveals one cancer-associated fibroblasts subtype
   linked to metastasis in breast cancer: MXRA5 as a potential novel marker
   for prognosis
SO AMERICAN JOURNAL OF CANCER RESEARCH
LA English
DT Article
DE MXRA5; cancer -associated fibroblasts; metastasis; single -cell
   analysis; breast cancer
ID TUMOR-GROWTH; HETEROGENEITY; PROGRESSION; EXPRESSION
AB Cancer-associated fibroblasts (CAFs) are prevalent in the tumor microenvironment of breast cancer, comprising a group of cell subpopulations with spatial, phenotypic, and functional heterogeneity. Due to the lack of specific markers for CAF subpopulations, their specific mechanisms in breast cancer remain unclear. We identified eight distinct CAF phenotypes in breast cancer using multiple single-cell RNA sequencing datasets and determined distinct transcription factors (TFs) of CAFs through SCENIC analysis. Our study highlights one CAF subtype in breast cancer, FN1+CAF2, associated with metastasis and macrophage polarization. We observed elevated FN1 expression in the stromal tissue of breast cancer patients. Furthermore, FN1 knockdown in CAFs reduced the migration ability of breast cancer cells. We identified a regulatory gene, MXRA5, in CAF2, which may play crucial roles in breast cancer. Our results indicated upregulated MXRA5 expression in breast cancer tissues and CAFs from patients with lymph node metastasis in the following experiment. Overall, our study reveals that the FN1+CAF2 subtype is associated with metastasis and suggests that MXRA5 may be a novel marker mediating the effects of CAF2 on breast cancer metastasis. This study enriches our understanding of CAF heterogeneity and offers new insights for treating breast cancer metastasis.
C1 [Deng, Huifang; Wen, Chengxu; Jiang, Shangxuan; Yu, Yuanhang; Zhang, Bo] Huazhong Univ Sci & Technol, Union Hosp, Tongji Med Coll, Dept Thyroid & Breast Surg, Wuhan 430022, Hubei, Peoples R China.
   [Zhao, Jianguo] Wuhan 1 Hosp, Dept Thyroid & Breast Surg, Wuhan 430022, Hubei, Peoples R China.
C3 Huazhong University of Science & Technology
RP Zhang, B (corresponding author), Huazhong Univ Sci & Technol, Union Hosp, Tongji Med Coll, Dept Thyroid & Breast Surg, Wuhan 430022, Hubei, Peoples R China.; Zhao, JG (corresponding author), Wuhan 1 Hosp, Dept Thyroid & Breast Surg, Wuhan 430022, Hubei, Peoples R China.
EM 3040114010@qq.com; union_bzhang@hust.edu.cn
FU National Natural Science Foundation of China [82372844]; Hubei Province
   Science and Technology Plan project [2022BGE233]
FX Thanks to the National Natural Science Foundation of China (Grant
   Number: 82372844) and the Hubei Province Science and Technology Plan
   project (Grant Number: 2022BGE233) for supporting this study. The study
   also thanks Dr. Kai Huang for providing scientific advice on
   bioinformatics analysis.
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NR 43
TC 1
Z9 1
U1 0
U2 4
PU E-CENTURY PUBLISHING CORP
PI MADISON
PA 40 WHITE OAKS LN, MADISON, WI 53711 USA
SN 2156-6976
J9 AM J CANCER RES
JI Am. J. Cancer Res.
PY 2024
VL 14
IS 2
PG 26
WC Oncology
WE Science Citation Index Expanded (SCI-EXPANDED)
SC Oncology
GA KI3K1
UT WOS:001179289200015
DA 2025-03-13
ER

PT J
AU Qiao, AX
   Gu, F
   Guo, XJ
   Zhang, XM
   Fu, L
AF Qiao, Aixiu
   Gu, Feng
   Guo, Xiaojing
   Zhang, Xinmin
   Fu, Li
TI Breast cancer-associated fibroblasts: their roles in tumor initiation,
   progression and clinical applications
SO FRONTIERS OF MEDICINE
LA English
DT Review
DE cancer-associated fibroblast; breast cancer; progression; prognosis
ID EPITHELIAL-MESENCHYMAL TRANSITION; STROMAL CAVEOLIN-1 EXPRESSION;
   CARCINOMA-ASSOCIATED FIBROBLASTS; GROWTH-FACTOR; TGF-BETA; MATRIX
   METALLOPROTEINASES; PROGNOSTIC VALUE; STEM-CELLS; MICROENVIRONMENT;
   DIFFERENTIATION
AB Breast cancer is the most common malignant tumor in women, and the incidence of this disease has increased in recent years because of changes in diet, living environment, gestational age, and other unknown factors. Previous studies focused on cancer cells, but an increasing number of recent studies have analyzed the contribution of cancer microenvironment to the initiation and progression of breast cancer. Cancer-associated fibroblasts (CAFs), the most abundant cells in tumor stroma, secrete various active biomolecules, including extracellular matrix components, growth factors, cytokines, proteases, and hormones. CAFs not only facilitate the initiation, growth, angiogenesis, invasion, and metastasis of cancer but also serve as biomarkers in the clinical diagnosis, therapy, and prognosis of breast cancer. In this article, we reviewed the literature and summarized the research findings on CAFs in breast cancer.
C1 [Qiao, Aixiu; Gu, Feng; Guo, Xiaojing; Fu, Li] Tianjin Med Univ Canc Inst & Hosp, Natl Clin Res Ctr Canc, Key Lab Breast Canc Prevent & Therapy, Minist Educ,Key Lab Canc Prevent & Therapy Tianji, Tianjin 300060, Peoples R China.
   [Qiao, Aixiu] Shanxi Med Univ, Dept Pathol, Taiyuan 030001, Peoples R China.
   [Zhang, Xinmin] Rowan Univ, Dept Pathol, Cooper Univ Hosp, One Cooper Plaza, Camden, NJ 08103 USA.
   [Zhang, Xinmin] Rowan Univ, Cooper Med Sch, One Cooper Plaza, Camden, NJ 08103 USA.
C3 Tianjin Medical University; Shanxi Medical University; Rowan University;
   Cooper University Hospital; Rowan University; Cooper Medical School of
   Rowan University
RP Fu, L (corresponding author), Tianjin Med Univ Canc Inst & Hosp, Natl Clin Res Ctr Canc, Key Lab Breast Canc Prevent & Therapy, Minist Educ,Key Lab Canc Prevent & Therapy Tianji, Tianjin 300060, Peoples R China.
EM fulijyb@hotmail.com
RI FU, Li/AAD-4775-2019
FU National Natural Science Foundation of China [30930038]
FX We apologize to those authors whose work was not cited because of space
   restrictions. This work was supported by a grant from the National
   Natural Science Foundation of China (No. 30930038).
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NR 100
TC 62
Z9 73
U1 2
U2 43
PU SPRINGER
PI NEW YORK
PA 233 SPRING ST, NEW YORK, NY 10013 USA
SN 2095-0217
EI 2095-0225
J9 FRONT MED-PRC
JI Front. Med.
PD MAR
PY 2016
VL 10
IS 1
BP 33
EP 40
DI 10.1007/s11684-016-0431-5
PG 8
WC Oncology; Medicine, Research & Experimental
WE Science Citation Index Expanded (SCI-EXPANDED)
SC Oncology; Research & Experimental Medicine
GA DI2WX
UT WOS:000373361000004
PM 26791754
DA 2025-03-13
ER

PT J
AU Al-Ansari, MM
   Al-Saif, M
   Arafah, M
   Eldali, AM
   Tulbah, A
   Al-Tweigeri, T
   Semlali, A
   Khabar, KS
   Aboussekhra, A
AF Al-Ansari, Mysoon M.
   Al-Saif, Maher
   Arafah, Maria
   Eldali, Abdelmonneim M.
   Tulbah, Asma
   Al-Tweigeri, Taher
   Semlali, Abdelhabib
   Khabar, Khalid S.
   Aboussekhra, Abdelilah
TI Clinical and functional significance of tumor/stromal ATR expression in
   breast cancer patients
SO BREAST CANCER RESEARCH
LA English
DT Article
DE ATR; AUF-1; Breast cancer; Cancer-associated fibroblasts; Disease-free
   survival
ID WHOLE CIGARETTE-SMOKE; MESSENGER-RNA; FIBROBLASTS; STABILITY; BINDING;
   IL-6
AB Background Most breast cancer-associated fibroblasts (CAFs) are active and important cancer-promoting cells, with significant impact on patient prognosis. Therefore, we investigated here the role of the protein kinase ATR in breast stromal fibroblasts in the prognosis of locally advanced breast cancer patients. Methods We have used immunohistochemistry to assess the level of ATR in breast cancer tissues and their adjacent normal tissues. Immunoblotting as well as quantitative RT-PCR were utilized to show the role of breast cancer cells and IL-6 as well as AUF-1 in downregulating ATR in breast stromal fibroblasts. Engineered human breast tissue model was also used to show that ATR-deficient breast stromal fibroblasts enhance the growth of breast cancer cells. Results We have shown that the protein kinase ATR is downregulated in cancer cells and their neighboring CAFs in breast cancer tissues as compared to their respective adjacent normal tissues. The implication of cancer cells in ATR knockdown in CAFs has been proven in vitro by showing that breast cancer cells downregulate ATR in breast fibroblasts in an IL-6/STAT3-dependent manner and via AUF-1. In another cohort of 103 tumors from locally advanced breast cancer patients, we have shown that absence or reduced ATR expression in tumoral cells and their adjacent stromal fibroblasts is correlated with poor overall survival as well as disease-free survival. Furthermore, ATR expression in CAFs was inversely correlated with tumor recurrence and progression. Conclusion ATR downregulation in breast CAFs is frequent, procarcinogenic, and correlated with poor patient survival.
C1 [Al-Ansari, Mysoon M.; Aboussekhra, Abdelilah] King Faisal Specialist Hosp & Res Ctr, Dept Mol Oncol, MBC 03, Riyadh 11211, Saudi Arabia.
   [Al-Ansari, Mysoon M.] King Saud Univ, Fac Sci & Med Studies, Dept Microbiol, Riyadh, Saudi Arabia.
   [Al-Saif, Maher; Khabar, Khalid S.] King Faisal Specialist Hosp & Res Ctr, Res Ctr, Mol BioMed Program, Riyadh 11211, Saudi Arabia.
   [Arafah, Maria] King Saud Univ, Dept Pathol, POB 2925, Riyadh 11461, Saudi Arabia.
   [Eldali, Abdelmonneim M.] King Faisal Specialist Hosp & Res Ctr, Dept Biostat Epidemiol & Sci Comp, Riyadh 11211, Saudi Arabia.
   [Tulbah, Asma] King Faisal Specialist Hosp & Res Ctr, Dept Pathol, Riyadh 11211, Saudi Arabia.
   [Al-Tweigeri, Taher] King Faisal Specialist Hosp & Res Ctr, Dept Oncol, Riyadh 11211, Saudi Arabia.
   [Semlali, Abdelhabib] Univ Laval Quebec, Fac Med Dent, Grp Rech Ecol Buccale, Local 1758,2420 Rue Terrasse, Quebec City, PQ G1V 0A6, Canada.
C3 King Faisal Specialist Hospital & Research Center; King Saud University;
   King Faisal Specialist Hospital & Research Center; King Saud University;
   King Faisal Specialist Hospital & Research Center; King Faisal
   Specialist Hospital & Research Center; King Faisal Specialist Hospital &
   Research Center; Laval University
RP Aboussekhra, A (corresponding author), King Faisal Specialist Hosp & Res Ctr, Dept Mol Oncol, MBC 03, Riyadh 11211, Saudi Arabia.
EM aboussekhra@kfshrc.edu.sa
RI Semlali, Abdelhabib/AAP-7043-2020; alsaif, maher/KIL-4957-2024;
   Aboussekhra, Abdelilah/JCD-8138-2023; Arafah, Maria/ABH-3517-2020;
   Al-Ansari, Mysoon/K-1915-2013; Khabar, Khalid/A-4772-2011
OI Al-Ansari, Mysoon/0000-0002-2501-691X; alsaif,
   Maher/0009-0005-9737-8273; Khabar, Khalid/0000-0003-1003-9788; Arafah,
   Maria/0000-0002-6847-5884
FU King Faisal Specialist Hospital and Research Centre
FX This work was solely supported by the King Faisal Specialist Hospital
   and Research Centre.
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NR 22
TC 8
Z9 9
U1 0
U2 2
PU BMC
PI LONDON
PA CAMPUS, 4 CRINAN ST, LONDON N1 9XW, ENGLAND
SN 1465-5411
EI 1465-542X
J9 BREAST CANCER RES
JI Breast Cancer Res.
PD MAY 15
PY 2020
VL 22
IS 1
AR 49
DI 10.1186/s13058-020-01289-4
PG 12
WC Oncology
WE Science Citation Index Expanded (SCI-EXPANDED)
SC Oncology
GA LS0IH
UT WOS:000536077300002
PM 32414408
OA gold, Green Published
DA 2025-03-13
ER

PT J
AU Park, SY
   Kim, HM
   Koo, JS
AF Park, Sung Yeon
   Kim, Hye Min
   Koo, Ja Seung
TI Differential expression of cancer-associated fibroblast-related proteins
   according to molecular subtype and stromal histology in breast cancer
SO BREAST CANCER RESEARCH AND TREATMENT
LA English
DT Article
DE Breast cancer; Cancer-associated fibroblast; Molecular subtype; Tumor
   stroma
ID ACTIVATION PROTEIN; TUMOR-STROMA; PODOPLANIN EXPRESSION;
   CLINICAL-IMPLICATIONS; PROGNOSTIC-FACTOR; TENASCIN-C; CELLS; CARCINOMA;
   S100A4; ALPHA
AB The purpose of this study aimed to investigate the clinicopathologic characteristics of breast cancer according to its cancer-associated fibroblast (CAF) phenotype. Immunohistochemistry staining of estrogen receptor, progesterone receptor, human epidermal growth factor receptor 2 (HER-2), Ki-67, podoplanin, prolyl 4-hydroxylase, fibroblast activation protein alpha (FAP alpha), S100A4, platelet-derived growth factor receptor alpha (PDGFR alpha), PDGFR beta, and chondroitin sulfate proteoglycan (NG2) was performed on tissue microarray consisting of 642 breast cancer cases. Samples were categorized into luminal A, luminal B, HER-2, or triple-negative breast cancer (TNBC) according to immunohistochemical results, whereas tumor stroma was classified into desmoplastic, sclerotic, normal-like, or inflammatory type based on histological findings. Expression of CAF-related proteins in the stroma differed depending on breast cancer molecular subtypes. All CAF-related protein expression was high (p < 0.05) in HER-2 type, whereas in luminal A, the expression of FAP alpha, PDGF alpha, PDGF beta, and NG2 was low, and in TNBC, the expression of podoplanin, prolyl 4-hydroxylase, and S100A4 was low. In the stromal component, CAF-related protein expression differed according to stromal phenotype (p < 0.001). The desmoplastic type showed high expression of podoplanin, prolyl 4-hydroxylase, S100A4, PDGFR alpha, and PDGFR beta, whereas the sclerotic type exhibited low expression of FAP alpha, PDGF alpha, PDGF beta, and NG2. The inflammatory type had high expression of FAP alpha and NG2 with low podoplanin, while normal-like type showed low expression of prolyl 4-hydroxylase and S100A4. Our results suggested that differential CAF-related protein expression depended on the molecular subtypes and stromal histologic features of breast cancer, indicating that in the future, this system could potentially use these markers for prognosis prediction and targeted therapy of breast cancer.
C1 [Park, Sung Yeon] Cheongna Dalton Sch, Inchon, South Korea.
   [Kim, Hye Min; Koo, Ja Seung] Yonsei Univ, Coll Med, Dept Pathol, Severance Hosp, Seoul 120752, South Korea.
C3 Yonsei University; Yonsei University Health System
RP Koo, JS (corresponding author), Yonsei Univ, Coll Med, Dept Pathol, Severance Hosp, 50 Yonsei Ro, Seoul 120752, South Korea.
EM kjs1976@yuhs.ac
RI Kim, Sun Jung/AAM-7334-2020; Kim, Hyo-Won/M-9932-2019
OI Kim, Hye Min/0000-0002-2899-9480; koo, ja seung/0000-0003-4546-4709
FU National R&D Program for Cancer Control, Ministry of Health & Welfare,
   Republic of Korea [1420080]; Yonsei University College of Medicine
   [6-2014-0131]
FX This study was supported by a grant from National R&D Program for Cancer
   Control, Ministry of Health & Welfare, Republic of Korea (1420080). This
   study was supported by a faculty research grant from Yonsei University
   College of Medicine for 2013 (6-2014-0131).
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NR 52
TC 65
Z9 74
U1 0
U2 21
PU SPRINGER
PI NEW YORK
PA ONE NEW YORK PLAZA, SUITE 4600, NEW YORK, NY, UNITED STATES
SN 0167-6806
EI 1573-7217
J9 BREAST CANCER RES TR
JI Breast Cancer Res. Treat.
PD FEB
PY 2015
VL 149
IS 3
BP 727
EP 741
DI 10.1007/s10549-015-3291-9
PG 15
WC Oncology
WE Science Citation Index Expanded (SCI-EXPANDED)
SC Oncology
GA CB6UC
UT WOS:000349761200015
PM 25667103
DA 2025-03-13
ER

PT J
AU Urban, L
   Novák, S
   Coma, M
   Dvoránková, B
   Lacina, L
   Sáchová, J
   Hradilová, M
   Svatonová, P
   Kolár, M
   Strnad, H
   Brezinová, J
   Smetana, K Jr
   Gál, P
   Szabo, P
AF Urban, Lukas
   Novak, Stepan
   Coma, Matus
   Dvorankova, Barbora
   Lacina, Lukas
   Sachova, Jana
   Hradilova, Miluse
   Svatonova, Petra
   Kolar, Michal
   Strnad, Hynek
   Brezinova, Jana
   Smetana, Karel
   Gal, Peter
   Szabo, Pavol
TI Unravelling heterogeneous effects of cancer-associated fibroblasts on
   poor prognosis markers in breast cancer EM-G3 cell line: <i>In
   vitro</i>-targeted treatment (anti-IL-6, anti-VEGF-A, anti-MFGE8) based
   on transcriptomic profiling
SO ONCOLOGY REPORTS
LA English
DT Article
DE epithelial-mesenchymal interaction; cell differentiation; tumor
   microenvironment; breast cancer; neutralizing antibody
ID EXPRESSION; GROWTH; HALLMARKS; DIAGNOSIS; VIMENTIN; INVASION
AB Breast cancer is the most frequently diagnosed cancer in women worldwide. Although dramatically increased survival rates of early diagnosed cases have been observed, late diagnosed patients and metastatic cancer may still be considered fatal. The present study's main focus was on cancer-associated fibroblasts (CAFs) which is an active component of the tumor microenvironment (TME) regulating the breast cancer ecosystem. Transcriptomic profiling and analysis of CAFs isolated from breast cancer skin metastasis, cutaneous basal cell carcinoma, and squamous cell carcinoma unravelled major gene candidates such as IL6, VEGFA and MFGE8 that induced co-expression of keratins-8/-14 in the EM-G3 cell line derived from infiltrating ductal breast carcinoma. Western blot analysis of selected keratins (keratin-8, -14, -18, -19) and epithelial-mesenchymal transition-associated markers (SLUG, SNAIL, ZEB1, E-/N-cadherin, vimentin) revealed specific responses pointing to certain heterogeneity of the studied CAF populations. Experimental in vitro treatment using neutralizing antibodies against IL-6, VEGF-A and MFGE8 attenuated the modulatory effect of CAFs on EM-G3 cells. The present study provided novel data in characterizing and understanding the interactions between CAFs and EM-G3 cells in vitro. CAFs of different origins support the pro-inflammatory microenvironment and influence the biology of breast cancer cells. This observation potentially holds significant interest for the development of novel, clinically relevant approaches targeting the TME in breast cancer. Furthermore, its implications extend beyond breast cancer and have the potential to impact a wide range of other cancer types.
C1 [Urban, Lukas; Coma, Matus; Gal, Peter] Pavol Jozef Safarik Univ Kosice, Med Fac, Dept Pharmacol, Kosice, Slovakia.
   [Urban, Lukas; Coma, Matus; Gal, Peter] East Slovak Inst Cardiovasc Dis Inc, Dept Biomed Res, Kosice 04011, Slovakia.
   [Novak, Stepan; Dvorankova, Barbora; Lacina, Lukas; Smetana, Karel; Szabo, Pavol] Charles Univ Prague, Fac Med 1, Inst Anat, Prague 12800, Czech Republic.
   [Novak, Stepan] Charles Univ Prague, Fac Med 1, Dept Otorhinolaryngol Head & Neck Surg, Prague 15006, Czech Republic.
   [Novak, Stepan] Univ Hosp Motol, Prague 15006, Czech Republic.
   [Dvorankova, Barbora; Lacina, Lukas; Smetana, Karel; Szabo, Pavol] Charles Univ Prague, Fac Med 1, BIOCEV, Vestec 25250, Czech Republic.
   [Dvorankova, Barbora; Lacina, Lukas; Smetana, Karel; Szabo, Pavol] Fac Sci, Vestec 25250, Czech Republic.
   [Lacina, Lukas] Charles Univ Prague, Gen Univ Hosp, Dept Dermatovenereol, Prague 12800, Czech Republic.
   [Lacina, Lukas] Charles Univ Prague, Fac Med 1, Prague 12800, Czech Republic.
   [Sachova, Jana; Hradilova, Miluse; Svatonova, Petra; Kolar, Michal; Strnad, Hynek] Czech Acad Sci, Lab Genom & Bioinformat, Inst Mol Genet, Prague 14220, Czech Republic.
   [Brezinova, Jana] Inst Hematol & Blood Transfus, Cytogenet Lab, Prague 12800, Czech Republic.
   [Gal, Peter] Comenius Univ, Fac Pharm, Dept Pharmacognosy, Bratislava 83232, Slovakia.
   [Gal, Peter] Charles Univ Prague, Fac Med 3, Prague Burn Ctr, Prague 10034, Czech Republic.
   [Gal, Peter] Slovak Acad Sci, Biomed Res Ctr, Inst Neurobiol, Kosice 04001, Slovakia.
   [Gal, Peter] East Slovak Inst Cardiovasc Dis Inc, Dept Biomed Res, 8 Ondavska Rd, Kosice 04011, Slovakia.
   [Szabo, Pavol] Charles Univ Prague, Inst Anat, Fac Med 1, 3 U Nemocnice Rd, Prague 12800, Czech Republic.
C3 University of Pavol Jozef Safarik Kosice; Charles University Prague;
   Charles University Prague; Motol University Hospital; Charles University
   Prague; General University Hospital Prague; Charles University Prague;
   Charles University Prague; Czech Academy of Sciences; Institute of
   Molecular Genetics of the Czech Academy of Sciences; Institute of
   Hematology Prague; Comenius University Bratislava; Charles University
   Prague; Slovak Academy of Sciences; Institute of Neurobiology, SAS;
   Charles University Prague
RP Gál, P (corresponding author), East Slovak Inst Cardiovasc Dis Inc, Dept Biomed Res, 8 Ondavska Rd, Kosice 04011, Slovakia.; Szabo, P (corresponding author), Charles Univ Prague, Inst Anat, Fac Med 1, 3 U Nemocnice Rd, Prague 12800, Czech Republic.
EM pavol.szabo@lf1.cuni.cz
RI Szabo, Pavol/R-5197-2016; Čoma, Matúš/AAZ-4781-2020; Lacina,
   Lukas/C-1149-2017; Kolář, Michal/A-3307-2012; Novak, Stepan/H-7755-2017;
   Smetana, Jr., Karel/D-7039-2017; Hradilova, Miluse/G-3829-2014; Urban,
   Lukas/KXR-2949-2024
OI Novak, Stepan/0000-0002-1174-0878; Smetana, Jr.,
   Karel/0000-0002-7878-8403; Hradilova, Miluse/0000-0001-6615-0149; Urban,
   Lukas/0000-0003-2769-4295
FU Operational Programme Research, Development, and Education within the
   projects: Center for Tumor Ecology-Research of the Cancer
   Microenvironment Supporting Cancer Growth and Spread
FX Not applicable.
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NR 56
TC 1
Z9 1
U1 3
U2 12
PU SPANDIDOS PUBL LTD
PI ATHENS
PA POB 18179, ATHENS, 116 10, GREECE
SN 1021-335X
EI 1791-2431
J9 ONCOL REP
JI Oncol. Rep.
PD JAN
PY 2024
VL 51
IS 1
AR 3
DI 10.3892/or.2023.8662
PG 12
WC Oncology
WE Science Citation Index Expanded (SCI-EXPANDED)
SC Oncology
GA Z4JT2
UT WOS:001111760900001
PM 37975220
OA hybrid, Green Published
DA 2025-03-13
ER

PT J
AU Choi, YP
   Lee, JH
   Gao, MQ
   Kim, BG
   Kang, S
   Kim, SH
   Cho, NH
AF Choi, Yoon Pyo
   Lee, Joo Hyun
   Gao, Ming-Qing
   Kim, Baek Gil
   Kang, Suki
   Kim, Se Hoon
   Cho, Nam Hoon
TI Cancer-associated fibroblast promote transmigration through endothelial
   brain cells in three-dimensional <i>in vitro</i> models
SO INTERNATIONAL JOURNAL OF CANCER
LA English
DT Article
DE breast cancer; brain metastasis; blood-brain barrier; cancer-associated
   fibroblast; 3D culture
ID STROMAL FIBROBLASTS; METASTASIS; BREAST; BARRIER; MICROENVIRONMENT;
   PROGRESSION; ACTIVATION; INTEGRINS; INVASION; BIOLOGY
AB Brain metastases are associated with high morbidity as well as with poor prognosis and survival in breast cancer patients. Despite its clinical importance, metastasis of breast cancer cells through the blood-brain barrier (BBB) is poorly understood. The objective of our study was to investigate whether cancer-associated fibroblasts (CAFs) play crucial roles in breast cancer brain metastasis. Using a cell adhesion assays, in vitro BBB permeability and transmigration assays and soft agar colony formation assays, we investigated the physical roles of CAFs in breast cancer brain metastasis. We also performed immunofluorescence, flow cytometric analysis, Droplet Digital PCR and Simon (TM) Simple Western System to confirm changes in expression levels. We established two novel three-dimensional (3D) culture systems using a perpendicular slide chamber and applying 3D embedded culture method to reflect brain metastasis conditions. With a newly developed device, CAFs was proven to promote cell adhesion to human brain microvascular endothelial cells, in vitro BBB permeability and transmigration and colony formation of breast cancer cells. Furthermore, CAFs enhanced the invasive migration of breast cancer cells in two kinds of 3D cultures. These 3D models also reliably recapitulate the initial steps of BBB transmigration, micro-metastasis and colonization. Expression of integrin alpha 5 beta 1 and alpha v beta 3, c-MET and alpha 2,6-siayltransferase was increased in breast cancer cells that migrated through the BBB. In conclusion, based on our in vitro BBB and co-culture models, our data suggest that CAFs may play a role in breast cancer brain metastasis.
C1 [Choi, Yoon Pyo] Yonsei Univ, Dept Chem, Natl Creat Res Ctr Biofunct Mol, Seoul 120752, South Korea.
   [Choi, Yoon Pyo] Yonsei Univ, Dept Chem, Brain Korea PLUS Project 21, Seoul 120752, South Korea.
   [Lee, Joo Hyun; Cho, Nam Hoon] Yonsei Univ, Brain Korea PLUS Project Med Sci 21, Seoul 120752, South Korea.
   [Gao, Ming-Qing] Northwest A&F Univ, Coll Vet Med, Key Lab Anim Biotechnol, Minist Agr, Yangling, Shaanxi, Peoples R China.
   [Kim, Baek Gil; Kim, Se Hoon; Cho, Nam Hoon] Yonsei Univ, Coll Med, Dept Pathol, Seoul 120752, South Korea.
   [Kang, Suki; Cho, Nam Hoon] Severance Biomed Sci Inst, Seoul, South Korea.
C3 Yonsei University; Yonsei University; Yonsei University; Northwest A&F
   University - China; Ministry of Agriculture & Rural Affairs; Yonsei
   University; Yonsei University Health System
RP Cho, NH (corresponding author), Yonsei Univ, Coll Med, Dept Pathol, 250 Seongsanno, Seoul 120752, South Korea.
EM cho1988@yuhs.ac
RI Kim, Sara/F-2951-2013; KIM, BAEK GIL/KCL-0984-2024
OI KIM, BAEK GIL/0000-0001-6270-1433; jo, namhun/0000-0002-0045-6441; Kim,
   Se Hoon/0000-0001-7516-7372; KANG, SUKI/0000-0002-9957-3479
FU Ministry of Education, Science and Technology (MEST) [2011-0009444,
   2012R1A2A4A01006435, CNH7]
FX Grant sponsor: Ministry of Education, Science and Technology (MEST);
   Grant numbers: 2011-0009444, 2012R1A2A4A01006435, CNH7
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NR 37
TC 39
Z9 46
U1 0
U2 51
PU WILEY-BLACKWELL
PI HOBOKEN
PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA
SN 0020-7136
EI 1097-0215
J9 INT J CANCER
JI Int. J. Cancer
PD NOV 1
PY 2014
VL 135
IS 9
BP 2024
EP 2033
DI 10.1002/ijc.28848
PG 10
WC Oncology
WE Science Citation Index Expanded (SCI-EXPANDED)
SC Oncology
GA AP3NU
UT WOS:000341983700008
PM 24643985
OA Bronze
DA 2025-03-13
ER

PT J
AU Danforth, DN
AF Danforth, David N.
TI The Role of Chronic Inflammation in the Development of Breast Cancer
SO CANCERS
LA English
DT Review
DE chronic inflammation; normal breast tissue; breast cancer; breast cancer
   development; obesity; microbiome; sterile inflammation
ID TUMOR-ASSOCIATED MACROPHAGES; C-REACTIVE PROTEIN; MESENCHYMAL
   STEM-CELLS; CROWN-LIKE STRUCTURES; TOLL-LIKE RECEPTORS; ADIPOSE-TISSUE;
   INNATE IMMUNITY; AROMATASE EXPRESSION; T-CELLS; PROGNOSTIC-SIGNIFICANCE
AB Simple Summary Chronic inflammation is an important cause of multiple cancers. While chronic inflammation is present in breast cancer and may influence its outcome, its role in the initiation and development of breast cancer is unclear. A review of the literature was conducted to determine if chronic inflammatory processes are present, both systemically and in normal breast tissue, which may contribute to the development of breast cancer in women. This indicates that several chronic inflammatory factors may influence breast cancer development, with some such as adipose tissue and obesity occurring early in breast carcinogenesis, while others, such as the microbiome and inflammation from genomic changes, may occur with the transition to malignancy. Chronic inflammation appears to be an important risk factor for breast cancer and may influence both the development and conduct of breast cancer. Chronic inflammation contributes to the malignant transformation of several malignancies and is an important component of breast cancer. The role of chronic inflammation in the initiation and development of breast cancer from normal breast tissue, however, is unclear and needs to be clarified. A review of the literature was conducted to define the chronic inflammatory processes in normal breast tissue at risk for breast cancer and in breast cancer, including the role of lymphocyte and macrophage infiltrates, chronic active adipocytes and fibroblasts, and processes that may promote chronic inflammation including the microbiome and factors related to genomic abnormalities and cellular injury. The findings indicate that in healthy normal breast tissue there is systemic evidence to suggest inflammatory changes are present and associated with breast cancer risk, and adipocytes and crown-like structures in normal breast tissue may be associated with chronic inflammatory changes. The microbiome, genomic abnormalities, and cellular changes are present in healthy normal breast tissue, with the potential to elicit inflammatory changes, while infiltrating lymphocytes are uncommon in these tissues. Chronic inflammatory changes occur prominently in breast cancer tissues, with important contributions from tumor-infiltrating lymphocytes and tumor-associated macrophages, cancer-associated adipocytes and crown-like structures, and cancer-associated fibroblasts, while the microbiome and DNA damage may serve to promote inflammatory events. Together, these findings suggest that chronic inflammation may play a role in influencing the initiation, development and conduct of breast cancer, although several chronic inflammatory processes in breast tissue may occur later in breast carcinogenesis.
C1 [Danforth, David N.] NCI, Surg Branch, Ctr Canc Res, NIH, Bethesda, MD 20892 USA.
C3 National Institutes of Health (NIH) - USA; NIH National Cancer Institute
   (NCI)
RP Danforth, DN (corresponding author), NCI, Surg Branch, Ctr Canc Res, NIH, Bethesda, MD 20892 USA.
EM david_danforth@nih.gov
FU Intramural Research Program, Center for Cancer Research, National Cancer
   Institute, National Institutes of Health, Bethesda, MD
FX This research was supported by the Intramural Research Program, Center
   for Cancer Research, National Cancer Institute, National Institutes of
   Health, Bethesda, MD.
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NR 149
TC 74
Z9 80
U1 10
U2 46
PU MDPI
PI BASEL
PA ST ALBAN-ANLAGE 66, CH-4052 BASEL, SWITZERLAND
EI 2072-6694
J9 CANCERS
JI Cancers
PD AUG
PY 2021
VL 13
IS 15
AR 3918
DI 10.3390/cancers13153918
PG 21
WC Oncology
WE Science Citation Index Expanded (SCI-EXPANDED)
SC Oncology
GA TV8ZN
UT WOS:000682004400001
PM 34359821
OA gold, Green Published
DA 2025-03-13
ER

PT J
AU Chen, B
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AF Chen, Bing
   Sang, Yuting
   Song, Xiaojin
   Zhang, Dong
   Wang, Lijuan
   Zhao, Wenjing
   Liang, Yiran
   Zhang, Ning
   Yang, Qifeng
TI Exosomal miR-500a-5p derived from cancer-associated fibroblasts promotes
   breast cancer cell proliferation and metastasis through targeting USP28
SO THERANOSTICS
LA English
DT Article
DE cancer-associated fibroblasts; exosome; miR-500a-5p; breast cancer;
   USP28
AB The tumor microenvironment contributes to tumor progression and metastasis. Cancer-associated fibroblasts (CAFs) form a major cellular component of the tumor microenvironment. In this study, we further explored the mechanisms underlying the tumor-promoting roles of CAFs.
   Methods: Patient-derived CAFs and normal fibroblasts (NFs) were isolated from breast carcinomas and adjacent normal breast tissue. Exosomes were isolated by ultracentrifugation and CAF-derived exosomal microRNAs were screened using next-generation sequencing technology. MiR-500a-5p expression was assessed by quantitative real-time polymerase chain reaction (qRT-PCR) and in situ hybridization; Tumor cell proliferation was determined by MTT assays and three-dimensioned (3D) cultures, and tumor metastasis was determined by Transwell assays in vitro. In vivo assays were performed in a nude mouse subcutaneous xenograft model.
   Results: We confirmed that CAF-derived exosomes significantly promoted the proliferation and metastasis of breast cancer cells. MiR-500a-5p was highly expressed in MDA-MB-231 and MCF7 cells treated with CAF-derived exosomes. The upregulation of miR-500a-5p was also confirmed in CAFs and CAF-derived exosomes. MiR-500a-5p was transferred from CAFs to the cancer cells, and subsequently promoted proliferation and metastasis by binding to ubiquitin-specific peptidase 28 (USP28).
   Conclusions: The present study demonstrates that CAFs promote breast cancer progression and metastasis via exosomal miR-500a-5p and indicate that inhibiting CAF-derived miR-500a-5p is an alternative modality for the treatment of breast cancer.
C1 [Sang, Yuting; Song, Xiaojin; Zhang, Dong; Liang, Yiran; Zhang, Ning; Yang, Qifeng] Shandong Univ, Dept Breast Surg, Gen Surg, Qilu Hosp, Jinan, Peoples R China.
   [Chen, Bing; Wang, Lijuan; Zhao, Wenjing; Yang, Qifeng] Shandong Univ, Qilu Hosp, Pathol Tissue Bank, Jinan, Peoples R China.
   [Yang, Qifeng] Shandong Univ, Res Inst Breast Canc, Jinan, Peoples R China.
C3 Shandong University; Shandong University; Shandong University
RP Yang, QF (corresponding author), Shandong Univ, Qilu Hosp, Dept Breast Surg, 107 Jinan Culture Rd, Jinan 250012, Peoples R China.
EM qifengy_sdu@163.com
RI liang, yiran/KDO-6280-2024; Wang, Lijuan/K-9297-2016; Song,
   Xiaojin/IVH-3738-2023; Zhang, Ning/GOJ-8058-2022
OI Zhang, Ning/0000-0002-6430-4236; Yang, Qifeng/0000-0003-0576-8513
FU National Natural Science Foundation of China [81702602, 81672613,
   81874119, 82072912]; Special Foundation for Taishan Scholars
   [ts20190971]; Special Support Plan for National High Level Talents (Ten
   Thousand Talents Program) [W01020103]; National Key Research and
   Development Program [2018YFC0114705]; Clinical Research Center of
   Shandong University [2020SDUCRCA015]; Qilu Hospital Clinical New
   Technology Developing Foundation [2018-7, 2019-3]; China Postdoctoral
   Science Foundation [2018M630785]
FX This work was supported by the National Natural Science Foundation of
   China (No. 81702602, 81672613, 81874119, 82072912), Special Foundation
   for Taishan Scholars (No. ts20190971), Special Support Plan for National
   High Level Talents (Ten Thousand Talents Program W01020103), National
   Key Research and Development Program (No. 2018YFC0114705), Funded by
   Clinical Research Center of Shandong University (No.2020SDUCRCA015),
   Qilu Hospital Clinical New Technology Developing Foundation (No. 2018-7;
   No. 2019-3), and the China Postdoctoral Science Foundation funded
   project (grants 2018M630785).
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NR 50
TC 142
Z9 150
U1 8
U2 43
PU IVYSPRING INT PUBL
PI LAKE HAVEN
PA PO BOX 4546, LAKE HAVEN, NSW 2263, AUSTRALIA
SN 1838-7640
J9 THERANOSTICS
JI Theranostics
PY 2021
VL 11
IS 8
BP 3932
EP 3947
DI 10.7150/thno.53412
PG 16
WC Medicine, Research & Experimental
WE Science Citation Index Expanded (SCI-EXPANDED)
SC Research & Experimental Medicine
GA QF5WS
UT WOS:000616965100026
PM 33664871
OA gold, Green Published
HC Y
HP N
DA 2025-03-13
ER

PT J
AU Vaziri, N
   Shariati, L
   Zarrabi, A
   Farazmand, A
   Javanmard, SH
AF Vaziri, Nazanin
   Shariati, Laleh
   Zarrabi, Ali
   Farazmand, Ali
   Haghjooy Javanmard, Shaghayegh
TI Cancer-Associated Fibroblasts Regulate the Plasticity of Breast Cancer
   Stemness through the Production of Leukemia Inhibitory Factor
SO LIFE-BASEL
LA English
DT Article
DE breast cancer; leukemia inhibitory factor; cancer stem cell;
   cancer-associated fibroblasts; LIF; LIFR signaling pathway
ID EPITHELIAL-MESENCHYMAL TRANSITION; STROMAL FIBROBLASTS; CELLS; PROMOTES;
   LIF; METASTASIS; ANGIOGENESIS; ACTIVATION; GROWTH
AB Simple Summary Cancer-associated fibroblasts (CAFs; as components of cancer stroma) use different signaling pathways to promote tumor progression and growth, invasion, and metastasis in diverse cancers. They have crosstalk with cancer cells during tumor progression. To investigate this crosstalk, in this study, a coculture system of CAF cells isolated from breast cancer patients with breast cancer cells was used to investigate leukemia inhibitory factor (LIF) production from CAFs. LIF is a signaling molecule that activates distinct signaling pathways through which cell cycle progression, cell death, adhesion, migration, and tumorigenesis are regulated. Leukemia inhibitory factor (LIF), as a member of the interleukin-6 cytokine family, plays a complex role in solid tumors. However, the effect of LIF as a tumor microenvironment factor on plasticity control in breast cancer remains largely unknown. In this study, an in vitro investigation is conducted to determine the crosstalk between breast cancer cells and fibroblasts. Based on the results, cancer-associated fibroblasts are producers of LIF in the cocultivation system with breast cancer cells. Treatment with the CAF-CM and human LIF protein significantly promoted stemness through the dedifferentiation process and regaining of stem-cell-like properties. In addition, the results indicate that activation of LIFR signaling in breast cancer cells in the existence of CAF-secreted LIF can induce Nanog and Oct4 expression and increase breast cancer stem cell markers CD24-/CD44+. In contrast, suppression of the LIF receptor by human LIF receptor inhibition antibody decreased the cancer stem cell markers. We found that LIF was frequently overexpressed by CAFs and that LIF expression is necessary for dedifferentiation of breast cancer cell phenotype and regaining of cancer stem cell properties. Our results suggest that targeting LIF/LIFR signaling might be a potent therapeutic strategy for breast cancer and the prevention of tumor recurrence.
C1 [Vaziri, Nazanin] Univ Tehran, Dept Cell & Mol Biol, Kish Int Campus, Kish 7941639982, Iran.
   [Shariati, Laleh] Isfahan Univ Med Sci, Canc Prevent Res, Esfahan 8158388994, Iran.
   [Shariati, Laleh] Isfahan Univ Med Sci, Sch Adv Med Technol, Dept Biomat Tissue Engn & Nanotechnol, Esfahan 8158388994, Iran.
   [Zarrabi, Ali] Istinye Univ, Fac Engn & Nat Sci, Dept Biomed Engn, TR-34396 Istanbul, Turkey.
   [Farazmand, Ali] Univ Tehran, Univ Coll Sci, Sch Biol, Dept Cell & Mol Biol, Tehran 1417614411, Iran.
   [Haghjooy Javanmard, Shaghayegh] Isfahan Univ Med Sci, Isfahan Cardiovasc Res Inst, Appl Physiol Res Ctr, Esfahan 8158388994, Iran.
C3 Isfahan University of Medical Sciences; Isfahan University of Medical
   Sciences; Istinye University; University of Tehran; Isfahan University
   of Medical Sciences
RP Farazmand, A (corresponding author), Univ Tehran, Univ Coll Sci, Sch Biol, Dept Cell & Mol Biol, Tehran 1417614411, Iran.; Javanmard, SH (corresponding author), Isfahan Univ Med Sci, Isfahan Cardiovasc Res Inst, Appl Physiol Res Ctr, Esfahan 8158388994, Iran.
EM vaziri.nazanin@yahoo.com; L.shariati@amt.mui.ac.ir;
   ali.zarrabi@istinye.edu.tr; afarazmand@ut.ac.ir;
   sh_haghjoo@med.mui.ac.ir
RI Haghjooy Javanmard, Shaghayegh/W-5060-2017; Zarrabi, Ali/U-2602-2019
OI Zarrabi, Ali/0000-0003-0391-1769
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NR 54
TC 15
Z9 19
U1 1
U2 7
PU MDPI
PI BASEL
PA ST ALBAN-ANLAGE 66, CH-4052 BASEL, SWITZERLAND
EI 2075-1729
J9 LIFE-BASEL
JI Life-Basel
PD DEC
PY 2021
VL 11
IS 12
AR 1298
DI 10.3390/life11121298
PG 13
WC Biology; Microbiology
WE Science Citation Index Expanded (SCI-EXPANDED)
SC Life Sciences & Biomedicine - Other Topics; Microbiology
GA XZ7CD
UT WOS:000737805200001
PM 34947829
OA Green Published, gold
DA 2025-03-13
ER

PT J
AU Yoon, CI
   Ahn, SG
   Cha, YJ
   Kim, D
   Bae, SJ
   Lee, JH
   Ooshima, A
   Yang, KM
   Park, SH
   Kim, SJ
   Jeong, J
AF Yoon, Chang-Ik
   Ahn, Sung-Gwe
   Cha, Yoon-Jin
   Kim, Dooreh
   Bae, Soong-June
   Lee, Ji-Hyung
   Ooshima, Akira
   Yang, Kyung-Min
   Park, Seok-Hee
   Kim, Seong-Jin
   Jeong, Joon
TI Metastasis Risk Assessment Using BAG2 Expression by Cancer-Associated
   Fibroblast and Tumor Cells in Patients with Breast Cancer
SO CANCERS
LA English
DT Article
DE BAG2; breast cancer; cancer-associated fibroblast; metastasis
ID PROTEIN
AB Simple Summary Cancer-associated fibroblasts (CAFs) promote tumor progression and play an important role in evading immune surveillance. The previous study showed that BAG2 could be elevated in cancer associated fibroblasts (CAFs). Here, we evaluated BAG2 expression of CAF and tumor cells and assessed metastasis risk in patients with breast cancer. We found that patients with either BAG2-high or BAG2(+) CAF had significantly worse distant metastasis-free survival than those with BAG2-double negative. Evaluation of BAG2 expression on both CAFs and tumor cells could be helpful to estimate the risk of metastasis in breast cancer. Few studies have examined the role of BAG2 in malignancies. We investigated the prognostic value of BAG2-expression in cancer-associated fibroblasts (CAFs) and tumor cells in predicting metastasis-free survival in patients with breast cancer. Tissue-microarray was constructed using human breast cancer tissues obtained by surgical resection between 1992 and 2015. BAG2 expression was evaluated by immunohistochemistry in CAFs or the tumor cells. BAG2 expression in the CAFs and cytoplasm of tumor cells was classified as positive and negative, and low and high, respectively. BAG2-CAF was evaluated in 310 patients and was positive in 67 (21.6%) patients. Kaplan-Meier plots showed that distant metastasis-free survival (DMFS) was lesser in patients with BAG2(+) CAF than in patients with BAG2(-) CAF (p = 0.039). Additionally, we classified the 310 patients into two groups: 109 in either BAG2-high or BAG2(+) CAF and 201 in BAG2-low and BAG2(-) CAF. DMFS was significantly reduced in patients with either BAG2-high or BAG2(+) CAF than in the patients of the other group (p = 0.005). Multivariable analysis demonstrated that DMFS was prolonged in patients with BAG2(-) CAF or BAG2-low. Evaluation of BAG2 expression on both CAFs and tumor cells could help in determining the risk of metastasis in breast cancer.
C1 [Yoon, Chang-Ik; Kim, Dooreh] Catholic Univ Korea, Coll Med, Dept Surg, Div Breast Surg,Seoul St Marys Hosp, Seoul 06591, South Korea.
   [Ahn, Sung-Gwe; Bae, Soong-June; Jeong, Joon] Yonsei Univ, Gangnam Severance Hosp, Dept Surg, Coll Med, Seoul 06273, South Korea.
   [Ahn, Sung-Gwe; Cha, Yoon-Jin; Bae, Soong-June; Jeong, Joon] Yonsei Univ, Inst Breast Canc Precis Med, Coll Med, Seoul 06273, South Korea.
   [Cha, Yoon-Jin] Yonsei Univ, Gangnam Severance Hosp, Dept Pathol, Coll Med, Seoul 06273, South Korea.
   [Lee, Ji-Hyung; Park, Seok-Hee] Sungkyunkwan Univ, Dept Biol Sci, Seobu Ro 2066, Suwon 16419, Gyeonggi Do, South Korea.
   [Ooshima, Akira; Yang, Kyung-Min; Kim, Seong-Jin] GILO Fdn, GILO Inst, Seoul 06668, South Korea.
   [Ooshima, Akira; Yang, Kyung-Min; Kim, Seong-Jin] Medpacto Inc, Seoul 06668, South Korea.
C3 Catholic University of Korea; Seoul St. Mary's Hospital; Yonsei
   University; Yonsei University Health System; Yonsei University; Yonsei
   University Health System; Yonsei University; Yonsei University Health
   System; Sungkyunkwan University (SKKU)
RP Jeong, J (corresponding author), Yonsei Univ, Gangnam Severance Hosp, Dept Surg, Coll Med, Seoul 06273, South Korea.; Jeong, J (corresponding author), Yonsei Univ, Inst Breast Canc Precis Med, Coll Med, Seoul 06273, South Korea.
EM fayn03@catholic.ac.kr; asg2004@yuhs.ac; yooncha@yuhs.ac;
   22100863@cmcnu.or.kr; mission815815@yuhs.ac; wlgud1990@skku.edu;
   aooshima@gilo.or.kr; yangkm@snu.ac.kr; parks@skku.edu;
   jasonsjkim@snu.ac.kr; gsjjoon@yuhs.ac
RI Lee, Ji Hyung/HNI-8824-2023; Ahn, Sung Gwe/AFD-8122-2022; Kim,
   Seong/AAV-1869-2020; Park, Joonhong/AAZ-9885-2020; Yang,
   Kyungmin/KOC-1513-2024
OI Jeong, Joon/0000-0003-0397-0005; Park, Seok Hee/0000-0002-6210-4927;
   Yoon, Chang Ik/0000-0002-7273-8886; Cha, Yoon Jin/0000-0002-5967-4064;
   Bae, Soong June/0000-0002-0012-9694; Ahn, Sung Gwe/0000-0002-8778-9686
FU (Basic Science Research Program through the NRF)
   [NRF-2016R1D1A1A09917675, NRF-2019R1C1C1002830]; National R&D Program
   for Cancer Control, Ministry of Health & Welfare, Republic of Korea
   [1520120]
FX This research was supported by the Basic Science Research Program
   through the NRF) (NRF-2016R1D1A1A09917675; NRF-2019R1C1C1002830).and
   grant from the National R&D Program for Cancer Control, Ministry of
   Health & Welfare, Republic of Korea (1520120).
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NR 27
TC 6
Z9 7
U1 0
U2 15
PU MDPI
PI BASEL
PA ST ALBAN-ANLAGE 66, CH-4052 BASEL, SWITZERLAND
EI 2072-6694
J9 CANCERS
JI Cancers
PD SEP
PY 2021
VL 13
IS 18
AR 4654
DI 10.3390/cancers13184654
PG 12
WC Oncology
WE Science Citation Index Expanded (SCI-EXPANDED)
SC Oncology
GA UV2JK
UT WOS:000699311500001
PM 34572878
OA gold, Green Published
DA 2025-03-13
ER

PT J
AU Diep, CH
   Spartz, A
   Truong, TH
   Dwyer, AR
   El-Ashry, D
   Lange, CA
AF Diep, Caroline H.
   Spartz, Angela
   Truong, Thu H.
   Dwyer, Amy R.
   El-Ashry, Dorraya
   Lange, Carol A.
TI Progesterone Receptor Signaling Promotes Cancer Associated Fibroblast
   Mediated Tumorigenicity in ER plus Breast Cancer
SO ENDOCRINOLOGY
LA English
DT Article
DE progesterone; CAF; FGF2; PD173074; breast cancer
ID HORMONE-INDEPENDENT GROWTH; TUMOR-GROWTH; STEM-CELLS; IN-VITRO;
   EXPRESSION; ESTROGEN; PHOSPHORYLATION; AROMATASE; ALPHA; IDENTIFICATION
AB Breast cancer progression involves intricate interactions between cancer cells and the tumor microenvironment (TME). This study elucidates the critical role of progesterone receptor (PR) signaling in mediating the protumorigenic effects of cancer-associated fibroblasts (CAFs) on estrogen receptor-positive (ER+) luminal breast cancer cells. We demonstrate that CAFs produce physiologically relevant levels of estrogen and progesterone, which significantly contribute to breast cancer tumorigenicity. Specifically, CAF conditioned media (CM) promoted PR-dependent anchorage-independent growth, tumorsphere formation/stem cell expansion, and CD44 upregulation. CAF cells formed co-clusters more frequently with PR+ breast cancer cells relative to PR-null models. While both PR isoforms mediated these actions, PR-A was a dominant driver of tumorsphere formation/stemness, while PR-B induced robust CD44 expression and CAF/tumor cell co-cluster formation. CD44 knockdown impaired CAF/tumor cell co-clustering. Fibroblast growth factor 2 (FGF2), also secreted by CAFs, phosphorylated PR (Ser294) in a MAPK-dependent manner and activated PR to enhance CD44 expression and breast cancer tumorigenicity. The FGF receptor (FGFR) inhibitor PD173074 diminished CAF- and FGF2-dependent PR activation, tumorsphere formation, and co-clustering. In summary, this study reveals a novel mechanism through which stromal CAFs orchestrate elevated PR signaling in ER+ luminal breast cancer via secretion of both progesterone and FGF2, a potent activator of ERK1/2. Understanding tumor cell/TME interactions provides insights into potential therapeutic strategies aimed at disrupting PR- and/or FGF2/FGFR-dependent signaling pathways to prevent early metastasis in patients with ER+ breast cancer.
C1 [Diep, Caroline H.; Spartz, Angela; Truong, Thu H.; Dwyer, Amy R.; Lange, Carol A.] Univ Minnesota, Masonic Canc Ctr, Minneapolis, MN 55455 USA.
   [El-Ashry, Dorraya] Univ Minnesota, Dept Lab Med & Pathol, Minneapolis, MN 55455 USA.
   [Lange, Carol A.] Univ Minnesota, Dept Med, Div Hematol Oncol & Transplantat, Minneapolis, MN 55455 USA.
C3 University of Minnesota System; University of Minnesota Twin Cities;
   University of Minnesota System; University of Minnesota Twin Cities;
   University of Minnesota System; University of Minnesota Twin Cities
RP Lange, CA (corresponding author), Univ Minnesota, 2231 6th St Southeast, Minneapolis, MN 55455 USA.
EM lange047@umn.edu
OI Dwyer, Amy/0000-0002-4422-1433; Diep, Ph.D.,
   Caroline/0000-0001-9011-6450; Lange, Carol/0000-0003-2751-3976; , Angela
   Spartz/0009-0006-1519-783X
FU Department of Defense [BC181035]; National Institutes of Health (NIH)
   [R01 CA229697]; Tickle Family Land Grant Endowed Chair in Breast Cancer
   Research; University of Minnesota University Imaging Centers (UIC)
   [SCR_020997]
FX The present study was supported by the Department of Defense (BC181035,
   to D.E-A. and C.A.L.), National Institutes of Health (NIH) R01 CA229697
   (to C.A.L.), and the Tickle Family Land Grant Endowed Chair in Breast
   Cancer Research (to C.A.L.). This work was supported by resources at the
   University of Minnesota University Imaging Centers (UIC) SCR_020997.
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NR 60
TC 2
Z9 2
U1 1
U2 1
PU ENDOCRINE SOC
PI WASHINGTON
PA 2055 L ST NW, SUITE 600, WASHINGTON, DC 20036 USA
SN 0013-7227
EI 1945-7170
J9 ENDOCRINOLOGY
JI Endocrinology
PD AUG 6
PY 2024
VL 165
IS 9
AR bqae092
DI 10.1210/endocr/bqae092
PG 17
WC Endocrinology & Metabolism
WE Science Citation Index Expanded (SCI-EXPANDED)
SC Endocrinology & Metabolism
GA A6V2R
UT WOS:001283888900001
PM 39041201
DA 2025-03-13
ER

PT J
AU Li, Q
   Yuan, H
   Zhao, G
   Zhang, J
   Li, SQ
   Gong, D
   Feng, TY
   Kou, QM
   Wang, QJ
   Wang, GR
   Li, S
   Li, K
   Lin, P
AF Li, Qin
   Yuan, Hang
   Zhao, Gang
   Zhang, Jie
   Li, Siqi
   Gong, Di
   Feng, Tianyu
   Kou, Qiming
   Wang, Qijing
   Wang, Guanru
   Li, Shan
   Li, Kai
   Lin, Ping
TI ZNF32 prevents the activation of cancer-associated fibroblasts through
   negative regulation of TGFB1 transcription in breast cancer
SO FASEB JOURNAL
LA English
DT Article
DE breast cancer; cancer-associated fibroblasts; normal fibroblasts;
   TGF-beta; tumor microenvironment; ZNF32
ID INDUCED APOPTOSIS; CELLS; PROMOTES; GROWTH; TRANSFORMATION; RECEPTOR;
   STRESS; EGR-1; BETA
AB Breast cancer is the most frequently diagnosed malignancy and the leading cause of cancer-related deaths in women worldwide. Cancer-associated fibroblasts (CAFs) are one of the fundamental cellular components of the tumor microenvironment and play a critical role in the initiation, progression, and therapy resistance of breast cancer. However, the detailed molecular mechanisms of CAFs activation from normal fibroblasts (NFs) are still not well understood. In the present study, we reported that ZNF32 expression in breast cancer cells was negatively correlated with CAF-related markers (FSP1, alpha-SMA, and FAP) in stromal fibroblasts, and loss of ZNF32 promoted the activation of CAFs, as evidenced by the enhanced proliferation and contractility of CAFs. ZNF32 deficiency-mediated fibroblast activation promoted the growth and metastasis of breast cancer cells in vitro and in vivo. Mechanistically, we demonstrated that ZNF32 inhibited TGFB1 transcription by directly binding to the -1968/-1962 region of the TGFB1 promoter, leading to the prevention of fibroblast activation. Altogether, our findings reveal an important mechanism by which ZNF32 suppression increases the transcription of the TGFB1 gene in breast cancer cells, and subsequently, elevated levels of secretory TGF-beta stimulate NFs transformation into CAFs, which in turn facilitates the malignant progression of breast cancer. Our data implicated ZNF32 as a potential therapeutic strategy against breast cancer.
C1 [Li, Qin; Yuan, Hang; Zhao, Gang; Zhang, Jie; Li, Siqi; Gong, Di; Feng, Tianyu; Kou, Qiming; Wang, Qijing; Wang, Guanru; Li, Shan; Li, Kai; Lin, Ping] Sichuan Univ, West China Hosp, State Key Lab Biotherapy, Lab Expt Oncol, Chengdu, Peoples R China.
   [Li, Qin; Yuan, Hang; Zhao, Gang; Zhang, Jie; Li, Siqi; Gong, Di; Feng, Tianyu; Kou, Qiming; Wang, Qijing; Wang, Guanru; Li, Shan; Li, Kai; Lin, Ping] Sichuan Univ, West China Hosp, Canc Ctr, Chengdu, Peoples R China.
   [Li, Qin; Yuan, Hang; Zhao, Gang; Zhang, Jie; Li, Siqi; Gong, Di; Feng, Tianyu; Kou, Qiming; Wang, Qijing; Wang, Guanru; Li, Shan; Li, Kai; Lin, Ping] Sichuan Univ, West China Hosp, Frontiers Sci Ctr Dis related Mol Network, Chengdu, Peoples R China.
   [Gong, Di] Chengdu Univ, Sch Basic Med Sci, Chengdu, Peoples R China.
   [Li, Kai; Lin, Ping] Sichuan Univ, West China Hosp, State Key Lab Biotherapy, Lab Expt Oncol, 1 Keyuan 4 Rd,Gaopeng Ave, Chengdu 610041, Sichuan, Peoples R China.
   [Li, Kai; Lin, Ping] Sichuan Univ, West China Hosp, Canc Ctr, 1 Keyuan 4 Rd,Gaopeng Ave, Chengdu 610041, Sichuan, Peoples R China.
   [Li, Kai; Lin, Ping] Sichuan Univ, West China Hosp, Frontiers Sci Ctr Dis related Mol Network, 1 Keyuan 4 Rd,Gaopeng Ave, Chengdu 610041, Sichuan, Peoples R China.
C3 Sichuan University; Sichuan University; Sichuan University; Chengdu
   University; Sichuan University; Sichuan University; Sichuan University
RP Li, K; Lin, P (corresponding author), Sichuan Univ, West China Hosp, State Key Lab Biotherapy, Lab Expt Oncol, 1 Keyuan 4 Rd,Gaopeng Ave, Chengdu 610041, Sichuan, Peoples R China.; Li, K; Lin, P (corresponding author), Sichuan Univ, West China Hosp, Canc Ctr, 1 Keyuan 4 Rd,Gaopeng Ave, Chengdu 610041, Sichuan, Peoples R China.; Li, K; Lin, P (corresponding author), Sichuan Univ, West China Hosp, Frontiers Sci Ctr Dis related Mol Network, 1 Keyuan 4 Rd,Gaopeng Ave, Chengdu 610041, Sichuan, Peoples R China.
EM likai@scu.edu.cn; linping@scu.edu.cn
RI Feng, Tian-Yu/AAX-3892-2020; li, siqi/GVS-6072-2022
OI yuan, hang/0000-0003-2607-4334
FU National Natural Science Foundation of China (NSFC) [82072933,
   81572604]; 1.3.5 project for disciplines of excellence Clinical Research
   Incubation Project, West China Hospital, Sichuan University
   [2020HXFH007]; China Postdoctoral Science Foundation [2021M702355];
   Department of Science and Technology of Sichuan Province (SPDST)
   [2022YFS0216, 2021YJ0126]
FX National Natural Science Foundation of China (NSFC), Grant/Award Number:
   82072933 and 81572604; 1 center dot 3 center dot 5 project for
   disciplines of excellence Clinical Research Incubation Project, West
   China Hospital, Sichuan University, Grant/Award Number: 2020HXFH007;
   China Postdoctoral Science Foundation, Grant/Award Number: 2021M702355;
   Department of Science and Technology of Sichuan Province (SPDST),
   Grant/Award Number: 2022YFS0216 and 2021YJ0126
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NR 57
TC 9
Z9 10
U1 2
U2 15
PU WILEY
PI HOBOKEN
PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA
SN 0892-6638
EI 1530-6860
J9 FASEB J
JI Faseb J.
PD APR
PY 2023
VL 37
IS 4
AR e22837
DI 10.1096/fj.202201801R
PG 16
WC Biochemistry & Molecular Biology; Biology; Cell Biology
WE Science Citation Index Expanded (SCI-EXPANDED)
SC Biochemistry & Molecular Biology; Life Sciences & Biomedicine - Other
   Topics; Cell Biology
GA 9Z3FP
UT WOS:000951029900001
PM 36934389
DA 2025-03-13
ER

PT J
AU Li, Y
   Wang, CY
   Huang, T
   Yu, XJ
   Tian, BL
AF Li, Yi
   Wang, Changyuan
   Huang, Ting
   Yu, Xijie
   Tian, Bole
TI The role of cancer-associated fibroblasts in breast cancer metastasis
SO FRONTIERS IN ONCOLOGY
LA English
DT Review
DE breast cancer; metastasis; cancer-associated fibroblasts (CAFs); tumor
   microenvironment (TME); extracellular matrix (ECM)
ID EPITHELIAL-MESENCHYMAL TRANSITION; ACTIVATION PROTEIN ALPHA;
   CARCINOMA-ASSOCIATED FIBROBLASTS; TERTIARY LYMPHOID STRUCTURES; STROMAL
   FIBROBLASTS; TUMOR-GROWTH; UP-REGULATION; STEM-CELLS; MATRIX
   METALLOPROTEINASES; ANTITUMOR IMMUNITY
AB Breast cancer deaths are primarily caused by metastasis. There are several treatment options that can be used to treat breast cancer. There are, however, a limited number of treatments that can either prevent or inhibit the spread of breast tumor metastases. Thus, novel therapeutic strategies are needed. Studies have increasingly focused on the importance of the tumor microenvironment (TME) in metastasis of breast cancer. As the most abundant cells in the TME, cancer-associated fibroblasts (CAFs) play important roles in cancer pathogenesis. They can remodel the structure of the extracellular matrix (ECM) and engage in crosstalk with cancer cells or other stroma cells by secreting growth factors, cytokines, and chemokines, as well as components of the ECM, which assist the tumor cells to invade through the TME and cause distant metastasis. Clinically, CAFs not only foster the initiation, growth, angiogenesis, invasion, and metastasis of breast cancer but also serve as biomarkers for diagnosis, therapy, and prediction of prognosis. In this review, we summarize the biological characteristics and subtypes of CAFs and their functions in breast cancer metastasis, focusing on their important roles in the diagnosis, prognosis, and treatment of breast cancer. Recent studies suggest that CAFs are vital partners of breast cancer cells that assist metastasis and may represent ideal targets for prevention and treatment of breast cancer metastasis.
C1 [Li, Yi; Huang, Ting] Univ Elect Sci & Technol China, Sichuan Prov Peoples Hosp, Dept Breast Surg, Chengdu, Peoples R China.
   [Wang, Changyuan; Tian, Bole] Sichuan Univ, West China Hosp, Dept Pancreat Surg, Chengdu, Peoples R China.
   [Wang, Changyuan] Guizhou Prov Peoples Hosp, Hepatobiliary Surg Dept 2, Guiyang, Peoples R China.
   [Yu, Xijie] Sichuan Univ, West China Hosp, Natl Clin Res Ctr Geriatr, Dept Endocrinol & Metab,Lab Endocrinol & Metab, Chengdu, Peoples R China.
C3 University of Electronic Science & Technology of China; Sichuan
   Provincial People's Hospital; Sichuan University; Sichuan University
RP Tian, BL (corresponding author), Sichuan Univ, West China Hosp, Dept Pancreat Surg, Chengdu, Peoples R China.; Yu, XJ (corresponding author), Sichuan Univ, West China Hosp, Natl Clin Res Ctr Geriatr, Dept Endocrinol & Metab,Lab Endocrinol & Metab, Chengdu, Peoples R China.
EM xijieyu@hotmail.com; hxtbl0338@163.com
RI changyuan, wang/AAF-5503-2019
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NR 187
TC 15
Z9 15
U1 3
U2 18
PU FRONTIERS MEDIA SA
PI LAUSANNE
PA AVENUE DU TRIBUNAL FEDERAL 34, LAUSANNE, CH-1015, SWITZERLAND
SN 2234-943X
J9 FRONT ONCOL
JI Front. Oncol.
PD JUL 11
PY 2023
VL 13
AR 1194835
DI 10.3389/fonc.2023.1194835
PG 15
WC Oncology
WE Science Citation Index Expanded (SCI-EXPANDED)
SC Oncology
GA M8HE0
UT WOS:001032562600001
PM 37496657
OA Green Published, gold
DA 2025-03-13
ER

PT J
AU Yan, ZQ
   Sheng, ZM
   Zheng, YH
   Feng, RJ
   Xiao, QP
   Shi, LH
   Li, HL
   Yin, CG
   Luo, H
   Hao, C
   Wang, WH
   Zhang, BG
AF Yan, Ziqian
   Sheng, Zhimei
   Zheng, Yuanhang
   Feng, Ruijun
   Xiao, Qinpei
   Shi, Lihong
   Li, Hongli
   Yin, Chonggao
   Luo, Hao
   Hao, Chong
   Wang, Wenhao
   Zhang, Baogang
TI Cancer-associated fibroblast-derived exosomal miR-18b promotes breast
   cancer invasion and metastasis by regulating TCEAL7
SO CELL DEATH & DISEASE
LA English
DT Article
ID TUMOR-SUPPRESSOR GENE; STROMAL FIBROBLASTS; EXPRESSION; CELLS;
   MICROENVIRONMENT; PROLIFERATION
AB Studies have shown that cancer-associated fibroblasts (CAFs) play an irreplaceable role in the occurrence and development of tumors. Therefore, exploring the action and mechanism of CAFs on tumor cells is particularly important. In this study, we compared the effects of CAFs-derived exosomes and normal fibroblasts (NFs)-derived exosomes on breast cancer cells migration and invasion. The results showed that exosomes from both CAFs and NFs could enter into breast cancer cells and CAFs-derived exosomes had a more enhancing effect on breast cancer cells migration and invasion than NFs-derived exosomes. Furthermore, microRNA (miR)-18b was upregulated in CAFs-derived exosomes, and CAFs-derived exosomes miR-18b can promote breast cancer cell migration and metastasis by specifically binding to the 3 ' UTR of Transcription Elongation Factor A Like 7 (TCEAL7). The miR-18b-TCEAL7 pathway promotes nuclear Snail ectopic activation by activating nuclear factor-kappa B (NF-kappa B), thereby inducing epithelial-mesenchymal transition (EMT) and promoting cell invasion and metastasis. Moreover, CAFs-derived exosomes miR-18b could promote mouse xenograft model tumor metastasis. Overall, our findings suggest that CAFs-derived exosomes miR-18b promote nuclear Snail ectopic by targeting TCEAL7 to activate the NF-kappa B pathway, thereby inducing EMT, invasion, and metastasis of breast cancer. Targeting CAFs-derived exosome miR-18b may be a potential treatment option to overcome breast cancer progression.
C1 [Yan, Ziqian; Sheng, Zhimei; Zheng, Yuanhang; Feng, Ruijun; Xiao, Qinpei; Luo, Hao; Zhang, Baogang] Weifang Med Univ, Dept Pathol, Weifang, Shandong, Peoples R China.
   [Yan, Ziqian; Sheng, Zhimei; Zheng, Yuanhang; Feng, Ruijun; Xiao, Qinpei; Luo, Hao; Zhang, Baogang] Weifang Med Univ, Affiliated Hosp, Dept Pathol, Weifang, Shandong, Peoples R China.
   [Shi, Lihong] Weifang Med Univ, Dept Pharmacol, Weifang, Shandong, Peoples R China.
   [Li, Hongli; Yin, Chonggao] Weifang Med Univ, Dept Med, Res Ctr, Weifang, Shandong, Peoples R China.
   [Hao, Chong] Maternal & Child Hlth Care Hosp Zibo, Dept Oncol, Zibo, Shandong, Peoples R China.
   [Wang, Wenhao] Weifang Med Univ, Dept Med Oncol, Affiliated Hosp, Weifang, Shandong, Peoples R China.
C3 Shandong Second Medical University; Shandong Second Medical University;
   Shandong Second Medical University; Shandong Second Medical University;
   Shandong Second Medical University
RP Zhang, BG (corresponding author), Weifang Med Univ, Dept Pathol, Weifang, Shandong, Peoples R China.; Zhang, BG (corresponding author), Weifang Med Univ, Affiliated Hosp, Dept Pathol, Weifang, Shandong, Peoples R China.
EM Zhangbg@wfmc.edu.cn
RI Luo, Hao/AAK-6619-2020; LI, Hongli/JMQ-9352-2023; Wang,
   Wenhao/ABO-5766-2022
OI hao, chong/0000-0003-2814-608X; Luo, Hao/0000-0001-5415-7474
FU National Natural Scientific Foundation of China
FX We sincerely thank our colleagues for their valuable suggestions and
   technical assistance for this research. This work was supported by
   National Natural Scientific Foundation of China.
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NR 57
TC 53
Z9 56
U1 4
U2 19
PU SPRINGERNATURE
PI LONDON
PA CAMPUS, 4 CRINAN ST, LONDON, N1 9XW, ENGLAND
SN 2041-4889
J9 CELL DEATH DIS
JI Cell Death Dis.
PD DEC 1
PY 2021
VL 12
IS 12
AR 1120
DI 10.1038/s41419-021-04409-w
PG 14
WC Cell Biology
WE Science Citation Index Expanded (SCI-EXPANDED)
SC Cell Biology
GA XG5IY
UT WOS:000724787500001
PM 34853307
OA Green Published, gold
DA 2025-03-13
ER

PT J
AU Guo, ZZ
   Zhang, H
   Fu, YM
   Kuang, JJ
   Zhao, B
   Zhang, LF
   Lin, J
   Lin, SH
   Wu, DH
   Xie, GZ
AF Guo, Zhaoze
   Zhang, Han
   Fu, Yiming
   Kuang, Junjie
   Zhao, Bei
   Zhang, LanFang
   Lin, Jie
   Lin, Shuhui
   Wu, Dehua
   Xie, Guozhu
TI Cancer-associated fibroblasts induce growth and radioresistance of
   breast cancer cells through paracrine IL-6
SO CELL DEATH DISCOVERY
LA English
DT Article
ID P53 EXPRESSION; MICROENVIRONMENT; CHEMORESISTANCE; METASTASIS;
   SILTUXIMAB; PATHWAY; STAT3
AB In breast cancer, the most numerous stromal cells are cancer-associated fibroblasts (CAFs), which are associated with disease progression and chemoresistance. However, few studies have explored the function of CAFs in breast cancer cell radiosensitivity. Here, CAF-derived conditioned media was observed to induce breast cancer cell growth and radioresistance. CAFs secrete interleukin 6 (IL-6) which activates signal transducer and activator of transcription 3 (STAT3) signaling pathway, thus promoting the growth and radioresistance of breast cancer cells. Treatment with an inhibitor of STAT3 or an IL-6 neutralizing antibody blocked the growth and radioresistance induced by CAFs. In in vivo mouse models, tocilizumab (an IL-6 receptor monoclonal antibody) abrogated CAF-induced growth and radioresistance. Moreover, in breast cancer, a poor response to radiotherapy was associated with IL-6 and p-STAT3 expression. These results indicated that IL-6 mediates cross-talk between breast cancer cells and CAFs in the tumor microenvironment. Our results identified the IL-6/STAT3 signaling pathway as an important therapeutic target in breast cancer radiotherapy.
C1 [Guo, Zhaoze; Zhang, Han; Fu, Yiming; Kuang, Junjie; Wu, Dehua; Xie, Guozhu] Southern Med Univ, Nanfang Hosp, Dept Radiat Oncol, Guangzhou, Guangdong, Peoples R China.
   [Guo, Zhaoze; Zhao, Bei] Southern Med Univ, Nanfang Hosp, Breast Ctr, Dept Gen Surg, Guangzhou, Guangdong, Peoples R China.
   [Zhang, LanFang] Southern Med Univ, Nanfang Hosp, Dept Stomatol, Guangzhou, Guangdong, Peoples R China.
   [Lin, Jie] Guangzhou Med Univ, Affiliated Canc Hosp & Inst, Dept Radiat Oncol, Guangzhou, Guangdong, Peoples R China.
   [Lin, Shuhui] Huazhong Univ Sci & Technol, Union Shenzhen Hosp, Nanshan Hosp, Dept Oncol, Shenzhen, Guangdong, Peoples R China.
C3 Southern Medical University - China; Southern Medical University -
   China; Southern Medical University - China; Guangzhou Medical
   University; Huazhong University of Science & Technology
RP Wu, DH; Xie, GZ (corresponding author), Southern Med Univ, Nanfang Hosp, Dept Radiat Oncol, Guangzhou, Guangdong, Peoples R China.
EM 18602062748@163.com; xieguozhu@126.com
RI wang, jinliang/AAA-2799-2021
OI Wu, De-Hua/0000-0003-0560-0016; Fu, Yiming/0000-0002-1895-4801; Guo,
   Zhaoze/0000-0001-8847-7740; Jie, Lin/0000-0002-4852-0342
FU Natural Science Foundation of Guangdong Province, China; 
   [2021A1515011537]
FX AcknowledgementsThis work was supported by the Natural Science
   Foundation of Guangdong Province, China (No. 2021A1515011537).
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NR 41
TC 46
Z9 46
U1 5
U2 18
PU SPRINGERNATURE
PI LONDON
PA CAMPUS, 4 CRINAN ST, LONDON, N1 9XW, ENGLAND
EI 2058-7716
J9 CELL DEATH DISCOV
JI Cell Death Discov.
PD JAN 13
PY 2023
VL 9
IS 1
AR 6
DI 10.1038/s41420-023-01306-3
PG 10
WC Cell Biology
WE Science Citation Index Expanded (SCI-EXPANDED)
SC Cell Biology
GA 7V1AR
UT WOS:000912553900001
PM 36635302
OA Green Published, gold
DA 2025-03-13
ER

PT J
AU Kim, HS
   Noh, YK
   Min, KW
   Kim, DH
   Kwon, MJ
   Pyo, JS
   Lee, JY
AF Kim, Hyung Suk
   Noh, Yung-Kyun
   Min, Kyueng-Whan
   Kim, Dong-Hoon
   Kwon, Mi Jung
   Pyo, Jung Soo
   Lee, Jeong-Yeon
TI Cancer-Associated Fibroblasts Together with a Decline in CD8+T Cells
   Predict a Worse Prognosis for Breast Cancer Patients
SO ANNALS OF SURGICAL ONCOLOGY
LA English
DT Article; Early Access
DE Cancer-associated fibroblasts; Breast cancer; Prognosis;
   Tumor-infiltrating lymphocytes; Machine learning; Drug
ID DRUG-SENSITIVITY; INHIBITORS; DISCOVERY
AB BackgroundCancer-associated fibroblasts (CAFs) play a crucial role in tumor microenvironment regulation and cancer progression. This study assessed the significance and predictive potential of CAFs in breast cancer prognosis.MethodsThe study included 1503 breast cancer patients. Cancer-associated fibroblasts were identified using morphologic features from hematoxylin and eosin slides. The study analyzed clinicopathologic parameters, survival rates, immune cells, gene sets, and prognostic models using gene-set enrichment analysis, in silico cytometry, pathway analysis, in vitro drug-screening, and gradient-boosting machine (GBM)-learning.ResultsThe presence of CAFs correlated significantly with young age, lymphatic invasion, and perineural invasion. In silico cytometry showed altered leukocyte subsets in the presence of CAFs, with decreased CD8+ T cells. Gene-set enrichment analysis showed associations with critical processes such as the epithelial-mesenchymal transition and immune modulation. Drug sensitivity analysis in breast cancer cell lines with varying fibroblast activation protein-alpha expression suggested that CAF-targeted therapies might enhance the efficacy of certain anticancer drugs including ARRY-520, ispinesib-mesylate, paclitaxel, and docetaxel. Integrating CAF presence with machine-learning improved survival prediction. For breast cancer patients, CAFs were independent prognostic markers for worse disease-specific survival and disease-free survival.ConclusionThis study highlighted the significance of CAFs in breast cancer biology and provided compelling evidence of their impact on patient outcomes and treatment response. The findings offer valuable insights into the potential of CAFs as prognostic and predictive biomarkers and support the development of CAF-targeted therapies to improve breast cancer management.
C1 [Kim, Hyung Suk] Hanyang Univ, Coll Med, Guri Hosp, Div Breast Surg,Dept Surg, Guri, South Korea.
   [Noh, Yung-Kyun] Hanyang Univ, Dept Comp Sci, Seoul, South Korea.
   [Noh, Yung-Kyun] Korea Inst Adv Study, Sch Computat Sci, Seoul, South Korea.
   [Min, Kyueng-Whan; Pyo, Jung Soo] Eulji Univ, Uijeongbu Eulji Med Ctr, Dept Pathol, Sch Med, Uijongbu, South Korea.
   [Kim, Dong-Hoon] Sungkyunkwan Univ, Sch Med, Kangbuk Samsung Hosp, Dept Pathol, Seoul, South Korea.
   [Kwon, Mi Jung] Hallym Univ, Coll Med, Dept Pathol, Sacred Heart Hosp, Anyang, South Korea.
   [Lee, Jeong-Yeon] Hanyang Univ, Coll Med, Dept Pathol, Seoul, South Korea.
C3 Hanyang University; Hanyang University; Korea Institute for Advanced
   Study (KIAS); Eulji University; Sungkyunkwan University (SKKU); Samsung
   Medical Center; Hallym University; Hanyang University
RP Min, KW (corresponding author), Eulji Univ, Uijeongbu Eulji Med Ctr, Dept Pathol, Sch Med, Uijongbu, South Korea.; Kim, DH (corresponding author), Sungkyunkwan Univ, Sch Med, Kangbuk Samsung Hosp, Dept Pathol, Seoul, South Korea.
EM kyueng@hanyang.ac.kr; idavid.kim@samsung.com
RI Kim, Hyo-Won/M-9932-2019; Kim, Heui-Soo/ABF-3773-2021; Min,
   Kyueng-Whan/F-3981-2017
OI Min, Kyueng-Whan/0000-0002-4757-9211
FU Eulji University [RS-2023-00220628]; Eulji University in 2023
FX This study was supported by Eulji University in 2023. Y.-K. Noh was
   partly supported by IITP/MSIT (RS-2023-00220628).
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NR 39
TC 3
Z9 3
U1 2
U2 8
PU SPRINGER
PI NEW YORK
PA ONE NEW YORK PLAZA, SUITE 4600, NEW YORK, NY, UNITED STATES
SN 1068-9265
EI 1534-4681
J9 ANN SURG ONCOL
JI Ann. Surg. Oncol.
PD 2023 DEC 13
PY 2023
DI 10.1245/s10434-023-14715-6
EA DEC 2023
PG 13
WC Oncology; Surgery
WE Science Citation Index Expanded (SCI-EXPANDED)
SC Oncology; Surgery
GA CQ2C9
UT WOS:001126634900001
PM 38093168
DA 2025-03-13
ER

PT J
AU Amornsupak, K
   Insawang, T
   Thuwajit, P
   O-Charoenrat, P
   Eccles, SA
   Thuwajit, C
AF Amornsupak, Kamolporn
   Insawang, Tonkla
   Thuwajit, Peti
   O-Charoenrat, Pornchai
   Eccles, Suzanne A.
   Thuwajit, Chanitra
TI Cancer-associated fibroblasts induce high mobility group box 1 and
   contribute to resistance to doxorubicin in breast cancer cells
SO BMC CANCER
LA English
DT Article
DE Breast cancer; Cancer-associated fibroblast; HMGB1; Chemoresistance
ID EPITHELIAL-MESENCHYMAL TRANSITION; INVASIVE DUCTAL CARCINOMA; TUMOR
   MICROENVIRONMENT; STROMAL FIBROBLASTS; HMGB1 RELEASE; EXPRESSION;
   CHEMOTHERAPY; PROTEIN; RAGE; CHEMORESISTANCE
AB Background: Cancer-associated fibroblasts and high mobility group box 1 (HMGB1) protein have been suggested to mediate cancer progression and chemotherapy resistance. The role of such fibroblasts in HMGB1 production in breast cancer is unclear. This study aimed to investigate the effects of cancer-associated fibroblasts on HMGB1 expression in breast cancer cells and its role in chemotherapeutic response.
   Methods: Breast cancer-associated fibroblasts (BCFs) and non-tumor-associated fibroblasts (NTFs) were isolated from human breast cancers or adjacent normal tissues and established as primary cultures in vitro. After confirmation of the activated status of these fibroblasts, conditioned-media (CM) were collected and applied to MDA-MB-231 human triple negative breast cancer cells. The levels of intracellular and extracellular HMGB1 were measured by real-time PCR and/or Western blot. The response of BCF-CM-pre-treated cancer cells to doxorubicin (Dox) was compared with those pre-treated with NTF-CM or control cultures. The effect of an HMGB1 neutralizing antibody on Dox resistance induced by extracellular HMGB1 from non-viable Dox-treated cancer cells or recombinant HMGB1 was also investigated.
   Results: Immunocytochemical analysis revealed that BCFs and NTFs were alpha-smooth muscle actin (ASMA) positive and cytokeratin 19 (CK19) negative cells: a phenotype consistent with that of activated fibroblasts. We confirmed that the CM from BCFs (but not NTFs), could significantly induce breast cancer cell migration. Intracellular HMGB1 expression was induced in BCF-CM-treated breast cancer cells and also in Dox-treated cells. Extracellular HMGB1 was strongly expressed in the CM after Dox-induced MDA-MB-231 cell death and was higher in cells pre-treated with BCF-CM than NTF-CM. Pre-treatment of breast cancer cells with BCF-CM induced a degree of resistance to Dox in accordance with the increased level of secreted HMGB1. Recombinant HMGB1 was shown to increase Dox resistance and this was associated with evidence of autophagy. Anti-HMGB1 neutralizing antibody significantly reduced the effect of extracellular HMGB1 released from dying cancer cells or of recombinant HMGB1 on Dox resistance.
   Conclusions: These findings highlight the potential of stromal fibroblasts to contribute to chemoresistance in breast cancer cells in part through fibroblast-induced HMGB1 production.
C1 [Amornsupak, Kamolporn; Insawang, Tonkla; Thuwajit, Peti; Thuwajit, Chanitra] Mahidol Univ, Fac Med, Dept Immunol, Siriraj Hosp, Bangkok 10700, Thailand.
   [O-Charoenrat, Pornchai] Mahidol Univ, Fac Med, Dept Surg, Siriraj Hosp, Bangkok 10700, Thailand.
   [Eccles, Suzanne A.] Inst Canc Res, Canc Res UK Canc Therapeut Unit, Sutton, Surrey, England.
C3 Mahidol University; Mahidol University; University of London; Institute
   of Cancer Research - UK; Cancer Research UK
RP Thuwajit, C (corresponding author), Mahidol Univ, Fac Med, Dept Immunol, Siriraj Hosp, Bangkok 10700, Thailand.
EM cthuwajit@yahoo.com
RI Thuwajit, Chanitra/AAT-7933-2021; Thuwajit, Peti/AAD-1014-2021
OI Thuwajit, Peti/0000-0003-0798-1510; Thuwajit,
   Chanitra/0000-0001-9506-6405
FU Mahidol University; Royal Golden Jubilee-Thailand Research Fund
   [PHD/0051/2552]
FX KA is the student in Graduate Program in Immunology, Department of
   Immunology, Faculty of Medicine Siriraj Hospital, Mahidol University.
   This project has been supported by the Mentorship Grant, Mahidol
   University. KA has been financial supported by Royal Golden
   Jubilee-Thailand Research Fund (RGJ-TRF : Grant No. PHD/0051/2552). The
   English editing of this manuscript was kindly performed in part by
   Professor James A. Will, University of Wisconsin, Madison, WI, USA.
   Figure 7 was produced using Servier Medical Art on www.servier.com. We
   thank Dr. Carol Box and Ms. Somaieh Hedayat (ICR) for assistance with
   the design of experiments described in Figure 6 and for helpful advice
   and discussions.
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NR 57
TC 104
Z9 115
U1 0
U2 31
PU BMC
PI LONDON
PA CAMPUS, 4 CRINAN ST, LONDON N1 9XW, ENGLAND
EI 1471-2407
J9 BMC CANCER
JI BMC Cancer
PD DEC 15
PY 2014
VL 14
AR 955
DI 10.1186/1471-2407-14-955
PG 12
WC Oncology
WE Science Citation Index Expanded (SCI-EXPANDED)
SC Oncology
GA AZ0WM
UT WOS:000347962800001
PM 25512109
OA Green Published, gold
DA 2025-03-13
ER

PT J
AU Cui, MM
   Dong, H
   Duan, WL
   Wang, XJ
   Liu, YP
   Shi, LH
   Zhang, BG
AF Cui, Meimei
   Dong, Hao
   Duan, Wanli
   Wang, Xuejie
   Liu, Yongping
   Shi, Lihong
   Zhang, Baogang
TI The relationship between cancer associated fibroblasts biomarkers and
   prognosis of breast cancer: a systematic review and meta-analysis
SO PEERJ
LA English
DT Review
DE Breast cancer; Cancer associated fibroblasts; Meta-analysis; Prognostic
   biomarkers
ID PODOPLANIN-POSITIVE FIBROBLASTS; STROMAL MYOFIBROBLASTS; EXPRESSION;
   PROTEINS; UNIVARIATE; SURVIVAL; IMPACT; TISSUE; BETA
AB Background: To elucidate the relationship between cancer-associated fibroblast (CAFs) biomarkers and the prognosis of breast cancer patients for individualized CAFs-targeting treatment. Methodology: PubMed, Web of Science, Cochrane, and Embase databases were searched for CAFs-related studies of breast cancer patients from their inception to September, 2023. Meta-analysis was performed using R 4.2.2 software. Sensitivity analyses were performed to explore the sources of heterogeneity. Funnel plot and Egger's test were used to assess the publication bias. Results: Twenty-seven studies including 6,830 patients were selected. Univariate analysis showed that high expression of platelet-derived growth factor receptor-beta (PDGFR-beta) (P = 0.0055), tissue inhibitor of metalloproteinase-2 (TIMP-2) (P < 0.0001), matrix metalloproteinase (MMP) 9 (P < 0.0001), MMP 11 (P < 0.0001) and MMP 13 (P = 0.0009) in CAFs were correlated with reduced recurrence-free survival (RFS)/disease-free survival (DFS)/metastasis-free survival (MFS)/event-free survival (EFS) respectively. Multivariate analysis showed that high expression of alpha-smooth muscle actin (alpha-SMA) (P = 0.0002), podoplanin (PDPN) (P = 0.0008), and PDGFR-beta (P = 0.0470) in CAFs was associated with reduced RFS/DFS/MFS/EFS respectively. Furthermore, PDPN and PDGFR-beta expression in CAFs of poorly differentiated breast cancer patients were higher than that of patients with relatively better differentiated breast cancer. In addition, there is a positive correlation between the expression of PDPN and human epidermal growth factor receptor-2 (HER-2). Conclusions: The high expression of alpha-SMA, PDPN, PDGFR-beta in CAFs leads to worse clinical outcomes in breast cancer, indicating their roles as prognostic biomarkers and potential therapeutic targets.
C1 [Cui, Meimei; Dong, Hao; Duan, Wanli; Wang, Xuejie; Liu, Yongping; Zhang, Baogang] Shandong Second Med Univ, Sch Basic Med Sci, Dept Pathol, Weifang 261053, Peoples R China.
   [Shi, Lihong] Shandong Second Med Univ, Sch Rehabil Med, Weifang, Shandong, Peoples R China.
C3 Shandong Second Medical University; Shandong Second Medical University
RP Shi, LH (corresponding author), Shandong Second Med Univ, Sch Rehabil Med, Weifang, Shandong, Peoples R China.
EM zbg0903@hotmail.com
RI Dong, Hao/M-9292-2015; wang, xuejie/HGW-1453-2022; Liu,
   Yongping/Q-9228-2017; Duan, Wanli/JXW-6805-2024
OI Duan, wanli/0009-0001-7560-5675
FU National Natural Scientific Foundation of China [82373124, 81872163,
   81672631]; Weifang Science and Technology Development Program
   [2021YX045, 2021YX072, 2023YX043]; Scientific and Technological
   Innovation Team [02141607]
FX This work was supported by the National Natural Scientific Foundation of
   China [No. 82373124, 81872163 and 81672631] , the Weifang Science and
   Technology Development Program [No. 2021YX045, 2021YX072 and 2023YX043]
   and the Scientific and Technological Innovation Team [No. 02141607] .
   The funders had no role in study design, data collection and analysis,
   decision to publish, or preparation of the manuscript.
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NR 61
TC 1
Z9 1
U1 0
U2 6
PU PEERJ INC
PI LONDON
PA 341-345 OLD ST, THIRD FLR, LONDON, EC1V 9LL, ENGLAND
SN 2167-8359
J9 PEERJ
JI PeerJ
PD FEB 23
PY 2024
VL 12
AR e16958
DI 10.7717/peerj.16958
PG 16
WC Multidisciplinary Sciences
WE Science Citation Index Expanded (SCI-EXPANDED)
SC Science & Technology - Other Topics
GA JO6D3
UT WOS:001174137900003
PM 38410801
OA Green Published, gold
DA 2025-03-13
ER

PT J
AU Tchou, J
   Kossenkov, AV
   Chang, LS
   Satija, C
   Herlyn, M
   Showe, LC
   Puré, E
AF Tchou, Julia
   Kossenkov, Andrew V.
   Chang, Lisa
   Satija, Celine
   Herlyn, Meenhard
   Showe, Louise C.
   Pure, Ellen
TI Human breast cancer associated fibroblasts exhibit subtype specific gene
   expression profiles
SO BMC MEDICAL GENOMICS
LA English
DT Article
ID STROMAL FIBROBLASTS; ACTIVATION PROTEIN; TUMOR MICROENVIRONMENT;
   DIPEPTIDYL-PEPTIDASE; REMODELING INTERFACE; CELLS; HETEROGENEITY;
   CARCINOMAS; THERAPY; GROWTH
AB Background: Breast cancer is a heterogeneous disease for which prognosis and treatment strategies are largely governed by the receptor status (estrogen, progesterone and Her2) of the tumor cells. Gene expression profiling of whole breast tumors further stratifies breast cancer into several molecular subtypes which also co-segregate with the receptor status of the tumor cells. We postulated that cancer associated fibroblasts (CAFs) within the tumor stroma may exhibit subtype specific gene expression profiles and thus contribute to the biology of the disease in a subtype specific manner. Several studies have reported gene expression profile differences between CAFs and normal breast fibroblasts but in none of these studies were the results stratified based on tumor subtypes.
   Methods: To address whether gene expression in breast cancer associated fibroblasts varies between breast cancer subtypes, we compared the gene expression profiles of early passage primary CAFs isolated from twenty human breast cancer samples representing three main subtypes; seven ER+, seven triple negative (TNBC) and six Her2+.
   Results: We observed significant expression differences between CAFs derived from Her2+ breast cancer and CAFs from TNBC and ER + cancers, particularly in pathways associated with cytoskeleton and integrin signaling. In the case of Her2+ breast cancer, the signaling pathways found to be selectively up regulated in CAFs likely contribute to the enhanced migration of breast cancer cells in transwell assays and may contribute to the unfavorable prognosis of Her2+ breast cancer.
   Conclusions: These data demonstrate that in addition to the distinct molecular profiles that characterize the neoplastic cells, CAF gene expression is also differentially regulated in distinct subtypes of breast cancer.
C1 [Tchou, Julia; Satija, Celine] Univ Penn, Perelman Sch Med, Rena Rowan Breast Ctr, Abramson Canc Ctr,Dept Surg,Div Endocrine & Oncol, Philadelphia, PA 19104 USA.
   [Kossenkov, Andrew V.; Chang, Lisa; Herlyn, Meenhard; Showe, Louise C.; Pure, Ellen] Wistar Inst Anat & Biol, Philadelphia, PA 19104 USA.
C3 University of Pennsylvania; The Wistar Institute
RP Tchou, J (corresponding author), Univ Penn, Perelman Sch Med, Rena Rowan Breast Ctr, Abramson Canc Ctr,Dept Surg,Div Endocrine & Oncol, Philadelphia, PA 19104 USA.
EM Julia.tchou@uphs.upenn.edu
FU NCI Cancer Center [2-P30-CA-016520-35]; Linda and Paul Richardson Breast
   Cancer Research Funds
FX This research was, in part, funded by the NCI Cancer Center Support
   Grant (2-P30-CA-016520-35) (J. Tchou), and the Linda and Paul Richardson
   Breast Cancer Research Funds (J. Tchou).
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NR 38
TC 82
Z9 95
U1 0
U2 20
PU BIOMED CENTRAL LTD
PI LONDON
PA 236 GRAYS INN RD, FLOOR 6, LONDON WC1X 8HL, ENGLAND
SN 1755-8794
J9 BMC MED GENOMICS
JI BMC Med. Genomics
PD SEP 6
PY 2012
VL 5
AR 39
DI 10.1186/1755-8794-5-39
PG 13
WC Genetics & Heredity
WE Science Citation Index Expanded (SCI-EXPANDED)
SC Genetics & Heredity
GA 044IF
UT WOS:000311612100001
PM 22954256
OA Green Published, gold
DA 2025-03-13
ER

PT J
AU Mao, Y
   Zhang, YZ
   Qu, Q
   Zhao, MZ
   Lou, Y
   Liu, JJ
   Huang, O
   Chen, XS
   Wu, JY
   Shen, KW
AF Mao, Yan
   Zhang, Yuzi
   Qu, Qing
   Zhao, Meizhong
   Lou, Ying
   Liu, Junjun
   Huang, Ou
   Chen, Xiaosong
   Wu, Jiayi
   Shen, Kunwei
TI Cancer-associated fibroblasts induce trastuzumab resistance in HER2
   positive breast cancer cells
SO MOLECULAR BIOSYSTEMS
LA English
DT Article
ID TUMOR MICROENVIRONMENT; HER2+BREAST CANCER; 1ST-LINE TREATMENT;
   INHIBITION; ACTIVATION; SURVIVAL; GROWTH; INTERLEUKIN-6; EXPRESSION;
   INCREASES
AB Whether and how cancer-associated fibroblasts induce trastuzumab resistance in HER2+ breast cancer is still elusive. We analyzed the percentage of cancer stem cells and multiple pathway status before and after trastuzumab treatment in HER2 positive breast cancer cells co-cultured with conditional medium (CM) from CAFs. The results suggest that CAFs induce trastuzumab resistance by expanding cancer stem cells and activating multiple pathways, such as NF-kappa B, JAK/STAT3 and PI3K/AKT; combination of an anti-IL6 antibody, or multiple pathway inhibitors with trastuzumab in HER2 positive breast cancer maybe a novel strategy to reverse trastuzumab resistance.
C1 [Mao, Yan; Zhang, Yuzi; Lou, Ying; Liu, Junjun; Huang, Ou; Chen, Xiaosong; Wu, Jiayi; Shen, Kunwei] Shanghai Jiao Tong Univ, Sch Med, Comprehens Breast Hlth Ctr, Shanghai, Peoples R China.
   [Qu, Qing] Shanghai Jiao Tong Univ, Sch Med, Ruijin Hosp, Dept Oncol, Shanghai, Peoples R China.
   [Zhao, Meizhong] Linyi Peoples Hosp, Dept Breast & Thyroid Surg, Linyi 276003, Shandong, Peoples R China.
C3 Shanghai Jiao Tong University; Shanghai Jiao Tong University
RP Shen, KW (corresponding author), Shanghai Jiao Tong Univ, Sch Med, Comprehens Breast Hlth Ctr, 197,Ruijin 2 Rd, Shanghai, Peoples R China.
EM kwshen@medmail.com.cn
RI junjun, liu/AAV-9545-2021; 吴, 家怡/GSI-7419-2022
FU Doctor Innovation funding of Shanghai Jiao Tong University School of
   Medicine [BXJ201213]; National Natural funding of China [81202087,
   81202088, 81172520]; Shanghai Municipal Science and Technology
   Commission funding [12ZR1446400, 12140901503]
FX Research in the authors' laboratory is supported by the Doctor
   Innovation funding of Shanghai Jiao Tong University School of Medicine
   (BXJ201213), National Natural funding of China (81202087, 81202088,
   81172520), Shanghai Municipal Science and Technology Commission funding
   (12ZR1446400, 12140901503).
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NR 32
TC 39
Z9 44
U1 0
U2 22
PU ROYAL SOC CHEMISTRY
PI CAMBRIDGE
PA THOMAS GRAHAM HOUSE, SCIENCE PARK, MILTON RD, CAMBRIDGE CB4 0WF, CAMBS,
   ENGLAND
SN 1742-206X
EI 1742-2051
J9 MOL BIOSYST
JI Mol. Biosyst.
PY 2015
VL 11
IS 4
BP 1029
EP 1040
DI 10.1039/c4mb00710g
PG 12
WC Biochemistry & Molecular Biology
WE Science Citation Index Expanded (SCI-EXPANDED)
SC Biochemistry & Molecular Biology
GA CE0KQ
UT WOS:000351493300005
PM 25648538
DA 2025-03-13
ER

PT J
AU Zhao, XL
   Lin, Y
   Jiang, J
   Tang, Z
   Yang, S
   Lu, L
   Liang, Y
   Liu, X
   Tan, J
   Hu, XG
   Niu, Q
   Fu, WJ
   Yan, ZX
   Guo, DY
   Ping, YF
   Wang, JM
   Zhang, X
   Kung, HF
   Bian, XW
   Yao, XH
AF Zhao, Xi-Long
   Lin, Yong
   Jiang, Jun
   Tang, Zhuo
   Yang, Shuai
   Lu, Lu
   Liang, Yan
   Liu, Xue
   Tan, Jiao
   Hu, Xu-Gang
   Niu, Qin
   Fu, Wen-Juan
   Yan, Ze-Xuan
   Guo, De-Yu
   Ping, Yi-Fang
   Wang, Ji Ming
   Zhang, Xia
   Kung, Hsiang-Fu
   Bian, Xiu-Wu
   Yao, Xiao-Hong
TI High-mobility group box 1 released by autophagic cancer-associated
   fibroblasts maintains the stemness of luminal breast cancer cells
SO JOURNAL OF PATHOLOGY
LA English
DT Article
DE autophagy; breast cancer-initiating cell (BCIC); cancer-associated
   fibroblast (CAF); high-mobility group box 1 (HMGB1); Toll-like receptor
   4 (TLR4)
ID UNCONVENTIONAL PROTEIN SECRETION; TUMOR-CELLS; HMGB1; METASTASIS;
   INHIBITION; GROWTH; CHEMOTHERAPY; INTERFERES; ACTIVATION; EXPRESSION
AB Cancer stem cells/cancer-initiating cells (CICs) and their microenvironmental niche play a vital role in malignant tumour recurrence and metastasis. Cancer-associated fibroblasts (CAFs) are major components of the niche of breast cancer-initiating cells (BCICs), and their interactions may profoundly affect breast cancer progression. Autophagy has been considered to be a critical process for CIC maintenance, but whether it is involved in the cross-talk between CAFs and CICs to affect tumourigenesis and pathological significance has not been determined. In this study, we found that the presence of CAFs containing high levels of microtubule-associated protein 1 light chain 3 (LC3II), a marker of autophagosomes, was associated with more aggressive luminal human breast cancer. CAFs in human luminal breast cancer tissues with high autophagy activity enriched BCICs with increased tumourigenicity. Mechanistically, autophagic CAFs released high-mobility group box 1 (HMGB1), which activated its receptor, Toll-like receptor (TLR) 4, expressed by luminal breast cancer cells, to enhance their stemness and tumourigenicity. Furthermore, immunohistochemistry of 180 luminal breast cancers revealed that high LC3II/TLR4 levels predicted an increased relapse rate and a poorer prognosis. Our findings demonstrate that autophagic CAFs play a critical role in promoting the progression of luminal breast cancer through an HMGB1-TLR4 axis, and that both autophagy in CAFs and TLR4 on breast cancer cells constitute potential therapeutic targets. Copyright (C) 2017 Pathological Society of Great Britain and Ireland. Published by John Wiley & Sons, Ltd.
C1 [Zhao, Xi-Long; Lin, Yong; Tang, Zhuo; Yang, Shuai; Lu, Lu; Liang, Yan; Liu, Xue; Tan, Jiao; Hu, Xu-Gang; Niu, Qin; Fu, Wen-Juan; Yan, Ze-Xuan; Guo, De-Yu; Ping, Yi-Fang; Zhang, Xia; Kung, Hsiang-Fu; Bian, Xiu-Wu; Yao, Xiao-Hong] Third Mil Med Univ, Southwest Hosp, Inst Pathol, Chongqing 400038, Peoples R China.
   [Zhao, Xi-Long; Lin, Yong; Tang, Zhuo; Yang, Shuai; Lu, Lu; Liang, Yan; Liu, Xue; Tan, Jiao; Hu, Xu-Gang; Niu, Qin; Fu, Wen-Juan; Yan, Ze-Xuan; Guo, De-Yu; Ping, Yi-Fang; Zhang, Xia; Kung, Hsiang-Fu; Bian, Xiu-Wu; Yao, Xiao-Hong] Third Mil Med Univ, Southwest Hosp, Southwest Canc Ctr, Chongqing 400038, Peoples R China.
   [Jiang, Jun; Liang, Yan] Third Mil Med Univ, Southwest Hosp, Breast Dis Ctr, Chongqing, Peoples R China.
   [Wang, Ji Ming] NCI, Canc & Inflammat Program, Ctr Canc Res, Frederick, MD 21701 USA.
C3 Army Medical University; Army Medical University; Army Medical
   University; National Institutes of Health (NIH) - USA; NIH National
   Cancer Institute (NCI)
RP Kung, HF; Bian, XW; Yao, XH (corresponding author), Third Mil Med Univ, Southwest Hosp, Inst Pathol, Chongqing 400038, Peoples R China.; Kung, HF; Bian, XW; Yao, XH (corresponding author), Third Mil Med Univ, Southwest Hosp, Southwest Canc Ctr, Chongqing 400038, Peoples R China.
EM hfkung@163.com; bianxiuwu@263.net; yxh15@hotmail.com
RI Zhang, Xia/B-8152-2008; Bian, Xiu-Wu/D-4736-2017
OI Zhao, XiLong/0000-0002-5182-9180; Bian, Xiu-Wu/0000-0003-4383-0197;
   Jiang, Jun/0000-0002-8931-9872
FU key project of National Natural Science Foundation of China [81230062];
   National Natural Science Foundation of China [81372684]; National Key
   Research and Development Programme of China Stem Cell and Translational
   Research [2016YFA0101203]; Key Laboratory of Tumour Immunopathology,
   Ministry of Education of China [2015jszl07]
FX The authors thank Mrs Wei Sun and Li-Ting Wang (Central Laboratory,
   Third Military Medical University, Chongqing, PR China) for technical
   assistance with laser confocal scanning microscopy. The authors also
   thank their colleagues for helpful comments. This project was supported
   by grants from the key project of National Natural Science Foundation of
   China (No. 81230062 to X-WB), the National Natural Science Foundation of
   China (No. 81372684 to X-HY), the National Key Research and Development
   Programme of China Stem Cell and Translational Research (2016YFA0101203
   to X-WB), and the open project supported by Key Laboratory of Tumour
   Immunopathology, Ministry of Education of China (No. 2015jszl07 to
   X-HY).
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NR 52
TC 87
Z9 98
U1 1
U2 36
PU WILEY
PI HOBOKEN
PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA
SN 0022-3417
EI 1096-9896
J9 J PATHOL
JI J. Pathol.
PD NOV
PY 2017
VL 243
IS 3
BP 376
EP 389
DI 10.1002/path.4958
PG 14
WC Oncology; Pathology
WE Science Citation Index Expanded (SCI-EXPANDED)
SC Oncology; Pathology
GA FK0DN
UT WOS:000413150600011
PM 28802057
OA Green Accepted
DA 2025-03-13
ER

PT J
AU Mollah, F
   Varamini, P
AF Mollah, Farhana
   Varamini, Pegah
TI Overcoming Therapy Resistance and Relapse in TNBC: Emerging Technologies
   to Target Breast Cancer-Associated Fibroblasts
SO BIOMEDICINES
LA English
DT Article
DE triple-negative breast cancer; breast cancer-associated fibroblasts;
   breast cancer; cancer-associated fibroblasts; chemoresistance;
   nanotechnology; microRNA; antibodies
ID CARCINOMA-ASSOCIATED FIBROBLASTS; MESENCHYMAL STEM-CELLS; FOLATE
   RECEPTOR-ALPHA; TUMOR MICROENVIRONMENT; ACTIVATION PROTEIN; PDGFR-BETA;
   STROMAL MYOFIBROBLASTS; CABOZANTINIB XL184; TENASCIN-C; METASTASIS
AB Breast cancer is the most diagnosed cancer and is the leading cause of cancer mortality in women. Triple-negative breast cancer (TNBC) is an aggressive form of breast cancer. Often, TNBC is not effectively treated due to the lack of specificity of conventional therapies and results in relapse and metastasis. Breast cancer-associated fibroblasts (BCAFs) are the predominant cells that reside in the tumor microenvironment (TME) and regulate tumorigenesis, progression and metastasis, and therapy resistance. BCAFs secrete a wide range of factors, including growth factors, chemokines, and cytokines, some of which have been proved to lead to a poor prognosis and clinical outcomes. This TME component has been emerging as a promising target due to its crucial role in cancer progression and chemotherapy resistance. A number of therapeutic candidates are designed to effectively target BCAFs with a focus on their tumor-promoting properties and tumor immune response. This review explores various agents targeting BCAFs in TNBC, including small molecules, nucleic acid-based agents, antibodies, proteins, and finally, nanoparticles.
C1 [Mollah, Farhana; Varamini, Pegah] Univ Sydney, Sch Pharm, Fac Med & Hlth, Sydney, NSW 2006, Australia.
   [Varamini, Pegah] Univ Sydney, Sydney Nano Inst, Sydney, NSW 2006, Australia.
C3 University of Sydney; University of Sydney
RP Varamini, P (corresponding author), Univ Sydney, Sch Pharm, Fac Med & Hlth, Sydney, NSW 2006, Australia.; Varamini, P (corresponding author), Univ Sydney, Sydney Nano Inst, Sydney, NSW 2006, Australia.
RI Varamini, Pegah/ABB-2824-2020; Varamini, Pegah/N-6917-2015
OI Varamini, Pegah/0000-0001-8658-9722
FU National Breast Cancer Foundation Research fellowship [PF-16-007]
FX FundingNational Breast Cancer Foundation Research fellowship and grant
   (Pegah Varamini PF-16-007).
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NR 177
TC 12
Z9 12
U1 1
U2 22
PU MDPI
PI BASEL
PA MDPI AG, Grosspeteranlage 5, CH-4052 BASEL, SWITZERLAND
EI 2227-9059
J9 BIOMEDICINES
JI Biomedicines
PD DEC
PY 2021
VL 9
IS 12
AR 1921
DI 10.3390/biomedicines9121921
PG 25
WC Biochemistry & Molecular Biology; Medicine, Research & Experimental;
   Pharmacology & Pharmacy
WE Science Citation Index Expanded (SCI-EXPANDED)
SC Biochemistry & Molecular Biology; Research & Experimental Medicine;
   Pharmacology & Pharmacy
GA XW4FR
UT WOS:000735577600001
PM 34944738
OA Green Published, gold
DA 2025-03-13
ER

PT J
AU Ruocco, MR
   Avagliano, A
   Granato, G
   Imparato, V
   Masone, S
   Masullo, M
   Nasso, R
   Montagnani, S
   Arcucci, A
AF Ruocco, Maria Rosaria
   Avagliano, Angelica
   Granato, Giuseppina
   Imparato, Valeria
   Masone, Stefania
   Masullo, Mariorosario
   Nasso, Rosarita
   Montagnani, Stefania
   Arcucci, Alessandro
TI Involvement of Breast Cancer-Associated Fibroblasts in Tumor
   Development, Therapy Resistance and Evaluation of Potential Therapeutic
   Strategies
SO CURRENT MEDICINAL CHEMISTRY
LA English
DT Review
DE Breast cancer; breast cancer associated fibroblasts; normal fibroblasts;
   estrogen; therapy resistance; tumor stroma
ID CARCINOMA-ASSOCIATED FIBROBLASTS; ACTIVATION PROTEIN-ALPHA;
   EPITHELIAL-MESENCHYMAL TRANSITION; NORMAL MAMMARY FIBROBLASTS;
   ESTROGEN-RECEPTOR; STROMAL FIBROBLASTS; GENE-EXPRESSION; GROWTH-FACTOR;
   AROMATASE EXPRESSION; GPER TRANSLOCATION
AB Breast cancer is the most common cancer in women, which incidence has increased in recent years. It is constituted by very heterogeneous tissue characterized by an abnormal microenvironment regulating tumor progression and providing evasion from cancer therapies. Breast cancer-associated fibroblasts (BCAFs) are the main cell type of breast cancer microenvironment and can represent up to 80% of the tumor mass. In particular, BCAFs induce cancer initiation, proliferation, invasion and metastasis by undergoing an activation process associated with the secretion of growth factors, cytokines, and paracrine interactions. Therapy resistance is the main cause of poor therapeutic results or even failure in breast cancer patients. Despite recent advances in breast cancer management, there is a need for new prognostic markers and novel agents for targeting key signalling pathways to either improve the efficacy of the current therapies, or reduce toxicity. In this view, BCAFs represent markers useful to clinical diagnosis, therapy, and prognosis of breast cancer. This review focuses on the role of BCAFs in cancer, and describes the processes of endocrine/chemotherapy resistance linked to BCAFs action. Moreover, it points to molecules and pathways regulating therapy resistance induced by BCAFs. Finally, potential therapeutic strategies targeting BCAFs and offering new tools in breast cancer therapy are highlighted.
C1 [Ruocco, Maria Rosaria; Nasso, Rosarita] Univ Naples Federico II, Dept Mol Med & Med Biotechnol, I-80131 Naples, Italy.
   [Avagliano, Angelica; Granato, Giuseppina; Imparato, Valeria; Montagnani, Stefania; Arcucci, Alessandro] Univ Naples Federico II, Dept Publ Hlth, I-80131 Naples, Italy.
   [Masone, Stefania] Univ Naples Federico II, Dept Clin Med & Surg, I-80131 Naples, Italy.
   [Masullo, Mariorosario; Nasso, Rosarita] Univ Naples Parthenope, Dept Movement Sci & Wellness, I-80133 Naples, Italy.
C3 University of Naples Federico II; University of Naples Federico II;
   University of Naples Federico II; Parthenope University Naples
RP Arcucci, A (corresponding author), Univ Naples Federico II, Dept Publ Hlth, I-80131 Naples, Italy.
EM alessandro.arcucci2@unina.it
RI Arcucci, Alessandro/AAV-7902-2020; Nasso, Rosarita/LNR-1806-2024;
   Avagliano, Angelica/ABI-2247-2020; masone, stefania/I-5077-2012;
   Masullo, Mariorosario/H-4884-2016
OI Nasso, Rosarita/0009-0000-6241-4856; Masullo,
   Mariorosario/0000-0003-4485-7383
FU P.O.R Campania FESR [2007-2013-O.O.2.1-CUPB25C13000280007]
FX This work was supported by a grant from P.O.R Campania FESR
   2007-2013-O.O.2.1-CUPB25C13000280007.
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NR 175
TC 32
Z9 35
U1 1
U2 13
PU BENTHAM SCIENCE PUBL LTD
PI SHARJAH
PA EXECUTIVE STE Y-2, PO BOX 7917, SAIF ZONE, 1200 BR SHARJAH, U ARAB
   EMIRATES
SN 0929-8673
EI 1875-533X
J9 CURR MED CHEM
JI Curr. Med. Chem.
PY 2018
VL 25
IS 29
BP 3414
EP 3434
DI 10.2174/0929867325666180309120746
PG 21
WC Biochemistry & Molecular Biology; Chemistry, Medicinal; Pharmacology &
   Pharmacy
WE Science Citation Index Expanded (SCI-EXPANDED)
SC Biochemistry & Molecular Biology; Pharmacology & Pharmacy
GA GX0HO
UT WOS:000447391200001
PM 29521203
OA Green Submitted
DA 2025-03-13
ER

PT J
AU Kwon, A
   Chae, IH
   You, E
   Kim, SH
   Ahn, SY
   Lee, OJ
   Park, ZY
   Rhee, S
   Huh, YH
   Song, WK
AF Kwon, Ahreum
   Chae, In Hee
   You, Eunae
   Kim, So Hee
   Ahn, Su-yeon
   Lee, Ok-Jun
   Park, Zee-Yong
   Rhee, Sangmyung
   Huh, Yun Hyun
   Song, Woo Keun
TI Extra domain A-containing fibronectin expression in
   <i>Spin90</i>-deficient fibroblasts mediates cancer-stroma interaction
   and promotes breast cancer progression
SO JOURNAL OF CELLULAR PHYSIOLOGY
LA English
DT Article
DE cancer-associated fibroblast; extracellular matrix; FN(+)EDA; SPIN90;
   tumor microenvironment
ID TUMOR MICROENVIRONMENT; EXTRACELLULAR-MATRIX; ED-A; CELL; METASTASIS;
   INTEGRIN; ACTIVATION; ADHESION; DIFFERENTIATION; ORGANIZATION
AB Cancer-associated fibroblasts (CAFs) in the tumor microenvironment play major roles in supporting cancer progression. A previous report showed that SPIN90 downregulation is correlated with CAF activation and that SPIN90-deficient CAFs promote breast cancer progression. However, the mechanisms that mediate cancer-stroma interaction and how such interactions regulate cancer progression are not well understood. Here, we show that extra domain A (EDA)-containing fibronectin (FN), FN(+)EDA, produced by mouse embryonic fibroblasts (MEFs) derived from Spin90-knockout (KO) mice increases their own myofibroblast differentiation, which facilitates breast cancer progression. Increased FN(+)EDA in Spin90-KO MEFs promoted fibril formation in the extracellular matrix (ECM) and specifically interacted with integrin alpha 4 beta 1 as the mediating receptor. Moreover, FN(+)EDA expression by Spin90-KO MEFs increased proliferation, migration, and invasion of breast cancer cells. Irigenin, a specific inhibitor of the interaction between integrin alpha 4 beta 1 and FN(+)EDA, significantly blocked the effects of FN(+)EDA, such as fibril formation by Spin90-KO MEFs and proliferation, migration, and invasion of breast cancer cells. In orthotopic breast cancer mouse models, irigenin injection remarkably reduced tumor growth and lung metastases. It was supported by that FN(+)EDA in assembled fibrils was accumulated in cancer stroma of human breast cancer patients in which SPIN90 expression was downregulated. Our data suggest that SPIN90 downregulation increases FN(+)EDA and promotes ECM stiffening in breast cancer stroma through an assembly of long FN(+)EDA-rich fibrils; moreover, engagement of the Integrin alpha 4 beta 1 receptor facilitates breast cancer progression. Inhibitory effects of irigenin on tumor growth and metastasis suggest the potential of this agent as an anticancer therapeutic.
C1 [Kwon, Ahreum; Chae, In Hee; Kim, So Hee; Ahn, Su-yeon; Park, Zee-Yong; Huh, Yun Hyun; Song, Woo Keun] Gwangju Inst Sci & Technol, Sch Life Sci, Cell Logist & Silver Hlth Res Ctr, 123 Cheomdangwagi Ro, Gwangju 61005, South Korea.
   [You, Eunae; Rhee, Sangmyung] Chung Ang Univ, Dept Life Sci, Seoul, South Korea.
   [Lee, Ok-Jun] Chungbuk Natl Univ, Dept Pathol, Coll Med, Cheongju, South Korea.
C3 Gwangju Institute of Science & Technology (GIST); Chung Ang University;
   Chungbuk National University
RP Song, WK (corresponding author), Gwangju Inst Sci & Technol, Sch Life Sci, Cell Logist & Silver Hlth Res Ctr, 123 Cheomdangwagi Ro, Gwangju 61005, South Korea.; Huh, YH (corresponding author), Gwangju Inst Sci & Technol, Sch Life Sci, 123 Cheomdangwagi Ro, Gwangju 61005, South Korea.
EM yhuh@gist.ac.kr; wksong@gist.ac.kr
RI Lee, Han/W-4924-2019; You, Eunae/KZU-8781-2024
OI Ahn, Suyeon/0000-0001-6992-3442; You, Eunae/0000-0001-9028-4024; Rhee,
   Sangmyung/0000-0003-2733-2147
FU GIST Research Institute; National Research Foundation of Korea
   [NRF-2016R1A5A1007318, NRF2016R1C1B1013237, NRF2018R1A2B2005639]
FX GIST Research Institute, Grant/Award Number: Silver Health Research
   Center; National Research Foundation of Korea, Grant/Award Numbers:
   NRF-2016R1A5A1007318, NRF2016R1C1B1013237, NRF2018R1A2B2005639
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NR 50
TC 12
Z9 15
U1 0
U2 11
PU WILEY
PI HOBOKEN
PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA
SN 0021-9541
EI 1097-4652
J9 J CELL PHYSIOL
JI J. Cell. Physiol.
PD MAY
PY 2020
VL 235
IS 5
BP 4494
EP 4507
DI 10.1002/jcp.29326
EA OCT 2019
PG 14
WC Cell Biology; Physiology
WE Science Citation Index Expanded (SCI-EXPANDED)
SC Cell Biology; Physiology
GA KK6JH
UT WOS:000491848700001
PM 31637720
DA 2025-03-13
ER

PT J
AU Louault, K
   Bonneaud, TL
   Séveno, C
   Gomez-Bougie, P
   Nguyen, F
   Gautier, F
   Bourgeois, N
   Loussouarn, D
   Kerdraon, O
   Barillé-Nion, S
   Jézéquel, P
   Campone, M
   Amiot, M
   Juin, PP
   Souazé, F
AF Louault, K.
   Bonneaud, T. L.
   Seveno, C.
   Gomez-Bougie, P.
   Nguyen, F.
   Gautier, F.
   Bourgeois, N.
   Loussouarn, D.
   Kerdraon, O.
   Barille-Nion, S.
   Jezequel, P.
   Campone, M.
   Amiot, M.
   Juin, P. P.
   Souaze, F.
TI Interactions between cancer-associated fibroblasts and tumor cells
   promote MCL-1 dependency in estrogen receptor-positive breast cancers
SO ONCOGENE
LA English
DT Article
ID BCL-2; CARCINOMA; DETERMINANT; SENSITIVITY; APOPTOSIS; FEATURES; IMPACT;
   IL-6
AB Selective inhibition of BCL-2 is expected to enhance therapeutic vulnerability in luminal estrogen receptor-positive breast cancers. We show here that the BCL-2 dependency of luminal tumor cells is nevertheless mitigated by breast cancer-associated fibroblasts (bCAFs) in a manner that defines MCL-1 as another critical therapeutic target. bCAFs favor MCL-1 expression and apoptotic resistance in luminal cancer cells in a IL-6 dependent manner while their own, robust, survival also relies on MCL-1. Studies based on ex vivo cultures of human luminal breast cancer tissues further argue that the contribution of stroma-derived signals to MCL-1 expression shapes BCL-2 dependency. Thus, MCL-1 inhibitors are beneficial for targeted apoptosis of breast tumor ecosystems, even in a subtype where MCL-1 dependency is not intrinsically driven by oncogenic pathways.
C1 [Louault, K.; Bonneaud, T. L.; Seveno, C.; Nguyen, F.; Gautier, F.; Bourgeois, N.; Barille-Nion, S.; Jezequel, P.; Campone, M.; Juin, P. P.; Souaze, F.] Univ Nantes, Univ Angers, INSERM, CRCINA,Team 8, Nantes, France.
   [Louault, K.; Bonneaud, T. L.; Seveno, C.; Gomez-Bougie, P.; Gautier, F.; Bourgeois, N.; Kerdraon, O.; Barille-Nion, S.; Jezequel, P.; Campone, M.; Amiot, M.; Juin, P. P.; Souaze, F.] SIRIC ILIAD, Nantes, France.
   [Gomez-Bougie, P.; Amiot, M.] Univ Nantes, Univ Angers, INSERM, CRCINA,Team 10, Nantes, France.
   [Nguyen, F.] Nantes Atlantic Coll Vet Med Food Sci & Engn, ONIRIS, Anim Canc, Nantes, France.
   [Gautier, F.; Kerdraon, O.; Jezequel, P.; Campone, M.; Juin, P. P.] ICO Rene Gauducheau, St Herblain, France.
   [Loussouarn, D.] CHU Nantes, Serv Anat Pathol, Nantes, France.
   [Juin, P. P.; Souaze, F.] CNRS GDR3697 Micronit, Tours, France.
C3 Institut National de la Sante et de la Recherche Medicale (Inserm);
   Nantes Universite; Universite d'Angers; Universite d'Angers; Institut
   National de la Sante et de la Recherche Medicale (Inserm); Nantes
   Universite; Ecole Nationale Veterinaire, Agroalimentaire et de
   l'Alimentation Nantes-Atlantique; UNICANCER; Institut de Cancerologie de
   l'Ouest (ICO); Nantes Universite; CHU de Nantes
RP Juin, PP; Souazé, F (corresponding author), Univ Nantes, Univ Angers, INSERM, CRCINA,Team 8, Nantes, France.; Juin, PP; Souazé, F (corresponding author), SIRIC ILIAD, Nantes, France.; Juin, PP (corresponding author), ICO Rene Gauducheau, St Herblain, France.; Juin, PP; Souazé, F (corresponding author), CNRS GDR3697 Micronit, Tours, France.
EM philippe.juin@univ-nantes.fr; frederique.souaze@univ-nantes.fr
RI JUIN, Philippe/Q-1338-2019; Souazé, Frédérique/K-7937-2015; campone,
   mario/L-4880-2015; Bougie, Patricia/K-9074-2015; Barille-Nion,
   Sophie/W-8103-2019
OI Louault, Kevin/0000-0002-2325-5757; Juin, Philippe/0000-0002-4997-3888;
   Barille-Nion, Sophie/0000-0001-5171-9937; Frederique,
   Souaze/0000-0003-0476-2603; Nguyen, Frederique/0000-0001-7203-2982;
   Gomez Bougie, Patricia/0000-0002-4846-4782
FU CIFRE grant (ANRT contract) [20150995]; Ligue contre le cancer; Odyssea;
   Canceropole Grand Ouest (MATURE project 2017-18); ARC [R15083NN]; ANR
   [15-CE18-0008]; INCa; DGOS (SIRIC ILIAD, INCa-DGOS Inserm) [12558]
FX This research was performed within the framework of a CIFRE grant (ANRT
   contract #20150995) for K. Louault at CRCINA and ONCOTHEREX. T.L
   Bonneaud was supported by a fellowship from Ligue contre le cancer. This
   work was supported by Odyssea, Canceropole Grand Ouest (MATURE project
   2017-18), ARC (R15083NN), ANR (15-CE18-0008), INCa and DGOS (SIRIC
   ILIAD, INCa-DGOS Inserm-12558).
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NR 39
TC 47
Z9 51
U1 0
U2 12
PU NATURE PUBLISHING GROUP
PI LONDON
PA MACMILLAN BUILDING, 4 CRINAN ST, LONDON N1 9XW, ENGLAND
SN 0950-9232
EI 1476-5594
J9 ONCOGENE
JI Oncogene
PD APR 25
PY 2019
VL 38
IS 17
BP 3261
EP 3273
DI 10.1038/s41388-018-0635-z
PG 13
WC Biochemistry & Molecular Biology; Oncology; Cell Biology; Genetics &
   Heredity
WE Science Citation Index Expanded (SCI-EXPANDED)
SC Biochemistry & Molecular Biology; Oncology; Cell Biology; Genetics &
   Heredity
GA HU8RI
UT WOS:000465557200011
PM 30631150
OA Green Published, hybrid
DA 2025-03-13
ER

PT J
AU Vivacqua, A
   Muoio, MG
   Miglietta, AM
   Maggiolini, M
AF Vivacqua, Adele
   Muoio, Maria Grazia
   Miglietta, Anna Maria
   Maggiolini, Marcello
TI Differential MicroRNA Landscape Triggered by Estrogens in Cancer
   Associated Fibroblasts (CAFs) of Primary and Metastatic Breast Tumors
SO CANCERS
LA English
DT Article
DE breast cancer; metastasis; CAFs; estrogens; microRNAs
ID GPER; ROLES; CELLS; EXPRESSION; GROWTH; PROGRESSION; PROMOTES; MIR-148A;
   GPR30; MIRNA
AB Cancer associated fibroblasts (CAFs) play a main role in breast cancer progression and metastasis. Estrogens modulate in breast CAFs the expression of microRNAs (miRNAs) that are involved in the development of many tumors. In order to provide novel insights on the regulation of miRNAs by estrogens in breast cancer, we analyzed the expression of 754 miRNAs in CAFs obtained from primary mammary tumors and CAFs derived from a cutaneous breast cancer metastasis. Using the TaqMann (TM) Human MicroRNA Array, we found that 17 beta-estradiol (E2) modulates numerous peculiar and common miRNAs in CAFs derived from primary and the metastatic malignancies. In particular, we assessed that E2 modulates 133 miRNAs (41 up and 92 downregulated) in CAFs derived from primary breast tumors, whereas E2 modulates 415 miRNAs (399 up and 16 downregulated) in CAFs derived from a cutaneous metastasis of breast carcinoma. Therefore, a number of miRNAs three times higher in metastatic CAFs with respect to primary breast CAFs was found modulated by E2. Our findings shed new light on the cumulative regulation of miRNAs by E2 in the main players of the tumor microenvironment as CAFs. Moreover, our data may be taken into consideration that is useful toward innovative prognostic and therapeutic approaches in breast cancer progression.
C1 [Vivacqua, Adele; Muoio, Maria Grazia; Maggiolini, Marcello] Univ Calabria, Dept Pharm Hlth & Nutr Sci, I-87036 Arcavacata Di Rende, CS, Italy.
   [Miglietta, Anna Maria] Reg Hosp Cosenza, Breast Unit, I-87100 Cosenza, Italy.
C3 University of Calabria
RP Vivacqua, A; Maggiolini, M (corresponding author), Univ Calabria, Dept Pharm Hlth & Nutr Sci, I-87036 Arcavacata Di Rende, CS, Italy.
EM adele.vivacqua@unical.it; mariagraziamuoio@libero.it;
   annamariamiglietta@virgilio.it; marcello.maggiolini@unical.it
RI Maggiolini, Marcello/Z-4729-2019; vivacqua, adele/I-2771-2015
OI vivacqua, adele/0000-0001-5333-8396
FU Associazione Italiana Ricerca sul Cancro (AIRC) [IG 21322]
FX This work has been supported by Associazione Italiana Ricerca sul Cancro
   (AIRC, IG 21322).
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NR 51
TC 15
Z9 15
U1 0
U2 5
PU MDPI
PI BASEL
PA ST ALBAN-ANLAGE 66, CH-4052 BASEL, SWITZERLAND
SN 2072-6694
J9 CANCERS
JI Cancers
PD MAR
PY 2019
VL 11
IS 3
AR 412
DI 10.3390/cancers11030412
PG 17
WC Oncology
WE Science Citation Index Expanded (SCI-EXPANDED)
SC Oncology
GA HZ0RT
UT WOS:000468550200142
PM 30909585
OA Green Published, gold, Green Submitted
DA 2025-03-13
ER

PT J
AU Sun, JH
   Du, RX
   Li, XJ
   Liu, CL
   Wang, DH
   He, XM
   Li, GD
   Zhang, K
   Wang, SN
   Hao, Q
   Zhang, YQ
   Li, M
   Gao, Y
   Zhang, C
AF Sun, Jiahui
   Du, Ruoxin
   Li, Xiaoju
   Liu, Chenlin
   Wang, Donghui
   He, Xiangmei
   Li, Guodong
   Zhang, Kuo
   Wang, Shuning
   Hao, Qiang
   Zhang, Yingqi
   Li, Meng
   Gao, Yuan
   Zhang, Cun
TI CD63+cancer-associated fibroblasts confer CDK4/6 inhibitor resistance to
   breast cancer cells by exosomal miR-20
SO CANCER LETTERS
LA English
DT Article
DE Breast cancer; CDK4/6 inhibitor resistance; Cancer -associated
   fibroblasts; Exosomes; miR-20
ID STEMNESS; CHEMORESISTANCE; CHEMOTHERAPY; MECHANISMS; BLOCKADE; THERAPY
AB Cyclin-dependent kinase 4 (CDK4) and CDK6 inhibitors (CDK4/6i) have rapidly received Food and Drug Administration (FDA) approval as a new type of therapy for patients with advanced hormone receptor -positive breast cancer. However, with the widespread application of CDK4/6i, drug resistance has become a new challenge for clinical practice and has greatly limited the treatment effect. Here, the whole microenvironment landscape of ER+ breast cancer tumors was revealed through single -cell RNA sequencing, and a specific subset of cancer -associated fibroblasts (CD63+ CAFs) was identified as highly enriched in CDK4/6i resistant tumor tissues. Then, we found that CD63+ CAFs can distinctly promote resistance to CDK4/6i in breast cancer cells and tumor xenografts. In addition, it was discovered that miR-20 is markedly enriched in the CD63+ CAFs-derived exosomes, which are used to communicate with ER+ breast cancer cells, leading to CDK4/6i resistance. Furthermore, exosomal miR-20 could directly target the RB1 mRNA 3 ' UTR and negatively regulate RB1 expression to decrease CDK4/6i sensitivity in breast cancer cells. Most importantly, we designed and synthesized cRGD-miR-20 sponge nanoparticles and found that they can enhance the therapeutic effect of CDK4/6i in breast cancer. In summary, our findings reveal that CD63+ CAFs can promote CDK4/6i resistance via exosomal miR-20, which induces the downregulation of RB1 in breast cancer cells, and suggest that CD63+ CAFs may be a novel therapeutic target to enhance CDK4/6i sensitivity.
C1 [Sun, Jiahui; Du, Ruoxin; Li, Xiaoju; Liu, Chenlin; Wang, Donghui; He, Xiangmei; Li, Guodong; Zhang, Kuo; Wang, Shuning; Hao, Qiang; Zhang, Yingqi; Li, Meng; Gao, Yuan; Zhang, Cun] Fourth Mil Med Univ, Biotechnol Ctr, Sch Pharm, State Key Lab Holist Integrat Management Gastroint, Xian 710032, Peoples R China.
   [Li, Xiaoju] Bioinformat Ctr AMMS, Beijing 100850, Peoples R China.
   [Li, Meng; Gao, Yuan; Zhang, Cun] Fourth Mil Med Univ, State Key Lab Holist Integrat Management Gastroint, 169 Changle West Rd, Xian 710032, Peoples R China.
C3 Air Force Military Medical University; Air Force Military Medical
   University
RP Li, M; Gao, Y; Zhang, C (corresponding author), Fourth Mil Med Univ, State Key Lab Holist Integrat Management Gastroint, 169 Changle West Rd, Xian 710032, Peoples R China.
EM limeng@fmmu.edu.cn; gaoyuan321@fmmu.edu.cn; zhangcun@fmmu.edu.cn
RI Du, Ruoxin/HMD-6703-2023; Wang, Dong-Hui/AAG-7297-2020
FU Shaanxi Science Fund for Distinguished Young Scholars [2022JC-53];
   National Natural Science Foundation of China [82072910, 81902678,
   82373894, 82304540, 82172788]; Natural Science Basic Research Program of
   Shaanxi Province [2022JM-512]
FX <BOLD>Acknowledgements</BOLD> This study was supported by grants from
   Shaanxi Science Fund for Distinguished Young Scholars (No. 2022JC-53) ,
   the National Natural Science Foundation of China (No. 82072910;
   81902678; 82373894; 82304540; 82172788) , the Natural Science Basic
   Research Program of Shaanxi Province (2022JM-512) .
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NR 48
TC 6
Z9 6
U1 3
U2 5
PU ELSEVIER IRELAND LTD
PI CLARE
PA ELSEVIER HOUSE, BROOKVALE PLAZA, EAST PARK SHANNON, CO, CLARE, 00000,
   IRELAND
SN 0304-3835
EI 1872-7980
J9 CANCER LETT
JI Cancer Lett.
PD APR 28
PY 2024
VL 588
AR 216747
DI 10.1016/j.canlet.2024.216747
EA FEB 2024
PG 13
WC Oncology
WE Science Citation Index Expanded (SCI-EXPANDED)
SC Oncology
GA OQ5Z3
UT WOS:001208765900001
PM 38403110
OA hybrid
DA 2025-03-13
ER

PT J
AU Eiro, N
   Cid, S
   Aguado, N
   Fraile, M
   de Pablo, N
   Fernández, B
   Domínguez, F
   González, LO
   Vizoso, FJ
AF Eiro, Noemi
   Cid, Sandra
   Aguado, Nuria
   Fraile, Maria
   de Pablo, Nagore
   Fernandez, Berta
   Dominguez, Francisco
   Gonzalez, Luis O.
   Vizoso, Francisco J.
TI MMP1 and MMP11 Expression in Peripheral Blood Mononuclear Cells upon
   Their Interaction with Breast Cancer Cells and Fibroblasts
SO INTERNATIONAL JOURNAL OF MOLECULAR SCIENCES
LA English
DT Article
DE inflammation and cancer; inflammatory cells; stroma; breast cancer; PBMC
ID REGULATORY T-CELLS; MATRIX METALLOPROTEINASES; INFLAMMATORY CELLS;
   DUCTAL CARCINOMA; GENE-EXPRESSION; TUMOR-MARKERS; IN-SITU; INHIBITORS;
   INTERLEUKIN-10; LYMPHOCYTES
AB Tumor-infiltrating immune cells phenotype is associated with tumor progression. However, little is known about the phenotype of the peripheral blood mononuclear cells (PBMC) from breast cancer patients. We investigated MMP1 and MMP11 expression in PBMC from breast cancer patients and we analyzed gene expression changes upon their interaction with cancer cells and cancer-associated fibroblasts (CAF). We measured the impact of PBMC on proinflammatory gene expression in breast cancer cells, normal fibroblast (NF), and CAF and the impact on proliferation and invasiveness capacity of breast cancer cells. Gene expression of MMP1 and MMP11 in PBMC from breast cancer patients (n = 54) and control (n = 28); expression of IL1A, IL6, IL17, IFN beta, and NF kappa B in breast cancer cell lines (MCF-7 and MDA-MB-231); and, additionally, IL10 and MMP11 in CAF and NF were analyzed by qRT-PCR before and after co-culture. Our results show the existence of a subpopulation of breast cancer patients (25.9%) with very high levels of MMP11 gene expression in PBMC. Also, gene expression of MMP1 and MMP11 increases in PBMC after co-culture with breast cancer cell lines, NF or CAF. PBMC from healthy or breast cancer patients induce an increased proliferation rate on MCF-7 and an increased invasiveness capacity of MDA-MB-231. Finally, we show a differential expression profile of inflammatory genes in NF and CAF when co-cultured with control or breast cancer PBMC. We have observed that MMPs' expression in PBMC is regulated by the microenvironment, while the expression of inflammatory genes in NF or CAF is differentially regulated by PBMC. These findings confirm the importance of the crosstalk between stromal cells and suggest that PBMC would play a role in promoting aggressive tumor behavior.
C1 [Eiro, Noemi; Cid, Sandra; Fraile, Maria; de Pablo, Nagore; Vizoso, Francisco J.] Fdn Hosp Jove, Res Unit, Gijon 33290, Spain.
   [Aguado, Nuria] Hosp Univ San Agustin, Dept Surg, Aviles 33401, Spain.
   [Fernandez, Berta] Hosp Univ Cent Asturias, Dept Surg, Oviedo 33011, Spain.
   [Dominguez, Francisco] Hosp Univ Cabuenes, Dept Anat Pathol, Gijon 33394, Spain.
   [Gonzalez, Luis O.] Fdn Hosp Jove, Dept Anat Pathol, Gijon 33209, Spain.
   [Vizoso, Francisco J.] Fdn Hosp Jove, Dept Surg, Gijon 33290, Spain.
C3 Central University Hospital Asturias; Hospital Universitario de Cabuenes
RP Vizoso, FJ (corresponding author), Fdn Hosp Jove, Res Unit, Gijon 33290, Spain.; Vizoso, FJ (corresponding author), Fdn Hosp Jove, Dept Surg, Gijon 33290, Spain.
EM noemi.eiro@gmail.com; sandra.cid.89@gmail.com; n.aguadosuarez@gmail.com;
   maria.fraile82@gmail.com; nagoredep@gmail.com; mbertafergo@gmail.com;
   fdoig59@yahoo.es; a.patologica2@hospitaldejove.com;
   investigacion@hospitaldejove.com
RI Eiro, Noemi/HNC-3166-2023; GONZALEZ, LUIS/AAT-9362-2021; Fernández,
   Berta/K-5927-2014; De Pablo, Nagore/AFV-1794-2022; Dominguez,
   Francisco/AAA-7260-2020; Eiro, Noemi/C-9510-2018
OI Gonzalez, Luis O/0009-0009-2665-6458; De Pablo,
   Nagore/0000-0001-9675-7689; Vizoso, Francisco/0000-0002-2827-5511; Eiro,
   Noemi/0000-0001-5840-4807; Fraile, Maria/0000-0002-0092-7805
FU Instituto de Salud Carlos III [PI13/02745, PI17/02236]; European Union
   (ERDF/ESF, "Investing in your future"); Gobierno del Principado de
   Asturias "Severo Ochoa" PhD Program [BP14-128]
FX This research was funded by Instituto de Salud Carlos III, grant number
   PI13/02745 and PI17/02236, and co-funded by European Union (ERDF/ESF,
   "Investing in your future"). Sandra Cid was the recipient of a
   fellowship financed by the Gobierno del Principado de Asturias "Severo
   Ochoa" PhD Program under Grant BP14-128. The APC was funded by Instituto
   de Salud Carlos III through grant number PI17/02236.
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NR 43
TC 12
Z9 12
U1 0
U2 8
PU MDPI
PI BASEL
PA ST ALBAN-ANLAGE 66, CH-4052 BASEL, SWITZERLAND
EI 1422-0067
J9 INT J MOL SCI
JI Int. J. Mol. Sci.
PD JAN
PY 2021
VL 22
IS 1
AR 371
DI 10.3390/ijms22010371
PG 16
WC Biochemistry & Molecular Biology; Chemistry, Multidisciplinary
WE Science Citation Index Expanded (SCI-EXPANDED)
SC Biochemistry & Molecular Biology; Chemistry
GA PP9MI
UT WOS:000606177300001
PM 33396463
OA gold, Green Published
DA 2025-03-13
ER

PT J
AU Eiro, N
   González, L
   Martínez-Ordoñez, A
   Fernandez-Garcia, B
   González, L
   Cid, S
   Dominguez, F
   Perez-Fernandez, R
   Vizoso, FJ
AF Eiro, Noemi
   Gonzalez, Lucia
   Martinez-Ordonez, Anxo
   Fernandez-Garcia, Belen
   Gonzalez, Luis O.
   Cid, Sandra
   Dominguez, Francisco
   Perez-Fernandez, Roman
   Vizoso, Francisco J.
TI Cancer-associated fibroblasts affect breast cancer cell gene expression,
   invasion and angiogenesis
SO CELLULAR ONCOLOGY
LA English
DT Article
DE Cancer-associated fibroblasts; Breast cancer; Tumor invasion;
   Angiogenesis; MMP11
ID MONONUCLEAR INFLAMMATORY CELLS; ENDOTHELIAL GROWTH-FACTOR; TUMOR
   MICROENVIRONMENT; TGF-BETA; TISSUE INHIBITOR; PROGNOSTIC VALUE;
   METASTASIS; CARCINOMAS; INTERLEUKIN-8; SURVIVAL
AB It has been reported that stromal cell features may affect the clinical outcome of breast cancer patients. Cancer associated fibroblasts (CAFs) represent one of the most abundant cell types within the breast cancer stroma. Here, we aimed to explore the influence of CAFs on breast cancer gene expression, as well as on invasion and angiogenesis.
   qRT-PCR was used to evaluate the expression of several cancer progression related genes (S100A4, TGF beta, FGF2, FGF7, PDGFA, PDGFB, VEGFA, IL-6, IL-8, uPA, MMP2, MMP9, MMP11 and TIMP1) in the human breast cancer-derived cell lines MCF-7 and MDA-MB-231, before and after co-culture with CAFs. Stromal mononuclear inflammatory cell (MIC) MMP11 expression was used to stratify primary tumors. In addition, we assessed the in vitro effects of CAFs on both MDA-MB-231 breast cancer cell invasion and endothelial cell (HUVEC) tube formation.
   We found that the expression levels of most of the genes tested were significantly increased in both breast cancer-derived cell lines after co-culture with CAFs from either MMP11+ or MMP11- MIC tumors. IL-6 and IL-8 showed an increased expression in both cancer-derived cell lines after co-culture with CAFs from MMP11+ MIC tumors. We also found that the invasive and angiogenic capacities of, respectively, MDA-MB-231 and HUVEC cells were increased after co-culture with CAFs, especially those from MMP11+ MIC tumors.
   Our data indicate that tumor-derived CAFs can induce up-regulation of genes involved in breast cancer progression. Our data additionally indicate that CAFs, especially those derived from MMP11+ MIC tumors, can promote breast cancer cell invasion and angiogenesis.
C1 [Eiro, Noemi; Gonzalez, Lucia; Fernandez-Garcia, Belen; Gonzalez, Luis O.; Cid, Sandra; Vizoso, Francisco J.] Fdn Hosp Jove, Unidad Invest, Gijon 33290, Asturias, Spain.
   [Martinez-Ordonez, Anxo; Perez-Fernandez, Roman] Univ Santiago de Compostela, Dept Physiol CIMUS, Santiago De Compostela 15782, Spain.
   [Gonzalez, Luis O.] Fdn Hosp Jove, Serv Anat Patol, Gijon 33290, Asturias, Spain.
   [Dominguez, Francisco] Hosp Cabuenes, Serv Anat Patol, Gijon 33394, Asturias, Spain.
   [Vizoso, Francisco J.] Fdn Hosp Jove, Serv Cirugia Gen, Gijon 33290, Asturias, Spain.
C3 Universidade de Santiago de Compostela; Hospital Universitario de
   Cabuenes
RP Eiro, N; Vizoso, FJ (corresponding author), Fdn Hosp Jove, Unidad Invest, Gijon 33290, Asturias, Spain.; Vizoso, FJ (corresponding author), Fdn Hosp Jove, Serv Cirugia Gen, Gijon 33290, Asturias, Spain.
EM investigacion@hospitaldejove.com; investigacion@hospitaldejove.com
RI Ordóñez, Anxo/L-1196-2014; GONZALEZ, LUIS/AAT-9362-2021; Eiro,
   Noemi/HNC-3166-2023; Dominguez, Francisco/AAA-7260-2020; González,
   Lucía/F-2065-2016; Perez-Fernandez, Roman/L-6342-2014; Eiro,
   Noemi/C-9510-2018
OI Perez-Fernandez, Roman/0000-0002-5894-0615; Martinez-Ordonez,
   Anxo/0000-0001-9649-2967; Gonzalez, Luis O/0009-0009-2665-6458; Vizoso,
   Francisco/0000-0002-2827-5511; Eiro, Noemi/0000-0001-5840-4807;
   Gonzalez, Lucia/0000-0002-6732-8073
FU Instituto de Salud Carlos III [PI13/02745]; Consejeria de Economia y
   Empleo del Principado de Asturias [GRUPIN14-116]; Ministerio de Economia
   y Competividad [SAF2015-69221-R]; Ministerio de Educacion [FPU14/00548];
   Gobierno del Principado de Asturias "Severo Ochoa" PhD Program
   [BP14-128]
FX This work was supported by grants to F. V from the Instituto de Salud
   Carlos III (PI13/02745) and from the Consejeria de Economia y Empleo del
   Principado de Asturias (GRUPIN14-116), and to R.P-F. from the Ministerio
   de Economia y Competividad (SAF2015-69221-R). A.M-O. is a predoctoral
   fellow from the Ministerio de Educacion (FPU14/00548). S.C. was
   recipient of a predoctoral fellowship financed by the Gobierno del
   Principado de Asturias "Severo Ochoa" PhD Program (BP14-128).
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NR 40
TC 77
Z9 82
U1 1
U2 42
PU SPRINGER
PI DORDRECHT
PA VAN GODEWIJCKSTRAAT 30, 3311 GZ DORDRECHT, NETHERLANDS
SN 2211-3428
EI 2211-3436
J9 CELL ONCOL
JI Cell. Oncol.
PD AUG
PY 2018
VL 41
IS 4
BP 369
EP 378
DI 10.1007/s13402-018-0371-y
PG 10
WC Oncology; Cell Biology; Pathology
WE Science Citation Index Expanded (SCI-EXPANDED)
SC Oncology; Cell Biology; Pathology
GA GR3CV
UT WOS:000442467200003
PM 29497991
DA 2025-03-13
ER

PT J
AU Wang, BY
   Liu, W
   Liu, CS
   Du, KP
   Guo, ZZ
   Zhang, GQ
   Huang, Z
   Lin, SH
   Cen, BH
   Tian, YH
   Yuan, YW
   Bu, JG
AF Wang, Baiyao
   Liu, Wei
   Liu, Chunshan
   Du, Kunpeng
   Guo, Zhaoze
   Zhang, Guoqian
   Huang, Zhong
   Lin, Shuhui
   Cen, Bohong
   Tian, Yunhong
   Yuan, Yawei
   Bu, Junguo
TI BIOLOGY CONTRIBUTION Cancer-Associated Fibroblasts Promote
   Radioresistance of Breast Cancer Cells via the HGF/c-Met Signaling
   Pathway
SO INTERNATIONAL JOURNAL OF RADIATION ONCOLOGY BIOLOGY PHYSICS
LA English
DT Article
ID GROWTH-FACTOR-BETA; IONIZING-RADIATION; RADIOTHERAPY; INHIBITION;
   RESISTANCE; MICROENVIRONMENT; CHEMORESISTANCE; METASTASIS; MASTECTOMY;
   SURGERY
AB Purpose: Cancer-associated fibroblasts (CAFs) are an integral part of the tumor microenvironment (TME), which is involved in therapy resistance. This study aimed to investigate the role of CAFs in radiosensitivity of breast cancer cells. Methods and Materials: The CAFs were isolated from the breast cancer tissues, and the conditioned medium was collected to culture breast cancer cells. Radiation-induced DNA damage was evaluated by immunofluorescence and western blotting. Cytokine array and enzyme-linked immunosorbent assay were performed to analyze the secretion of cytokines and growth factors. An in vitro clonogenic survival assay and in vivo xenograft mouse model were performed to determine the radiosensitivity of breast cancer cells. Finally, the expression of hepatocyte growth factor (HGF) and c-Met in the breast cancer tissues were detected by immunohistochemistry. Results: The CAFs were found to secrete HGF to activate the c-Met signaling pathway, which induced epithelial-to-mesenchymal transition, growth, and radioresistance of breast cancer cells. Furthermore, radiation was observed to enhance HGF secretion by CAFs and increase c-Met expression in breast cancer cells, which led to HGF/c-Met signaling pathway activation. Moreover, radiation-induced tumor necrosis factor a (TNFa) secretion by breast cancer cells promoted CAF proliferation and HGF secretion. Additionally, HGF and c-Met high expression were associated with worse recurrence-free survival in patients with breast cancer who had received radiation therapy. Conclusions: The findings revealed that HGF and TNFa are critical for the crosstalk between breast cancer cells and CAFs in the TME and that the HGF/c-Met signaling pathway is a promising therapeutic target for radiosensitizing breast cancer. & COPY; 2023 The Authors. Published by Elsevier Inc. This is an open access article under the CC BY-NC-ND license (http://creativecommons.
C1 [Wang, Baiyao; Liu, Wei; Liu, Chunshan; Du, Kunpeng; Zhang, Guoqian; Huang, Zhong; Cen, Bohong; Tian, Yunhong; Yuan, Yawei] Guangzhou Med Univ, Dept Radiat Oncol, Affiliated Canc Hosp & Inst, Guangzhou, Guangdong, Peoples R China.
   [Guo, Zhaoze] Southern Med Univ, Nanfang Hosp, Breast Ctr, Dept Gen Surg, Guangzhou, Guangdong, Peoples R China.
   [Lin, Shuhui] Huazhong Univ Sci, Dept Oncol, Shenzhen, Guangdong, Peoples R China.
   [Lin, Shuhui] Nanshan Hosp, Technol Union Shenzhen Hosp, Shenzhen, Guangdong, Peoples R China.
   [Yuan, Yawei; Bu, Junguo] Guangdong Second Prov Gen Hosp, Dept Oncol, Guangzhou, Guangdong, Peoples R China.
C3 Guangzhou Medical University; Southern Medical University - China
RP Yuan, YW (corresponding author), Guangzhou Med Univ, Dept Radiat Oncol, Affiliated Canc Hosp & Inst, Guangzhou, Guangdong, Peoples R China.; Yuan, YW; Bu, JG (corresponding author), Guangdong Second Prov Gen Hosp, Dept Oncol, Guangzhou, Guangdong, Peoples R China.
EM yuanyawei@gzhmu.edu.cn; bujg@gd2h.org.cn
OI Guo, Zhaoze/0000-0001-8847-7740
FU National Natural Science Foundation of China [81872195, 82003210,
   2020028]; science and tech-nology projects of Shenzhen Nanshan District
   [2020028]; China Postdoctoral Science Foundation
FX This study was supported by the National Natural Science Foundation of
   China (Nos. 81773354, 81872195, and 82003210) , the science and
   tech-nology projects of Shenzhen Nanshan District (No. 2020028) , and
   the China Postdoctoral Science Foundation (No. 2021M700950) .
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NR 52
TC 21
Z9 21
U1 5
U2 26
PU ELSEVIER SCIENCE INC
PI NEW YORK
PA STE 800, 230 PARK AVE, NEW YORK, NY 10169 USA
SN 0360-3016
EI 1879-355X
J9 INT J RADIAT ONCOL
JI Int. J. Radiat. Oncol. Biol. Phys.
PD JUL 1
PY 2023
VL 116
IS 3
BP 640
EP 654
DI 10.1016/j.ijrobp.2022.12.029
EA JUN 2023
PG 15
WC Oncology; Radiology, Nuclear Medicine & Medical Imaging
WE Science Citation Index Expanded (SCI-EXPANDED)
SC Oncology; Radiology, Nuclear Medicine & Medical Imaging
GA P9DX0
UT WOS:001053618600001
PM 36586496
OA hybrid
DA 2025-03-13
ER

PT J
AU Shin, E
   Koo, JS
AF Shin, Eunah
   Koo, Ja Seung
TI Glucose Metabolism and Glucose Transporters in Breast Cancer
SO FRONTIERS IN CELL AND DEVELOPMENTAL BIOLOGY
LA English
DT Review
DE breast cancer; glucose metabolism; glucose transporter; pentose
   phosphate pathway; serine; glycine pathway
ID PENTOSE-PHOSPHATE PATHWAY; HYPOXIA-INDUCIBLE FACTOR-1-ALPHA;
   TUMOR-ASSOCIATED MACROPHAGES; ESTROGEN-RECEPTOR-ALPHA; PROMOTES
   CELL-PROLIFERATION; SMALL-MOLECULE INHIBITOR; PYRUVATE-KINASE M2;
   STEM-CELL; AEROBIC GLYCOLYSIS; SERINE SYNTHESIS
AB Breast cancer is the most common malignancy in women worldwide and is associated with high mortality rates despite the continuously advancing treatment strategies. Glucose is essential for cancer cell metabolism owing to the Warburg effect. During the process of glucose metabolism, various glycolytic metabolites, such as serine and glycine metabolites, are produced and other metabolic pathways, such as the pentose phosphate pathway (PPP), are associated with the process. Glucose is transported into the cell by glucose transporters, such as GLUT. Breast cancer shows high expressions of glucose metabolism-related enzymes and GLUT, which are also related to breast cancer prognosis. Triple negative breast cancer (TNBC), which is a high-grade breast cancer, is especially dependent on glucose metabolism. Breast cancer also harbors various stromal cells such as cancer-associated fibroblasts and immune cells as tumor microenvironment, and there exists a metabolic interaction between these stromal cells and breast cancer cells as explained by the reverse Warburg effect. Breast cancer is heterogeneous, and, consequently, its metabolic status is also diverse, which is especially affected by the molecular subtype, progression stage, and metastatic site. In this review, we will focus on glucose metabolism and glucose transporters in breast cancer, and we will additionally discuss their potential applications as cancer imaging tracers and treatment targets.</p>
C1 [Shin, Eunah; Koo, Ja Seung] Yonsei Univ, Coll Med, Dept Pathol, Seoul, South Korea.
C3 Yonsei University; Yonsei University Health System
RP Koo, JS (corresponding author), Yonsei Univ, Coll Med, Dept Pathol, Seoul, South Korea.
EM kjs1976@yuhs.ac
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NR 255
TC 95
Z9 101
U1 13
U2 99
PU FRONTIERS MEDIA SA
PI LAUSANNE
PA AVENUE DU TRIBUNAL FEDERAL 34, LAUSANNE, CH-1015, SWITZERLAND
SN 2296-634X
J9 FRONT CELL DEV BIOL
JI Front. Cell. Dev. Biol.
PD SEP 6
PY 2021
VL 9
AR 728759
DI 10.3389/fcell.2021.728759
PG 18
WC Cell Biology; Developmental Biology
WE Science Citation Index Expanded (SCI-EXPANDED)
SC Cell Biology; Developmental Biology
GA US6VG
UT WOS:000697564100001
PM 34552932
OA Green Published, gold
DA 2025-03-13
ER

PT J
AU Xu, J
   Lu, Y
   Qiu, SB
   Chen, ZN
   Fan, Z
AF Xu, Jing
   Lu, Yang
   Qiu, Songbo
   Chen, Zhi-Nan
   Fan, Zhen
TI A novel role of EMMPRIN/CD147 in transformation of quiescent fibroblasts
   to cancer-associated fibroblasts by breast cancer cells
SO CANCER LETTERS
LA English
DT Article
DE EMMPRIN/CD147; Cancer-associated fibroblasts; Epithelial-to-mesenchymal
   transition; alpha-SMA; Cancer stroma
ID COLLAGENASE-STIMULATING FACTOR; AUTOCRINE MOTILITY FACTOR; SMOOTH MUSCLE
   ACTIN; MESENCHYMAL TRANSITION; E-CADHERIN; CD147; EXPRESSION; CARCINOMA;
   INVASION; HAB18G/CD147
AB We tested the novel hypothesis that EMMPRIN/CD147, a transmembrane glycoprotein overexpressed in breast cancer cells, has a previously unknown role in transforming fibroblasts to cancer-associated fibroblasts, and that cancer-associated fibroblasts in turn induce epithelial-to-mesenchymal transition of breast cancer cells. Co-culture of fibroblasts with breast cancer cells or treatment of fibroblasts with breast cancer cell conditioned culture medium or recombinant EMMPRIN/CD147 induced expression of alpha-SMA in the fibroblasts in an EMMPRIN/CD147-dependent manner and promoted epithelial-to-mesenchymal transition of breast cancer cells and enhanced cell migration potential. These findings support a novel role of EMMPRIN/CD147 in regulating the interaction between cancer and stroma. (C) 2013 Elsevier Ireland Ltd. All rights reserved.
C1 [Xu, Jing; Lu, Yang; Qiu, Songbo; Fan, Zhen] Univ Texas MD Anderson Canc Ctr, Dept Expt Therapeut, Houston, TX 77030 USA.
   [Xu, Jing; Chen, Zhi-Nan] Fourth Mil Med Univ, Dept Cell Biol, Xian 710032, Peoples R China.
   [Xu, Jing; Chen, Zhi-Nan] Fourth Mil Med Univ, Natl Key Discipline Cell Biol, Cell Engn Res Ctr, State Key Lab Canc Biol, Xian 710032, Peoples R China.
C3 University of Texas System; UTMD Anderson Cancer Center; Air Force
   Military Medical University; Air Force Military Medical University
RP Chen, ZN (corresponding author), Fourth Mil Med Univ, Dept Cell Biol, 169 West Changle St, Xian 710032, Peoples R China.
EM znchen@fmmu.edu.cn; zfan@mdanderson.org
RI Xu, Jing/AAX-7869-2020
OI Xu, Jing/0000-0002-2035-3482; Chen, Zhi-Nan/0000-0001-5512-4623
FU US Department of Defense [W81XWH-11-1-0107]; Breast Cancer Research
   Foundation; China National Basic Research Program (the 973 Program)
   award [2009CB521704]; China National Natural Science Foundation
   [30800573]; NIH through MD Anderson's Cancer Center [CA016672]
FX This work was supported in part by US Department of Defense
   Congressionally Directed Medical Research Program award W81XWH-11-1-0107
   (to Z.F.), a Breast Cancer Research Foundation award (to Z.F.), China
   National Basic Research Program (the 973 Program) award 2009CB521704 (to
   Z-N.C.), and China National Natural Science Foundation award 30800573
   (to J.X.). The work was also supported in part by the NIH through MD
   Anderson's Cancer Center Support Grant, CA016672. We thank Stephanie
   Deming of the Department of Scientific Publications at The University of
   Texas MD Anderson Cancer Center for editorial assistance.
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NR 48
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Z9 35
U1 0
U2 25
PU ELSEVIER IRELAND LTD
PI CLARE
PA ELSEVIER HOUSE, BROOKVALE PLAZA, EAST PARK SHANNON, CO, CLARE, 00000,
   IRELAND
SN 0304-3835
EI 1872-7980
J9 CANCER LETT
JI Cancer Lett.
PD JUL 28
PY 2013
VL 335
IS 2
BP 380
EP 386
DI 10.1016/j.canlet.2013.02.054
PG 7
WC Oncology
WE Science Citation Index Expanded (SCI-EXPANDED)
SC Oncology
GA 168CE
UT WOS:000320682500015
PM 23474495
OA Green Accepted
DA 2025-03-13
ER

PT J
AU Jung, YY
   Lee, YK
   Koo, JS
AF Jung, Yoon Yang
   Lee, Yu Kyung
   Koo, Ja Seung
TI Expression of cancer-associated fibroblast-related proteins in adipose
   stroma of breast cancer
SO TUMOR BIOLOGY
LA English
DT Article
DE Adipocyte; Breast cancer; Cancer-associated fibroblast; Tumor stroma
ID ACTIVATION PROTEIN; TUMOR MICROENVIRONMENT; EXTRACELLULAR-MATRIX;
   COLON-CANCER; TENASCIN-C; CELLS; CARCINOMA; ALPHA; MYOFIBROBLASTS;
   INHIBITION
AB Cancer-associated fibroblasts (CAFs) play key roles in tumor microenvironment; they are thought to originate from adipocytes. This study aimed to evaluate CAF-related protein expression and its implications in breast cancer. Of the 939 enrolled breast cancer patients, 642 had fibrous and 297 had adipose stroma. The status of estrogen receptor, progesterone receptor, human epidermal growth factor receptor 2 (HER-2), Ki-67, podoplanin, prolyl 4-hydroxylase, fibroblast activation protein alpha (FAP alpha), S100A4, platelet-derived growth factor receptor alpha (PDGFR alpha), PDGFR beta, and chondroitin sulfate proteoglycan (NG2) was evaluated via tissue microarrays. Tumors were divided into luminal A, luminal B, HER-2, or triple-negative breast cancer subtypes according to their molecular status. Luminal A subtype was more prevalent in breast cancer of adipose stroma type, whereas other molecular subtypes were more common in fibrous stroma type (p < 0.001). Tumor cell expression of podoplanin and FAP alpha was higher in adipose stroma type, while higher expression of prolyl 4-hydroxylase and PDGFR alpha was observed in fibrous stroma type. Furthermore, adipose stroma type exhibited higher stromal expression of podoplanin, FAP alpha, PDGFR beta, and NG2, whereas fibrous stroma type had higher prolyl 4-hydroxylase and S100A4 expression. In adipose stroma type, tumor positivity (p = 0.034) and stromal positivity (p = 0.005) of prolyl 4-hydroxylase were associated with shorter disease-free survival, and stromal prolyl 4-hydroxylase positivity was with shorter overall survival (p < 0.001). In conclusion, expression of CAF-related proteins was observed in breast cancer, with different profiles between adipose and fibrous stroma types. Prolyl 4-hydrolase status might be of prognostic value in adipose stroma type.
C1 [Jung, Yoon Yang; Lee, Yu Kyung; Koo, Ja Seung] Yonsei Univ, Severance Hosp, Coll Med, Dept Pathol, Seoul 120752, South Korea.
C3 Yonsei University; Yonsei University Health System
RP Koo, JS (corresponding author), Yonsei Univ, Severance Hosp, Coll Med, Dept Pathol, 50 Yonsei Ro, Seoul 120752, South Korea.
EM kjs1976@yuhs.ac
RI Kim, Sun Jung/AAM-7334-2020; JUNG, YOON/T-3655-2019
OI koo, ja seung/0000-0003-4546-4709
FU National R&D Program for Cancer Control, Ministry of Health & Welfare,
   Republic of Korea [1420080]; Basic Science Research Program through the
   National Research Foundation of Korea (NRF) - Ministry-of Science, ICT,
   and Future Planning [2015R1A1A1A05001209]
FX This study was supported by a grant from the National R&D Program for
   Cancer Control, Ministry of Health & Welfare, Republic of Korea
   (1420080). This research was supported by the Basic Science Research
   Program through the National Research Foundation of Korea (NRF) funded
   by the Ministry-of Science, ICT, and Future Planning
   (2015R1A1A1A05001209).
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NR 34
TC 34
Z9 41
U1 0
U2 15
PU SPRINGER
PI DORDRECHT
PA VAN GODEWIJCKSTRAAT 30, 3311 GZ DORDRECHT, NETHERLANDS
SN 1010-4283
EI 1423-0380
J9 TUMOR BIOL
JI Tumor Biol.
PD NOV
PY 2015
VL 36
IS 11
BP 8685
EP 8695
DI 10.1007/s13277-015-3594-9
PG 11
WC Oncology
WE Science Citation Index Expanded (SCI-EXPANDED)
SC Oncology
GA CY1CA
UT WOS:000366143100056
PM 26044562
DA 2025-03-13
ER

PT J
AU Castillo-Sanchez, R
   Churruca-Schuind, A
   Martinez-Ival, M
   Salazar, EP
AF Castillo-Sanchez, Rocio
   Churruca-Schuind, Ander
   Martinez-Ival, Mileidy
   Perez Salazar, Eduardo
TI Cancer-associated Fibroblasts Communicate with Breast Tumor Cells
   Through Extracellular Vesicles in Tumor Development
SO TECHNOLOGY IN CANCER RESEARCH & TREATMENT
LA English
DT Review
DE cancer-associated fibroblasts; extracellular vesicles; breast cancer;
   stroma; microenvironment
ID MESENCHYMAL STEM-CELLS; MEMBRANE-VESICLES; ACTIVATED PLATELETS; STROMAL
   CELLS; EARLY-STAGE; IN-VITRO; EXOSOMES; MICROVESICLES; PROMOTES;
   MICROPARTICLES
AB Breast cancer is the leading cause of cancer death among women worldwide. In solid tumors, the microenvironment plays a critical role in tumor development, and it has been described a communication between the different cell types that conform the stroma, including fibroblasts, pericytes, adipocytes, immune cells and cancer-associated fibroblasts. Intercellular communication is bidirectional, complex, multifactorial and is mediated by the secretion of molecules and extracellular vesicles. The extracellular vesicles are vesicles limited by two membranes that are secreted by normal and cancer cells into the extracellular space. Extracellular vesicle cargo is complex and includes proteins, miRNAs, DNA and lipids, and their composition is specific to their parent cells. Extracellular vesicles are taken up for neighboring or distant cells. Particularly, extracellular vesicles from breast cancer cells are taken up for fibroblasts and it induces the activation of fibroblasts into cancer-associated fibroblasts. Interestingly, cancer associated fibroblasts release extracellular vesicles that are taken up for breast cancer cells and promote migration, invasion, proliferation, epithelial-mesenchymal transition, changes in metabolism, chemoresistance, evasion of immune system and remodeling of extracellular matrix. In addition, the enrichment of specific cargos in extracellular vesicles of breast cancer patients has been suggested to be used as biomarkers of the disease. Here we review the current literature about the intercommunication between tumor cells and cancer associated fibroblasts through extracellular vesicles in breast cancer.
C1 [Castillo-Sanchez, Rocio; Churruca-Schuind, Ander; Martinez-Ival, Mileidy; Perez Salazar, Eduardo] Cinvestav IPN, Dept Biol Celular, Av IPN 2508, Mexico City 07360, DF, Mexico.
C3 CINVESTAV - Centro de Investigacion y de Estudios Avanzados del
   Instituto Politecnico Nacional
RP Salazar, EP (corresponding author), Cinvestav IPN, Dept Biol Celular, Av IPN 2508, Mexico City 07360, DF, Mexico.
EM eduardo.perez@cinvestav.mx
RI Perez Salazar, Eduardo/HNS-4953-2023
OI Perez Salazar, Eduardo/0000-0002-3041-7902
FU CONACYT-Mexico
FX The authors disclosed receipt of the following financial support for the
   research, authorship, and/or publication of this article. Rocio
   CastilloSanchez was supported by a grant from CONACYT-Mexico.
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NR 134
TC 9
Z9 10
U1 1
U2 11
PU SAGE PUBLICATIONS INC
PI THOUSAND OAKS
PA 2455 TELLER RD, THOUSAND OAKS, CA 91320 USA
SN 1533-0346
EI 1533-0338
J9 TECHNOL CANCER RES T
JI Technol. Cancer Res. Treat.
PD OCT
PY 2022
VL 21
AR 15330338221131647
DI 10.1177/15330338221131647
PG 15
WC Oncology
WE Science Citation Index Expanded (SCI-EXPANDED)
SC Oncology
GA 5I9SZ
UT WOS:000868690700001
PM 36222020
OA Green Published, gold
DA 2025-03-13
ER

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   ten Dijke, Peter
TI Cancer-associated fibroblast-derived Gremlin 1 promotes breast cancer
   progression
SO BREAST CANCER RESEARCH
LA English
DT Article
DE Gremlin 1; Cancer-associated fibroblasts; Breast cancer; Invasion;
   Zebrafish
ID MORPHOGENETIC PROTEIN ANTAGONIST; TGF-BETA; COLORECTAL-CANCER; STROMAL
   CELLS; STEM-CELLS; METASTASIS; EXPRESSION; BINDING; IDENTIFICATION;
   INFLAMMATION
AB Background Bone morphogenetic proteins (BMPs) have been reported to maintain epithelial integrity and to antagonize the transforming growth factor beta (TGF beta)-induced epithelial to mesenchymal transition. The expression of soluble BMP antagonists is dysregulated in cancers and interrupts proper BMP signaling in breast cancer. Methods In this study, we mined the prognostic role of BMP antagonists GREMLIN 1 (GREM1) in primary breast cancer tissues using in-house and publicly available datasets. We determined which cells express GREM1 RNA using in situ hybridization (ISH) on a breast cancer tissue microarray. The effects of Grem1 on the properties of breast cancer cells were assessed by measuring the mesenchymal/stem cell marker expression and functional cell-based assays for stemness and invasion. The role of Grem1 in breast cancer-associated fibroblast (CAF) activation was measured by analyzing the expression of fibroblast markers, phalloidin staining, and collagen contraction assays. The role of Grem1 in CAF-induced breast cancer cell intravasation and extravasation was studied by utilizing xenograft zebrafish breast cancer (co-) injection models. Results Expression analysis of clinical breast cancer datasets revealed that high expression of GREM1 in breast cancer stroma is correlated with a poor prognosis regardless of the molecular subtype. The large majority of human breast cancer cell lines did not express GREM1 in vitro, but breast CAFs did express GREM1 both in vitro and in vivo. Transforming growth factor beta (TGF beta) secreted by breast cancer cells, and also inflammatory cytokines, stimulated GREM1 expression in CAFs. Grem1 abrogated bone morphogenetic protein (BMP)/SMAD signaling in breast cancer cells and promoted their mesenchymal phenotype, stemness, and invasion. Moreover, Grem1 production by CAFs strongly promoted the fibrogenic activation of CAFs and promoted breast cancer cell intravasation and extravasation in co-injection xenograft zebrafish models. Conclusions Our results demonstrated that Grem1 is a pivotal factor in the reciprocal interplay between breast cancer cells and CAFs, which promotes cancer cell invasion. Targeting Grem1 could be beneficial in the treatment of breast cancer patients with high Grem1 expression.
C1 [Ren, Jiang; van Dam, Hans; ten Dijke, Peter] Leiden Univ, Oncode Inst, Dept Cell & Chem Biol, Med Ctr, Einthovenweg 20, NL-2333 ZC Leiden, Netherlands.
   [Smid, Marcel; Martens, John W. M.] Erasmus Univ, Erasmus MC Canc Inst, Dept Med Oncol, Med Ctr, Rotterdam, Netherlands.
   [Iaria, Josephine; Zhu, Hong Jian] Univ Melbourne, Royal Melbourne Hosp, Dept Surg, Parkville, Vic, Australia.
   [Salvatori, Daniela C. F.] Leiden Univ, Cent Lab Anim Facil, Med Ctr, Leiden, Netherlands.
C3 Leiden University; Leiden University Medical Center (LUMC); Leiden
   University - Excl LUMC; Erasmus University Rotterdam; Erasmus MC;
   Erasmus MC Cancer Institute; Melbourne Health; Royal Melbourne Hospital;
   University of Melbourne; Leiden University - Excl LUMC; Leiden
   University; Leiden University Medical Center (LUMC)
RP ten Dijke, P (corresponding author), Leiden Univ, Oncode Inst, Dept Cell & Chem Biol, Med Ctr, Einthovenweg 20, NL-2333 ZC Leiden, Netherlands.
EM p.ten_dijke@lumc.nl
RI Salvatori, Damiano/KEH-2624-2024; ten Dijke, Peter/AAG-4660-2021
OI Zhu, Hong-Jian/0000-0002-1478-995X; Salvatori,
   Daniela/0009-0005-3006-8502; ten Dijke, Peter/0000-0002-7234-342X; van
   Dam, Hans/0000-0002-8307-4325; Smid, Marcel/0000-0003-0605-1901
FU Cancer GenomiCs.nl (CGC.nl); China Scholarship Council (CSC)
FX This research was supported by Cancer GenomiCs.nl (CGC.nl). Jiang Ren
   was supported by The China Scholarship Council (CSC) during his PhD
   study at Leiden University Medical Center.
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NR 61
TC 99
Z9 107
U1 0
U2 31
PU BMC
PI LONDON
PA CAMPUS, 4 CRINAN ST, LONDON N1 9XW, ENGLAND
SN 1465-5411
EI 1465-542X
J9 BREAST CANCER RES
JI Breast Cancer Res.
PD SEP 18
PY 2019
VL 21
IS 1
AR 109
DI 10.1186/s13058-019-1194-0
PG 19
WC Oncology
WE Science Citation Index Expanded (SCI-EXPANDED)
SC Oncology
GA IZ3YY
UT WOS:000487022700003
PM 31533776
OA gold, Green Published
DA 2025-03-13
ER

PT J
AU Masjedi, A
   Hashemi, V
   Hojjat-Farsangi, M
   Ghalamfarsa, G
   Azizi, G
   Yousefi, M
   Jadidi-Niaragh, F
AF Masjedi, Ali
   Hashemi, Vida
   Hojjat-Farsangi, Mohammad
   Ghalamfarsa, Ghasem
   Azizi, Gholamreza
   Yousefi, Mehdi
   Jadidi-Niaragh, Farhad
TI The significant role of interleukin-6 and its signaling pathway in the
   immunopathogenesis and treatment of breast cancer
SO BIOMEDICINE & PHARMACOTHERAPY
LA English
DT Review
DE Interleukin-6; interleukin-6 receptor; Breast cancer; Treatment
ID ANTI-INTERLEUKIN-6 MONOCLONAL-ANTIBODY; SMALL-MOLECULE INHIBITOR;
   CONSTITUTIVE ACTIVATION; NONPEPTIDE ANTAGONIST; THERAPEUTIC TARGET;
   TUMOR ANGIOGENESIS; RECEPTOR ANTIBODY; ESTROGEN-RECEPTOR;
   SUPPRESSOR-CELLS; MULTIPLE-MYELOMA
AB Despite remarkable improvements in cancer treatment approaches, breast cancer is still the main cause of cancer-related death in women. Its principal cause is the resistance of the cancer cells against conventional anticancer therapeutics, mainly in advanced disease stages. It has been shown that chronic inflammation in the tumor microenvironment facilitates tumor growth and induces resistance toward chemo- and radiotherapy. Overexpression of interleukin-6 (IL-6) cytokine in the tumor microenvironment has been demonstrated in numerous tumors including breast cancer. Tumor cells and tumor-associated fibroblasts are the major sources of IL-6 secretion in the tumor microenvironment. Several studies have demonstrated the immunopathogenic function of IL-6 and its signaling in the tumor growth, metastasis, and therapeutic resistance in the breast cancer. Therefore, it seems that targeting IL-6 and/or its receptor in combination with other potent anticancer therapies may be a potent therapeutic approach for breast cancer therapy.
C1 [Masjedi, Ali; Yousefi, Mehdi] Tabriz Univ Med Sci, Drug Appl Res Ctr, Tabriz, Iran.
   [Masjedi, Ali; Yousefi, Mehdi; Jadidi-Niaragh, Farhad] Tabriz Univ Med Sci, Fac Med, Dept Immunol, Tabriz, Iran.
   [Masjedi, Ali] Tabriz Univ Med Sci, Student Res Comm, Tabriz, Iran.
   [Hashemi, Vida] Maragheh Univ Med Sci, Fac Med, Dept Basic Sci, Maragheh, Iran.
   [Hojjat-Farsangi, Mohammad] Karolinska Univ Hosp Solna, Immune & Gene Therapy Lab,Dept Oncolpathol, CCK, Stockholm, Sweden.
   [Hojjat-Farsangi, Mohammad] Karolinska Inst, Stockholm, Sweden.
   [Hojjat-Farsangi, Mohammad] Bushehr Univ Med Sci, Sch Med, Dept Immunol, Bushehr, Iran.
   [Ghalamfarsa, Ghasem] Yasuj Univ Med Sci, Cellular & Mol Res Ctr, Yasuj, Iran.
   [Azizi, Gholamreza] Alborz Univ Med Sci, Noncommunicable Dis Res Ctr, Karaj, Iran.
   [Jadidi-Niaragh, Farhad] Tabriz Univ Med Sci, Immunol Res Ctr, Tabriz, Iran.
C3 Tabriz University of Medical Science; Tabriz University of Medical
   Science; Tabriz University of Medical Science; Karolinska Institutet;
   Karolinska University Hospital; Karolinska Institutet; Yasouj
   University; Tabriz University of Medical Science
RP Jadidi-Niaragh, F (corresponding author), Tabriz Univ Med Sci, Immunol Res Ctr, Tabriz, Iran.
EM jadidif@tbzmed.ac.ir
RI Ghalamfarsa, Ghasem/M-5790-2017; yousefi, mehdi/HHZ-3147-2022;
   Jadidi-Niaragh, Farhad/D-3985-2017; Masjedi, Ali/AAB-6293-2019; Azizi,
   Gholamreza/B-9477-2018; Hojat Farsangi, Mohammad/E-8171-2018
OI Jadidi-Niaragh, Farhad/0000-0002-4641-882X; Yousefi,
   Mehdi/0000-0003-0099-6728; Azizi, Gholamreza/0000-0001-5658-2511; Hojat
   Farsangi, Mohammad/0000-0002-0589-5523; Masjedi, Ali/0000-0002-7692-0925
FU National Institute for Medical Research Development (NIMAD) [972850]
FX None of the authors has any conflict of interest to declare. This study
   was supported in part by grant no. 972850 from National Institute for
   Medical Research Development (NIMAD).
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NR 136
TC 198
Z9 208
U1 5
U2 37
PU ELSEVIER FRANCE-EDITIONS SCIENTIFIQUES MEDICALES ELSEVIER
PI ISSY-LES-MOULINEAUX
PA 65 RUE CAMILLE DESMOULINS, CS50083, 92442 ISSY-LES-MOULINEAUX, FRANCE
SN 0753-3322
EI 1950-6007
J9 BIOMED PHARMACOTHER
JI Biomed. Pharmacother.
PD DEC
PY 2018
VL 108
BP 1415
EP 1424
DI 10.1016/j.biopha.2018.09.177
PG 10
WC Medicine, Research & Experimental; Pharmacology & Pharmacy
WE Science Citation Index Expanded (SCI-EXPANDED)
SC Research & Experimental Medicine; Pharmacology & Pharmacy
GA HA2UZ
UT WOS:000450101800159
PM 30372844
OA hybrid
HC Y
HP N
DA 2025-03-13
ER

PT J
AU Li, XH
   Zhou, J
   Xiao, MM
   Zhao, LY
   Zhao, Y
   Wang, SS
   Gao, SS
   Zhuang, Y
   Niu, Y
   Li, SJ
   Li, XB
   Zhu, YY
   Zhang, MH
   Tang, J
AF Li, Xinhui
   Zhou, Jian
   Xiao, Mingming
   Zhao, Lingyu
   Zhao, Yan
   Wang, Shuoshuo
   Gao, Shuangshu
   Zhuang, Yuan
   Niu, Yi
   Li, Shijun
   Li, Xiaobo
   Zhu, Yuanyuan
   Zhang, Minghui
   Tang, Jing
TI Uncovering the Subtype-Specific Molecular Characteristics of Breast
   Cancer by Multiomics Analysis of Prognosis-Associated Genes, Driver
   Genes, Signaling Pathways, and Immune Activity
SO FRONTIERS IN CELL AND DEVELOPMENTAL BIOLOGY
LA English
DT Article
DE breast cancer; molecular subtypes; driver gene; immune infiltration;
   prognosis
ID TUMOR MUTATION BURDEN; CELL INFILTRATION; LANDSCAPE; PORTRAITS
AB Breast cancer is a heterogeneous malignant disease with different prognoses and has been divided into four molecular subtypes. It is believed that molecular events occurring in breast stem/progenitor cells contribute to the carcinogenesis and development of different breast cancer subtypes. However, these subtype-specific molecular characteristics are largely unknown. In this study, we employed 1217 breast cancer samples from The Cancer Genome Atlas (TCGA) database for a multiomics analysis of the molecular characteristics of different breast cancer subtypes based on PAM50 algorithms. We detected the expression changes of subtype-specific genes and revealed that the expression of particular subtype-specific genes significantly affected prognosis. We also investigated the mutations and copy number variations (CNVs) of breast cancer driver genes and the representative genes of ten signaling pathways in different subtypes and revealed several subtype-specifically altered genes. Moreover, we detected the infiltration of various immune cells in different subtypes of breast cancer and showed that the infiltration levels of major immune cell types are different among these subtypes. Additionally, we investigated the factors affecting the immune infiltration level and the immune cytolytic activity in different breast cancer subtypes, namely, the mutation burden, genome instability and cancer-associated fibroblast (CAF) infiltration. This study may shed light on the molecular events contributing to carcinogenesis and development and provide potential markers and targets for the clinical diagnosis and treatment of different breast cancer subtypes.
C1 [Li, Xinhui] Harbin Med Univ, Coll Bioinformat Sci & Technol, Harbin, Peoples R China.
   [Zhou, Jian] Southern Univ Sci & Technol, Sch Med, Shenzhen, Peoples R China.
   [Xiao, Mingming] Peoples Hosp Liaoning Prov, Dept Pathol, Shenyang, Peoples R China.
   [Zhao, Lingyu; Wang, Shuoshuo; Gao, Shuangshu; Zhuang, Yuan; Li, Xiaobo; Zhu, Yuanyuan; Tang, Jing] Harbin Med Univ, Dept Pathol, Harbin, Peoples R China.
   [Zhao, Yan; Niu, Yi; Zhang, Minghui] Chifeng City Hosp, Dept Oncol, Chifeng, Peoples R China.
   [Li, Shijun] Chifeng City Hosp, Dept Pathol, Chifeng, Peoples R China.
C3 Harbin Medical University; Southern University of Science & Technology;
   Harbin Medical University
RP Zhu, YY; Tang, J (corresponding author), Harbin Med Univ, Dept Pathol, Harbin, Peoples R China.; Zhang, MH (corresponding author), Chifeng City Hosp, Dept Oncol, Chifeng, Peoples R China.
EM yuanyuanzhu0214@163.com; cfzhangminghui@163.com; jinghmu@163.com
RI Jing, Tang/JLM-8180-2023; zhu, yuanyuan/HKN-9839-2023; Zhou,
   yin/HGE-2329-2022; zhao, Yanxia/AAV-8756-2021
FU Natural Science Foundation of Inner Mongolia [2020MS08084]; Inner
   Mongolia Science & Technology Plan Project [201802133, 2020GG0297]
FX This study was supported by the Natural Science Foundation of Inner
   Mongolia (No. 2020MS08084 to MZ) and the Inner Mongolia Science &
   Technology Plan Project (Nos. 201802133 and 2020GG0297 to MZ).
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NR 35
TC 14
Z9 15
U1 2
U2 24
PU FRONTIERS MEDIA SA
PI LAUSANNE
PA AVENUE DU TRIBUNAL FEDERAL 34, LAUSANNE, CH-1015, SWITZERLAND
SN 2296-634X
J9 FRONT CELL DEV BIOL
JI Front. Cell. Dev. Biol.
PD JUL 1
PY 2021
VL 9
AR 689028
DI 10.3389/fcell.2021.689028
PG 13
WC Cell Biology; Developmental Biology
WE Science Citation Index Expanded (SCI-EXPANDED)
SC Cell Biology; Developmental Biology
GA TJ5YL
UT WOS:000673556700001
PM 34277633
OA Green Published, gold
DA 2025-03-13
ER

PT J
AU Yu, Y
   Xiao, CH
   Tan, LD
   Wang, QS
   Li, XQ
   Feng, YM
AF Yu, Y.
   Xiao, C-H
   Tan, L-D
   Wang, Q-S
   Li, X-Q
   Feng, Y-M
TI Cancer-associated fibroblasts induce epithelial-mesenchymal transition
   of breast cancer cells through paracrine TGF-β signalling
SO BRITISH JOURNAL OF CANCER
LA English
DT Article
DE CAFs; TGF-beta; EMT; breast cancer
ID STROMAL FIBROBLASTS; EXPRESSION; GROWTH; ACTIVATION; PROMOTE; MODEL
AB Background: Cancer-associated fibroblasts (CAFs) activated by tumour cells are the predominant type of stromal cells in breast cancer tissue. The reciprocal effect of CAFs on breast cancer cells and the underlying molecular mechanisms are not fully characterised.
   Methods: Stromal fibroblasts were isolated from invasive breast cancer tissues and the conditioned medium of cultured CAFs (CAF-CM) was collected to culture the breast cancer cell lines MCF-7, T47D and MDA-MB-231. Neutralising antibody and small-molecule inhibitor were used to block the transforming growth factor-beta (TGF-beta) signalling derived from CAF-CM, which effect on breast cancer cells.
   Results: The stromal fibroblasts isolated from breast cancer tissues showed CAF characteristics with high expression levels of alpha-smooth muscle actin and SDF1/CXCL12. The CAF-CM transformed breast cancer cell lines into more aggressive phenotypes, including enhanced cell-extracellular matrix adhesion, migration and invasion, and promoted epithelial-mesenchymal transition (EMT). Cancer-associated fibroblasts secreted more TGF-beta 1 than TGF-beta 2 and TGF-beta 3, and activated the TGF-beta/Smad signalling pathway in breast cancer cells. The EMT phenotype of breast cancer cells induced by CAF-CM was reversed by blocking TGF-beta 1 signalling.
   Conclusion: Cancer-associated fibroblasts promoted aggressive phenotypes of breast cancer cells through EMT induced by paracrine TGF-beta 1. This might be a common mechanism for acquiring metastatic potential in breast cancer cells with different biological characteristics.
C1 [Yu, Y.; Tan, L-D; Wang, Q-S; Li, X-Q; Feng, Y-M] Tianjin Med Univ Canc Inst & Hosp, Dept Biochem & Mol Biol, Natl Clin Res Ctr Canc, Tianjin 300060, Peoples R China.
   [Xiao, C-H] Tianjin Med Univ Canc Inst & Hosp, Dept Breast Surg, Natl Clin Res Ctr Canc, Tianjin 300060, Peoples R China.
   [Xiao, C-H; Wang, Q-S; Li, X-Q; Feng, Y-M] Tianjin Med Univ Canc Inst & Hosp, Key Lab Breast Canc Prevent & Treatment, Natl Clin Res Ctr Canc, Minist Educ, Tianjin 300060, Peoples R China.
C3 Tianjin Medical University; Tianjin Medical University; Tianjin Medical
   University
RP Feng, YM (corresponding author), Tianjin Med Univ Canc Inst & Hosp, Dept Biochem & Mol Biol, Natl Clin Res Ctr Canc, Huan Hu Xi Rd, Tianjin 300060, Peoples R China.
EM ymfeng@tijmu.edu.cn
RI Li, Xiao-Qing/HKO-4048-2023; Yu, Yue/AAG-8381-2020
OI Li, Xiao-Qing/0000-0002-9815-6040
FU National Natural Science Foundation of China [30872518, 81272357]; Major
   Program of Applied Basic Research Projects of Tianjin [09JCZDJC19800,
   13JCZDJC30100]
FX This work was supported by the National Natural Science Foundation of
   China (No. 30872518 and No. 81272357), the Major Program of Applied
   Basic Research Projects of Tianjin (No. 09JCZDJC19800 and No.
   13JCZDJC30100).
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TC 507
Z9 579
U1 11
U2 185
PU NATURE PUBLISHING GROUP
PI LONDON
PA MACMILLAN BUILDING, 4 CRINAN ST, LONDON N1 9XW, ENGLAND
SN 0007-0920
EI 1532-1827
J9 BRIT J CANCER
JI Br. J. Cancer
PD FEB 4
PY 2014
VL 110
IS 3
BP 724
EP 732
DI 10.1038/bjc.2013.768
PG 9
WC Oncology
WE Science Citation Index Expanded (SCI-EXPANDED)
SC Oncology
GA AA6RT
UT WOS:000331226400022
PM 24335925
OA Green Published, hybrid
HC Y
HP N
DA 2025-03-13
ER

PT J
AU Musielak, M
   Piwocka, O
   Kulcenty, K
   Ampula, K
   Adamczyk, B
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   Suchorska, WM
   Malicki, J
AF Musielak, Marika
   Piwocka, Oliwia
   Kulcenty, Katarzyna
   Ampula, Karolina
   Adamczyk, Beata
   Piotrowski, Igor
   Fundowicz, Magdalena
   Kruszyna-Mochalska, Marta
   Suchorska, Wiktoria M.
   Malicki, Julian
TI Biological heterogeneity of primary cancer-associated fibroblasts
   determines the breast cancer microenvironment
SO AMERICAN JOURNAL OF CANCER RESEARCH
LA English
DT Article
DE Cancer associated fibroblasts; tumor microenvironment; breast cancer;
   primary cell lines; oncology
ID MESENCHYMAL STROMAL CELLS; TUMOR MICROENVIRONMENT; DRUG-RESISTANCE;
   ACTIVATION; MYOFIBROBLASTS; ENVIRONMENT; TRANSITION; SUBTYPES; IL-6
AB Cancer-associated fibroblasts are a highly heterogeneous group of cells whose phenotypes and gene alterations are still under deep investigation. As a part of tumor microenvironment, they are the focus of a growing number of studies. Cancer-associated fibroblasts might become a new target of breast cancer therapy, but still more tests and analyses are needed to understand mechanisms and interactions between them and breast cancer cells. The study aimed to isolate cancer associated fibroblasts from breast cancer tissue and to phenotype the isolated cell lines. We focused on various cancer-associated fibroblast characteristic biomarkers and those that might differentiate various cancer-associated fibroblasts' subtypes. Patients with a histological diagnosis of invasive breast cancer (diameter & LE;15 mm) and qualified for primary surgical treatment were enrolled in the study. Cell lines were isolated from breast cancer biopsy. For the phenotyping, we used flow cytometry, immunofluorescence and RT-qPCR analysis. Based on our study, there was no indication of a clear pattern in the cancer-associated fibroblasts' classification. Results of cancer-associated fibroblasts expression were highly heterogeneous, and specific subtypes were not defined. Moreover, comparing cancer-associated fibroblasts divided into groups based on BC subtypes from which they were isolated also did not allow to notice of any clear pattern of expressions. In the future, a higher number of analyzed cancer-associated fibroblast cell lines should be investigated to find expression schemes.
C1 [Musielak, Marika; Piotrowski, Igor; Kruszyna-Mochalska, Marta; Suchorska, Wiktoria M.; Malicki, Julian] Poznan Univ Med Sci, Dept Electroradiol, Poznan, Poland.
   [Musielak, Marika] Poznan Univ Med Sci, Doctoral Sch, Poznan, Poland.
   [Musielak, Marika; Piwocka, Oliwia; Kulcenty, Katarzyna; Ampula, Karolina; Piotrowski, Igor; Suchorska, Wiktoria M.] Greater Poland Canc Ctr, Dept Med Phys, Radiobiol Lab, Poznan, Poland.
   [Piwocka, Oliwia; Ampula, Karolina] Adam Mickiewicz Univ, Fac Biol, Poznan, Poland.
   [Adamczyk, Beata] Greater Poland Canc Ctr, Breast Surg Oncol Dept, Poznan, Poland.
   [Fundowicz, Magdalena] Greater Poland Canc Ctr, Radiotherapy Ward I, Poznan, Poland.
   [Kruszyna-Mochalska, Marta; Malicki, Julian] Greater Poland Canc Ctr, Med Phys Dept, Poznan, Poland.
C3 Poznan University of Medical Sciences; Poznan University of Medical
   Sciences; Wielkopolskie Centrum Onkologii; Adam Mickiewicz University;
   Wielkopolskie Centrum Onkologii; Wielkopolskie Centrum Onkologii;
   Wielkopolskie Centrum Onkologii
RP Musielak, M (corresponding author), Poznan Univ Med Sci, Dept Electroradiol, Poznan, Poland.
EM mari-ka.musielak@wco.pl
RI Suchorska, Wiktoria/CAG-0479-2022; Kruszyna-Mochalska,
   Marta/HNB-6117-2023; Malicki, Julian/Q-7606-2017
OI Piwocka, Oliwia/0000-0001-7343-9872
FU National Science Centre Poland;  [2019/35/B/NZ7/04342]
FX Acknowledgements The author obtained funds for the preparation of a
   doctoral dissertation from the National Science Centre Poland as part of
   financing a doctoral scholarship on the basis of decision number
   DEC-2019/35/B/NZ7/04342. This re-search was funded by the National
   Science Centre Poland (grant number: 2019/35/B/NZ7/04342) .
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NR 59
TC 7
Z9 7
U1 1
U2 8
PU E-CENTURY PUBLISHING CORP
PI MADISON
PA 40 WHITE OAKS LN, MADISON, WI 53711 USA
SN 2156-6976
J9 AM J CANCER RES
JI Am. J. Cancer Res.
PY 2022
VL 12
IS 9
BP 4411
EP 4427
PG 17
WC Oncology
WE Science Citation Index Expanded (SCI-EXPANDED)
SC Oncology
GA 5B4KY
UT WOS:000863540900021
PM 36225645
DA 2025-03-13
ER

PT J
AU Brechbuhl, HM
   Finlay-Schultz, J
   Yamamoto, TM
   Gillen, AE
   Cittelly, DM
   Tan, AC
   Sams, SB
   Pillai, MM
   Elias, AD
   Robinson, WA
   Sartorius, CA
   Kabos, P
AF Brechbuhl, Heather M.
   Finlay-Schultz, Jessica
   Yamamoto, Tomomi M.
   Gillen, Austin E.
   Cittelly, Diana M.
   Tan, Aik-Choon
   Sams, Sharon B.
   Pillai, Manoj M.
   Elias, Anthony D.
   Robinson, William A.
   Sartorius, Carol A.
   Kabos, Peter
TI Fibroblast Subtypes Regulate Responsiveness of Luminal Breast Cancer to
   Estrogen
SO CLINICAL CANCER RESEARCH
LA English
DT Article
ID GROWTH-FACTOR RECEPTOR; EVEROLIMUS PLUS EXEMESTANE; PROGRESSION-FREE
   SURVIVAL; TAMOXIFEN RESISTANCE; ENDOCRINE THERAPY;
   PROGNOSTIC-SIGNIFICANCE; CD10 EXPRESSION; DOWN-REGULATION;
   POOR-PROGNOSIS; GENE SIGNATURE
AB Purpose: Antiendocrine therapy remains the most effective treatment for estrogen receptor-positive (ER+) breast cancer, but development of resistance is a major clinical complication. Effective targeting of mechanisms that control the loss of ER dependency in breast cancer remains elusive. We analyzed breast cancer-associated fibroblasts (CAF), the largest component of the tumor microenvironment, as a factor contributing to ER expression levels and antiendocrine resistance. Experimental Design: Tissues from patients with ER+ breast cancer were analyzed for the presence of CD146-positive (CD146pos) and CD146-negative (CD146neg) fibroblasts. ERdependent proliferation and tamoxifen sensitivity were evaluated in ER+ tumor cells cocultured with CD146pos or CD146neg fibroblasts. RNA sequencing was used to develop a highconfidence gene signature that predicts for disease recurrence in tamoxifen-treated patients with ER+ breast cancer.
   Results: We demonstrate that ER+ breast cancers contain two CAF subtypes defined by CD146 expression. CD146neg CAFs suppress ER expression in ER+ breast cancer cells, decrease tumor cell sensitivity to estrogen, and increase tumor cell resistance to tamoxifen therapy. Conversely, the presence of CD146pos CAFs maintains ER expression in ER+ breast cancer cells and sustains estrogen-dependent proliferation and sensitivity to tamoxifen. Conditioned media from CD146pos CAFs with tamoxifen-resistant breast cancer cells are sufficient to restore tamoxifen sensitivity. Gene expression profiles of patient breast tumors with predominantly CD146neg CAFs correlate with inferior clinical response to tamoxifen and worse patient outcomes.
   Conclusions: Our data suggest that CAF composition contributes to treatment response and patient outcomes in ER+ breast cancer and should be considered a target for drug development.
C1 [Brechbuhl, Heather M.; Yamamoto, Tomomi M.; Gillen, Austin E.; Tan, Aik-Choon; Elias, Anthony D.; Robinson, William A.; Kabos, Peter] Univ Colorado Denver, Dept Med, Div Med Oncol, Aurora, CO 80045 USA.
   [Finlay-Schultz, Jessica; Cittelly, Diana M.; Sams, Sharon B.; Sartorius, Carol A.] Univ Colorado Denver, Dept Pathol, Aurora, CO USA.
   [Pillai, Manoj M.] Yale Canc Ctr, Div Hematol, Sect Hematol, New Haven, CT USA.
   [Pillai, Manoj M.] Yale Univ, Sch Med, New Haven, CT USA.
C3 Children's Hospital Colorado; University of Colorado System; University
   of Colorado Anschutz Medical Campus; Children's Hospital Colorado;
   University of Colorado System; University of Colorado Anschutz Medical
   Campus; Yale University; Yale New Haven Hospital; Yale University
RP Brechbuhl, HM (corresponding author), Univ Colorado Denver, Dept Med, Div Med Oncol, Aurora, CO 80045 USA.; Kabos, P (corresponding author), Univ Colorado, Anschutz Med Campus,12801 E 17th Ave MS 8117, Aurora, CO 80045 USA.
EM heather.brechbuhl@ucdenver.edu; Peter.Kabos@ucdenver.edu
RI ; Tan, Aik Choon/A-3135-2011
OI Robinson, William/0000-0003-1875-9691; Finlay-Schultz,
   Jessica/0000-0002-7855-9870; Cittelly, Diana/0000-0002-8392-0800; Tan,
   Aik Choon/0000-0003-2955-8369; Gillen, Austin/0000-0003-2928-6308
FU NIH [NCI CA164048, CA205044, HL104070, CA140985]; Grohne Fund for Stem
   Cell Research for Breast Cancer; Cancer League of Colorado; University
   of Colorado Cancer Center's Flow Cytometry Shared Resource - NCI
   [P30CA046934]
FX This work was supported in part by NIH (NCI CA164048 and CA205044 to P.
   Kabos, HL104070 to M. Pillai, and CA140985 to C. Sartorius), Grohne Fund
   for Stem Cell Research for Breast Cancer (to P. Kabos), and the Cancer
   League of Colorado (to P. Kabos). Additional support was provided in
   part by the University of Colorado Cancer Center's Flow Cytometry Shared
   Resource funded by NCI grant P30CA046934.
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NR 53
TC 164
Z9 181
U1 0
U2 14
PU AMER ASSOC CANCER RESEARCH
PI PHILADELPHIA
PA 615 CHESTNUT ST, 17TH FLOOR, PHILADELPHIA, PA 19106-4404 USA
SN 1078-0432
EI 1557-3265
J9 CLIN CANCER RES
JI Clin. Cancer Res.
PD APR 1
PY 2017
VL 23
IS 7
BP 1710
EP 1721
DI 10.1158/1078-0432.CCR-15-2851
PG 12
WC Oncology
WE Science Citation Index Expanded (SCI-EXPANDED)
SC Oncology
GA EQ7KK
UT WOS:000398262700012
PM 27702820
OA Green Submitted, Green Accepted
DA 2025-03-13
ER

PT J
AU Sheng, ZM
   Wang, XJ
   Ding, XD
   Zheng, YH
   Guo, A
   Cui, JY
   Ma, J
   Duan, WL
   Dong, H
   Zhang, HX
   Cui, MM
   Su, WX
   Zhang, BG
AF Sheng, Zhimei
   Wang, Xuejie
   Ding, Xiaodi
   Zheng, Yuanhang
   Guo, Ai
   Cui, Jiayu
   Ma, Jing
   Duan, Wanli
   Dong, Hao
   Zhang, Hongxing
   Cui, Meimei
   Su, Wenxia
   Zhang, Baogang
TI Exosomal miRNA-92a derived from cancer-associated fibroblasts promote
   invasion and metastasis in breast cancer by regulating G3BP2
SO CELLULAR SIGNALLING
LA English
DT Article
DE Exosomes; Cancer-associated fibroblast; Breast cancer; G3BP2; miR-92a
ID TUMOR MICROENVIRONMENT; PROLIFERATION; CELLS; MIR-92A-3P; SECRETION;
   PROTEINS
AB Cancer-associated Fibroblasts (CAFs) exert a tumor-promoting effect in various cancers, including breast cancer. CAFs secrete exosomes containing miRNA and proteins, influencing the tumor microenvironment. In this study, we identified CAF-derived exosomes that transport functional miR-92a from CAFs to tumor cells, thereby intensifying the aggressiveness of breast cancer. CAFs downregulate the expression of G3BP2 in breast cancer cells, and a significant elevation in miR-92a levels in CAF-derived exosomes was observed. Both in vitro and in vivo experiments demonstrate that miR-92a enhances breast cancer cell migration and invasion by directly targeting G3BP2, functioning as a tumor-promoting miRNA. We validated that the RNA-binding proteins SNRPA facilitate the transfer of CAF-derived exosomal miR-92a to breast cancer cells. The reduction of G3BP2 protein by CAF-derived exosomes releases TWIST1 into the nucleus, promoting epithelial-mesenchymal transition (EMT) and further exacerbating breast cancer progression. Moreover, CAF-derived exosomal miR-92a induces tumor invasion and metastasis in mice. Overall, our study reveals that CAF-derived exosomal miR-92a serves as a promoter in the migration and invasion of breast cancer cells by reducing G3BP2 and may represent a potential novel tumor marker for breast cancer.
C1 [Sheng, Zhimei; Wang, Xuejie; Ding, Xiaodi; Guo, Ai; Duan, Wanli; Dong, Hao; Zhang, Hongxing; Cui, Meimei; Zhang, Baogang] Shandong Second Med Univ, Sch Basic Med Sci, Dept Pathol, Weifang, Shandong, Peoples R China.
   [Sheng, Zhimei; Cui, Jiayu; Zhang, Baogang] Shandong Second Med Univ, Affiliated Hosp, Dept Pathol, Weifang, Shandong, Peoples R China.
   [Zheng, Yuanhang] Weifang Peoples Hosp, Dept Pathol, Weifang, Shandong, Peoples R China.
   [Su, Wenxia] Second Med Univ, Dept Physiol, Weifang, Shandong, Peoples R China.
   [Zhang, Baogang] Shandong Second Med Univ, Dept Pathol, Weifang 261053, Peoples R China.
C3 Shandong Second Medical University; Shandong Second Medical University;
   Naval Medical University; Shandong Second Medical University
RP Zhang, BG (corresponding author), Shandong Second Med Univ, Dept Pathol, Weifang 261053, Peoples R China.
EM Zhangbg@wfmc.edu.cn
RI Duan, Wanli/JXW-6805-2024
OI Duan, wanli/0009-0001-7560-5675
FU National Natural Science Foundation of China [82373124, 81872163,
   81672631, 82000172, ZR2023QH087]; Shandong Provincial Natural Science
   Foundation
FX This work was supported by the National Natural Science Foundation of
   China (82373124, 81872163, 81672631, 82000172) ; project ZR2023QH087
   supported by Shandong Provincial Natural Science Foundation.
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NR 54
TC 9
Z9 9
U1 2
U2 4
PU ELSEVIER SCIENCE INC
PI NEW YORK
PA STE 800, 230 PARK AVE, NEW YORK, NY 10169 USA
SN 0898-6568
EI 1873-3913
J9 CELL SIGNAL
JI Cell. Signal.
PD JUL
PY 2024
VL 119
AR 111182
DI 10.1016/j.cellsig.2024.111182
EA APR 2024
PG 14
WC Cell Biology
WE Science Citation Index Expanded (SCI-EXPANDED)
SC Cell Biology
GA QO1G2
UT WOS:001221715900001
PM 38640983
OA hybrid, Green Submitted
DA 2025-03-13
ER

PT J
AU Gao, MQ
   Kim, BG
   Kang, S
   Choi, YP
   Yoon, JH
   Cho, NH
AF Gao, Ming-Qing
   Kim, Baek Gil
   Kang, Suki
   Choi, Yoon Pyo
   Yoon, Joo-Heon
   Cho, Nam Hoon
TI Human breast cancer-associated fibroblasts enhance cancer cell
   proliferation through increased TGF-α cleavage by ADAM17
SO CANCER LETTERS
LA English
DT Article
DE ADAM17; Breast cancer; Cancer-associated fibroblasts; TGF-alpha; Cell
   proliferation
ID STROMAL FIBROBLASTS; TACE INHIBITORS; METALLOPROTEINASES; PROGRESSION;
   ACTIVATION; GROWTH; EGFR; EXPRESSION; INTERFACE; RECEPTOR
AB We demonstrate here increased expression of ADAM17 protein in cancer-associated fibroblasts (CAFs) extracted from human breast carcinomas compared with donor-matched normal fibroblasts, and TGF-alpha secretion positively correlates with ADAM17 expression in these cells. In SK-BR-3 cells co-cultured with CAFs, CAF-secreted TGF-alpha promotes cell proliferation by activation of EGFR, Akt, and ERIC, but it does not promote cell migration. Furthermore, anti-TGF-alpha neutralizing antibodies antagonize the CAF-dependent increase in proliferation and activation of EGFR, Akt and ERIC. Thus, pharmacologic inhibition of ADAM17 and TGF-alpha may have therapeutic potential for the treatment of breast cancer when fibroblast-directed therapy is considered. (C) 2013 Elsevier Ireland Ltd. All rights reserved.
C1 [Gao, Ming-Qing; Kim, Baek Gil; Kang, Suki; Cho, Nam Hoon] Yonsei Univ, Coll Med, Dept Pathol, Seoul 120752, South Korea.
   [Choi, Yoon Pyo; Cho, Nam Hoon] Yonsei Univ, Coll Med, Brain Korea Project Med Sci 21, Seoul 120752, South Korea.
   [Kang, Suki; Yoon, Joo-Heon; Cho, Nam Hoon] Severance Biomed Sci Inst, Seoul 120752, South Korea.
   [Gao, Ming-Qing] Northwest A&F Univ, Coll Vet Med, Yangling 712100, Shaanxi, Peoples R China.
C3 Yonsei University; Yonsei University Health System; Yonsei University;
   Yonsei University Health System; Northwest A&F University - China
RP Yoon, JH (corresponding author), Yonsei Univ, Coll Med, Severance Biomed Sci Inst, 134 Sinchon Dong, Seoul 120752, South Korea.
EM jhyoon@yuhs.ac; cho1988@yuhs.ac
RI Yoon, Joo-Heon/E-5781-2016; KIM, BAEK GIL/KCL-0984-2024
OI Yoon, Joo-Heon/0000-0003-2404-7156
FU Basic Science Research Program through the National Research Foundation
   of Korea (NRF); Ministry of Education, Science and Technology (MEST)
   [2012R1A2A4A01006435]; Mid-career Researcher Program through an NRF
   Grant from the MEST [2012R1A2A4A01006435]; Basic Science Research
   Program through the National Research Foundation of Korea (NRF);
   Ministry of Education, Science and Technology (MEST)
   [2012R1A2A4A01006435]; Mid-career Researcher Program through an NRF
   Grant from the MEST [2012R1A2A4A01006435]
FX This research was supported by the Basic Science Research Program
   through the National Research Foundation of Korea (NRF), funded by the
   Ministry of Education, Science and Technology (MEST) (No.
   2012R1A2A4A01006435; CNH) and by the Mid-career Researcher Program
   through an NRF Grant from the MEST (No. 2012R1A2A4A01006435; CNH).
   Preparation of the manuscript was done with the assistance of BioScience
   Writers LLC, Houston, TX, USA.
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NR 27
TC 34
Z9 42
U1 1
U2 26
PU ELSEVIER IRELAND LTD
PI CLARE
PA ELSEVIER HOUSE, BROOKVALE PLAZA, EAST PARK SHANNON, CO, CLARE, 00000,
   IRELAND
SN 0304-3835
EI 1872-7980
J9 CANCER LETT
JI Cancer Lett.
PD AUG 9
PY 2013
VL 336
IS 1
BP 240
EP 246
DI 10.1016/j.canlet.2013.05.011
PG 7
WC Oncology
WE Science Citation Index Expanded (SCI-EXPANDED)
SC Oncology
GA 178WJ
UT WOS:000321477800027
PM 23684931
DA 2025-03-13
ER

PT J
AU Lee, YT
   Tan, YJ
   Falasca, M
   Oon, CE
AF Lee, Yeuan Ting
   Tan, Yi Jer
   Falasca, Marco
   Oon, Chern Ein
TI Cancer-Associated Fibroblasts: Epigenetic Regulation and Therapeutic
   Intervention in Breast Cancer
SO CANCERS
LA English
DT Review
DE breast cancer; cancer-associated fibroblasts; heterogeneity; epigenetic;
   post-translational modification; DNA methylation; miRNA dysregulation
ID EPITHELIAL-MESENCHYMAL TRANSITION; CARCINOMA-ASSOCIATED FIBROBLASTS;
   TGF-BETA; STROMAL CELLS; GENE-EXPRESSION; TUMOR STROMA; PHASE-II; DNA
   METHYLATION; STEM-CELLS; INVASION
AB Simple Summary
   Drug resistance and insensitivity to treatments are the main challenges in breast cancer therapy. Cancer-associated fibroblasts (CAFs) are heterogeneous stromal cells with prevailing roles in cancer development and progression. Epigenetic alterations are essential in regulating CAF activation and heterogeneity. These modifications are druggable targets that can be reversed using pharmacological interventions. CAFs therefore, have a remarkable potential as a therapeutic target in breast cancer. This review provides an update on the mechanisms of epigenetic modulation in breast cancer and discusses the challenges of translating the optimism of CAF-directed therapies from bench to clinic.
   Breast cancer is the leading cause of cancer-related mortality in women worldwide. Cancer-associated fibroblasts (CAFs) are a heterogeneous population of cells in the solid tumour microenvironment. These cells are positively linked to breast cancer progression. Breast CAFs can be categorised into distinct subtypes according to their roles in breast carcinogenesis. Epigenetic modifications change gene expression patterns as a consequence of altered chromatin configuration and DNA accessibility to transcriptional machinery, without affecting the primary structure of DNA. Epigenetic dysregulation in breast CAFs may enhance breast cancer cell survival and ultimately lead to therapeutic resistance. A growing body of evidence has described epigenetic modulators that target histones, DNA, and miRNA as a promising approach to treat cancer. This review aims to summarise the current findings on the mechanisms involved in the epigenetic regulation in breast CAFs and discusses the potential therapeutic strategies via targeting these factors.
C1 [Lee, Yeuan Ting; Tan, Yi Jer; Oon, Chern Ein] Univ Sains Malaysia, Inst Res Mol Med INFORMM, George Town 11800, Malaysia.
   [Falasca, Marco] Curtin Univ, Curtin Hlth Innovat Res Inst, Sch Pharm & Biomed Sci, Metab Signalling Grp, Perth, WA 6102, Australia.
C3 Universiti Sains Malaysia; Curtin University
RP Oon, CE (corresponding author), Univ Sains Malaysia, Inst Res Mol Med INFORMM, George Town 11800, Malaysia.; Falasca, M (corresponding author), Curtin Univ, Curtin Hlth Innovat Res Inst, Sch Pharm & Biomed Sci, Metab Signalling Grp, Perth, WA 6102, Australia.
EM yeuanting@student.usm.my; yijer_tan@student.usm.my;
   Marco.Falasca@curtin.edu.au; chern.oon@usm.my
RI Oon, Chern/B-3684-2013; Lee, Yeuan Ting/Q-5720-2018; Falasca,
   Marco/S-4020-2016
OI Tan, Yi Jer/0000-0003-2145-2105; Lee, Yeuan Ting/0000-0001-9356-5681;
   Falasca, Marco/0000-0002-9801-7235; Oon, Chern Ein/0000-0002-4685-6408
FU USM Postgraduate Research Attachment Fund (PGRA); L'Oreal-UNESCO for
   Women in Science Fellowship [304/CIPPM/650806/L117]
FX Yeuan Ting Lee was supported by the USM Postgraduate Research Attachment
   Fund (PGRA) for short research attachment at Curtin University. Chern
   Ein Oon was supported by the L'Oreal-UNESCO for Women in Science
   Fellowship (304/CIPPM/650806/L117).
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NR 160
TC 35
Z9 38
U1 2
U2 17
PU MDPI
PI BASEL
PA ST ALBAN-ANLAGE 66, CH-4052 BASEL, SWITZERLAND
EI 2072-6694
J9 CANCERS
JI Cancers
PD OCT
PY 2020
VL 12
IS 10
AR 2949
DI 10.3390/cancers12102949
PG 23
WC Oncology
WE Science Citation Index Expanded (SCI-EXPANDED)
SC Oncology
GA OJ7ZT
UT WOS:000584175000001
PM 33066013
OA gold, Green Published
DA 2025-03-13
ER

PT J
AU Xi, CF
   Song, ZD
   Cui, QY
   Zhao, Y
   Li, KF
   Kang, H
AF Xi, Chunfang
   Song, Zhendi
   Cui, Qingyu
   Zhao, Ye
   Li, Kaifu
   Kang, Hua
TI Elevated MMP1 Expression in Carcinoma-Associated Fibroblasts of Breast
   Cancer Contributes to Tumor Progression and Unfavorable Prognosis
SO ANNALS OF CLINICAL AND LABORATORY SCIENCE
LA English
DT Article
DE MMP1; breast cancer; cancer associated fibroblasts; cell behavior;
   prognosis
ID MATRIX METALLOPROTEINASE-1; TISSUE; MICROENVIRONMENT; THERAPY; STROMA
AB Objective. Previous studies have shown that cancer-associated fibroblasts (CAFs) may play a role in tumor growth and development through paracrine action. Several studies reported upregulated matrix metallopeptidase 1 (MMP1) expression in various cancers. The aim is to investigate the role of elevated MMP1 expression in CAFs of breast cancer. Methods. A total of 203 cases were used for immunohistochemical analysis based on multiple clinical parameters. Tissues for primary cultures of CAFs were collected from 10 breast cancer patients who underwent complete surgical resection of their tumors. MMP1 expression in primary CAFs was detected using reverse transcription-quantitative PCR and western blotting. MMP1-overexpressing CAFs were established via lentiviral transfection, followed by cell functional assays and animal xenograft experiments. Results. MMP1 expression in CAFs of breast cancer was significantly associated with T stage, triple -negative breast cancer status, neoadjuvant chemotherapy status and Ki67 expression. Additionally, MMP1 expression was closely correlated with unfavorable prognosis based on overall survival and disease-free survival analyses. Elevated MMP1 expression in CAFs was verified to promote cell adhesion, invasion, proliferation abilities and attenuate chemosensitivity to Taxotere treatment. Conclusion. The results indicated that MMP1 expression in CAFs may participate in the malignant phenotype and unfavorable prognosis of breast cancer.
C1 [Xi, Chunfang; Cui, Qingyu; Zhao, Ye; Li, Kaifu; Kang, Hua] Capital Med Univ, Xuanwu Hosp, Ctr Thyroid & Breast Surg, Dept Gen Surg, 45 Changchun St, Beijing 100053, Peoples R China.
   [Xi, Chunfang] Shanxi Prov Peoples Hosp, Dept Gen Surg, Taiyuan, Peoples R China.
   [Song, Zhendi] Qingdao Municipal Hosp, Dept Gen Surg, Qingdao, Shandong, Peoples R China.
C3 Capital Medical University; Shanxi People's Hospital; Qingdao Municipal
   Hospital
RP Kang, H (corresponding author), Capital Med Univ, Xuanwu Hosp, Ctr Thyroid & Breast Surg, Dept Gen Surg, 45 Changchun St, Beijing 100053, Peoples R China.
EM kanghua@xwh.ccmu.edu.cn
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NR 36
TC 0
Z9 0
U1 1
U2 2
PU ASSOC CLINICAL SCIENTISTS
PI MIDDLEBURY
PA PO BOX 1287, MIDDLEBURY, VT 05753 USA
SN 0091-7370
EI 1550-8080
J9 ANN CLIN LAB SCI
JI Ann. Clin. Lab. Sci.
PD JAN-FEB
PY 2024
VL 54
IS 1
BP 66
EP 75
PG 10
WC Medical Laboratory Technology
WE Science Citation Index Expanded (SCI-EXPANDED)
SC Medical Laboratory Technology
GA SQ5Y6
UT WOS:001235942400001
PM 38514057
DA 2025-03-13
ER

PT J
AU Luque, M
   Sanz-Alvarez, M
   Santamaria, A
   Zazo, S
   Cristobal, I
   de la Fuente, L
   Minguez, P
   Eroles, P
   Rovira, A
   Albanell, J
   Madoz-Gurpide, J
   Rojo, F
AF Luque, Melani
   Sanz-Alvarez, Marta
   Santamaria, Andrea
   Zazo, Sandra
   Cristobal, Ion
   de la Fuente, Lorena
   Minguez, Pablo
   Eroles, Pilar
   Rovira, Ana
   Albanell, Joan
   Madoz-Gurpide, Juan
   Rojo, Federico
TI Targeted Therapy Modulates the Secretome of Cancer-Associated
   Fibroblasts to Induce Resistance in HER2-Positive Breast Cancer
SO INTERNATIONAL JOURNAL OF MOLECULAR SCIENCES
LA English
DT Article
DE breast cancer; HER2-positive; tumour microenvironment; targeted therapy;
   trastuzumab; resistance; cancer-associated fibroblast; label-free
   proteomics; miRNA
ID TRASTUZUMAB RESISTANCE; DOCETAXEL RESISTANCE; STROMAL FIBROBLASTS;
   PROMOTE EMT; CELL-LINE; EXPRESSION; PROGRESSION; STAT3; IDENTIFICATION;
   METASTASIS
AB The combination of trastuzumab plus pertuzumab plus docetaxel as a first-line therapy in patients with HER2-positive metastatic breast cancer has provided significant clinical benefits compared to trastuzumab plus docetaxel alone. However, despite the therapeutic success of existing therapies targeting HER2, tumours invariably relapse. Therefore, there is an urgent need to improve our understanding of the mechanisms governing resistance, so that specific therapeutic strategies can be developed to provide improved efficacy. It is well known that the tumour microenvironment (TME) has a significant impact on cancer behaviour. Cancer-associated fibroblasts (CAFs) are essential components of the tumour stroma that have been linked to acquired therapeutic resistance and poor prognosis in breast cancer. For this reason, it would be of interest to identify novel biomarkers in the tumour stroma that could emerge as therapeutic targets for the modulation of resistant phenotypes. Conditioned medium experiments carried out in our laboratory with CAFs derived from HER2-positive patients showed a significant capacity to promote resistance to trastuzumab plus pertuzumab therapies in two HER2-positive breast cancer cell lines (BCCLs), even in the presence of docetaxel. In order to elucidate the components of the CAF-conditioned medium that may be relevant in the promotion of BCCL resistance, we implemented a multiomics strategy to identify cytokines, transcription factors, kinases and miRNAs in the secretome that have specific targets in cancer cells. The combination of cytokine arrays, label-free LC-MS/MS quantification and miRNA analysis to explore the secretome of CAFs under treatment conditions revealed several up- and downregulated candidates. We discuss the potential role of some of the most interesting candidates in generating resistance in HER2-positive breast cancer.
C1 [Luque, Melani; Sanz-Alvarez, Marta; Santamaria, Andrea; Zazo, Sandra; Madoz-Gurpide, Juan; Rojo, Federico] Fdn Jimenez Diaz Univ Hosp Hlth Res Inst IIS FJD, UAM, CIBERONC, Dept Pathol, Madrid 28040, Spain.
   [Cristobal, Ion] Hlth Res Inst Fdn Jimenez Diaz IIS FJD, UAM, OncoHlth Inst, Translat Oncol Div, Madrid 28040, Spain.
   [de la Fuente, Lorena; Minguez, Pablo] Hlth Res Inst Fdn Jimenez Diaz IIS FJD, Ctr Biomed Network Res Rare Dis CIBERER, Genet Dept, UAM,ISCIII, Madrid 28040, Spain.
   [Eroles, Pilar] CIBERONC, Inst Hlth Res INCLIVA, Valencia 46010, Spain.
   [Eroles, Pilar] Univ Valencia, Dept Physiol, Valencia 46010, Spain.
   [Rovira, Ana; Albanell, Joan] IMIM Hosp del Mar Res Inst, Canc Res Program, Barcelona 08003, Spain.
   [Rovira, Ana; Albanell, Joan] Hosp del Mar CIBERONC, Med Oncol Dept, Barcelona 08003, Spain.
   [Albanell, Joan] Univ Pompeu Fabra, Fac Med, Dept Expt & Hlth Sci, Barcelona 08002, Spain.
C3 CIBER - Centro de Investigacion Biomedica en Red; CIBERONC; Autonomous
   University of Madrid; Fundacion Jimenez Diaz; Autonomous University of
   Madrid; Instituto de Salud Carlos III; CIBER - Centro de Investigacion
   Biomedica en Red; CIBERER; Autonomous University of Madrid; Fundacion
   Jimenez Diaz; CIBER - Centro de Investigacion Biomedica en Red;
   CIBERONC; University of Valencia; Hospital del Mar Research Institute;
   Hospital del Mar; Pompeu Fabra University; University of Barcelona
RP Madoz-Gurpide, J; Rojo, F (corresponding author), Fdn Jimenez Diaz Univ Hosp Hlth Res Inst IIS FJD, UAM, CIBERONC, Dept Pathol, Madrid 28040, Spain.
EM melani.luque@quironsalud.es; marta.sanza@quironsalud.es;
   andreasantamaria_95@hotmail.com; szazo@fjd.es;
   ion.cristobal@quironsalud.es; lorena.fuente@quironsalud.es;
   pablominguez@gmail.com; Pilar.Eroles@uv.es; arovira@imim.es;
   96087@parcdesalutmar.cat; JMadoz@fjd.es; FRojo@fjd.es
RI Rojo, Federico/S-6551-2016; Minguez, Pablo/D-4822-2013; Rovira,
   Ana/ABH-5661-2020
OI Eroles, Pilar/0000-0003-2708-6206; Minguez, Pablo/0000-0003-4099-9421;
   MADOZ-GURPIDE, JUAN/0000-0001-8094-4076; Rovira,
   Ana/0000-0003-1301-2599; Cristobal, Ion/0000-0003-0234-4213
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NR 97
TC 10
Z9 11
U1 3
U2 21
PU MDPI
PI BASEL
PA ST ALBAN-ANLAGE 66, CH-4052 BASEL, SWITZERLAND
SN 1661-6596
EI 1422-0067
J9 INT J MOL SCI
JI Int. J. Mol. Sci.
PD DEC
PY 2021
VL 22
IS 24
AR 13297
DI 10.3390/ijms222413297
PG 31
WC Biochemistry & Molecular Biology; Chemistry, Multidisciplinary
WE Science Citation Index Expanded (SCI-EXPANDED)
SC Biochemistry & Molecular Biology; Chemistry
GA XZ5UB
UT WOS:000737715700001
PM 34948097
OA Green Published, gold
DA 2025-03-13
ER

PT J
AU Schoppmann, SF
   Berghoff, A
   Dinhof, C
   Jakesz, R
   Gnant, M
   Dubsky, P
   Jesch, B
   Heinzl, H
   Birner, P
AF Schoppmann, Sebastian F.
   Berghoff, Anna
   Dinhof, Carina
   Jakesz, Raimund
   Gnant, Michael
   Dubsky, Peter
   Jesch, Bettina
   Heinzl, Harald
   Birner, Peter
TI Podoplanin-expressing cancer-associated fibroblasts are associated with
   poor prognosis in invasive breast cancer
SO BREAST CANCER RESEARCH AND TREATMENT
LA English
DT Article
DE Cancer-associated fibroblasts; Breast cancer; Metastasis; Prognosis
ID MESENCHYMAL TRANSITION; MONOCLONAL-ANTIBODY; LYMPH-NODE; PHASE-II;
   STROMA; ACTIVATION; CARCINOMA; MARKER; GROWTH; TUMORS
AB While cancer research has been focused on tumor cells for many years, evidence is growing that the tumor stroma and in particular cancer-associated fibroblasts (CAFs) in particular play essential roles in the progression of human malignant disease. In human lung cancer, CAFs expressing the transmembrane protein podoplanin were shown to have significant influence on the patients' prognosis. In this study, we investigated the presence and prognostic role of podoplanin-expressing CAFs in a large series of patients with invasive breast cancer. Podoplanin expression was evaluated immunohistochemically in 367 breast cancers. Tumors with a parts per thousand yen10% distinct podoplanin staining were considered as positive (CAF+). Cytoplasmic podoplanin expression of tumor cells was considered as positive when a parts per thousand yen5% of tumor cells showed a distinct podoplanin expression. In normal breast tissue, no podoplanin-expressing fibrocytes were found. Thirty-three patients (9%) with breast cancer showed podoplanin expression in CAFs. In 28 patients (8%), a podoplanin expression in tumor cells was observed. A strong negative correlation of CAF+ with estrogen receptor status (p < 0.001), and a significant association with higher histological grading (p < 0.001) was seen. In multivariable analysis, CAFs+ was an independent prognostic factor for disease free (1.78 Hazard ratio; p = 0.026) and overall survival (2.304 Hazard ratio; p = 0.002) in patients with breast cancer. Podoplanin-expressing CAFs contribute to the prognosis of invasive breast cancer, indicating a highly aggressive subgroup. CAFs may present a highly selective target for anti-cancer therapies in patients with invasive breast cancer.
C1 [Schoppmann, Sebastian F.; Jakesz, Raimund; Gnant, Michael; Dubsky, Peter; Jesch, Bettina] Med Univ Vienna, Dept Surg, Gen Hosp, A-1090 Vienna, Austria.
   [Berghoff, Anna] Med Univ Vienna, Inst Neurol, A-1090 Vienna, Austria.
   [Dinhof, Carina] Univ Appl Sci, Krems, Austria.
   [Heinzl, Harald] Med Univ Vienna, Sect Clin Biometr, A-1090 Vienna, Austria.
   [Birner, Peter] Med Univ Vienna, Clin Inst Pathol, A-1090 Vienna, Austria.
C3 Medical University of Vienna; Medical University of Vienna; Medical
   University of Vienna; Medical University of Vienna
RP Schoppmann, SF (corresponding author), Med Univ Vienna, Dept Surg, Gen Hosp, Waehringer Guertel 18-20, A-1090 Vienna, Austria.
EM sebastian.schoppmann@meduniwien.ac.at
RI Schoppmann, Sebastian/M-5831-2019; Schoppmann, Sebastian F./K-1530-2017;
   Gnant, Michael/AAN-7054-2020
OI Schoppmann, Sebastian F./0000-0002-1725-7086; Berghoff, Anna
   Sophie/0000-0001-9379-6797; Dinhof, Carina/0009-0004-6139-7301; Gnant,
   Michael/0000-0003-1002-2118
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NR 31
TC 93
Z9 103
U1 1
U2 20
PU SPRINGER
PI NEW YORK
PA ONE NEW YORK PLAZA, SUITE 4600, NEW YORK, NY, UNITED STATES
SN 0167-6806
EI 1573-7217
J9 BREAST CANCER RES TR
JI Breast Cancer Res. Treat.
PD JUL
PY 2012
VL 134
IS 1
BP 237
EP 244
DI 10.1007/s10549-012-1984-x
PG 8
WC Oncology
WE Science Citation Index Expanded (SCI-EXPANDED)
SC Oncology
GA 974LS
UT WOS:000306437500022
PM 22350732
DA 2025-03-13
ER

PT J
AU Jung, YY
   Kim, HM
   Koo, JS
AF Jung, Yoon Yang
   Kim, Hye Min
   Koo, Ja Seung
TI The role of cancer-associated fibroblasts in breast cancer pathobiology
SO HISTOLOGY AND HISTOPATHOLOGY
LA English
DT Review
DE Breast cancer; Cancer-associated fibroblast; Tumor microenvironment
ID EPITHELIAL-MESENCHYMAL TRANSITION; INVASIVE DUCTAL CARCINOMA; STROMAL
   FIBROBLASTS; TUMOR MICROENVIRONMENT; CAVEOLIN-1 EXPRESSION;
   PROGNOSTIC-SIGNIFICANCE; ACTIVATION PROTEIN; SIGNALING PATHWAY;
   OXIDATIVE STRESS; STEM-CELLS
AB The role of the tumor microenvironment (TME) is critical in cancer pathobiology. Of the components of the TME, cancer-associated fibroblasts (CAFs) play a major role. Breast cancer is a typical tumor type, forming abundant tumor stroma, and CAFs are involved in various aspects of breast cancer, including carcinogenesis, tumor progression, invasion, metastasis, inflammation, metabolism, therapy resistance, and prognosis. Various factors, such as growth factors, cytokines, hormones secreted from CAFs, paracrine effects promoted by the extracellular matrix (ECM), and mechanical pressure, are involved in cancer development, and there are various crosstalk and signaling pathways among CAFs, cancer cells, epithelial cells, and the ECM. Recent studies have evaluated the potential of CAFs as therapeutic targets in breast cancer. In this review, we discuss the role of CAFs and their clinical implications.
C1 [Jung, Yoon Yang; Kim, Hye Min; Koo, Ja Seung] Yonsei Univ, Coll Med, Dept Pathol, Seoul 120752, South Korea.
C3 Yonsei University; Yonsei University Health System
RP Koo, JS (corresponding author), Yonsei Univ, Coll Med, Dept Pathol, Severance Hosp, 50 Yonsei Ro, Seoul 120752, South Korea.
EM kjs1976@yuhs.ac
RI JUNG, YOON/T-3655-2019; Kim, Hyo-Won/M-9932-2019; Kim, Sun
   Jung/AAM-7334-2020
OI koo, ja seung/0000-0003-4546-4709; Kim, Hye Min/0000-0002-2899-9480
FU National R&D Program for Cancer Control, Ministry of Health & Welfare,
   Republic of Korea [1420080]; Basic Science Research Program through
   National Research Foundation of Korea (NRF) - Ministry of Science, ICT,
   and Future Planning [2015R1A1A1A05001209]
FX This study was supported by a grant from the National R&D Program for
   Cancer Control, Ministry of Health & Welfare, Republic of Korea
   (1420080). This research was supported by the Basic Science Research
   Program through the National Research Foundation of Korea (NRF) funded
   by the Ministry of Science, ICT, and Future Planning
   (2015R1A1A1A05001209).
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NR 90
TC 16
Z9 17
U1 3
U2 27
PU F HERNANDEZ
PI MURCIA
PA PLAZA FUENSANTA 2-7 C, 30008 MURCIA, SPAIN
SN 0213-3911
EI 1699-5848
J9 HISTOL HISTOPATHOL
JI Histol. Histopath.
PD APR
PY 2016
VL 31
IS 4
BP 371
EP 378
PG 8
WC Cell Biology; Pathology
WE Science Citation Index Expanded (SCI-EXPANDED)
SC Cell Biology; Pathology
GA DG3WH
UT WOS:000372000700003
PM 26627101
DA 2025-03-13
ER

PT J
AU Cohen, N
   Mundhe, D
   Deasy, SK
   Adler, O
   Ershaid, N
   Shami, T
   Levi-Galibov, O
   Wassermann, R
   Scherz-Shouval, R
   Erez, N
AF Cohen, Noam
   Mundhe, Dhanashree
   Deasy, Sarah K.
   Adler, Omer
   Ershaid, Nour
   Shami, Tamar
   Levi-Galibov, Oshrat
   Wassermann, Rina
   Scherz-Shouval, Ruth
   Erez, Neta
TI Breast Cancer-Secreted Factors Promote Lung Metastasis by Signaling
   Systemically to Induce a Fibrotic Premetastatic Niche
SO CANCER RESEARCH
LA English
DT Article
ID TUMOR PROGRESSION; TGF-BETA; ACTIVIN; FIBROSIS; MICROENVIRONMENT;
   MIGRATION
AB Metastatic cancer is largely incurable and is the main cause of cancer-related deaths. The metastatic microenvironment facilitates formation of metastases. Cancer-associated fibroblasts (CAF) are crucial players in generating a hospitable metastatic niche by mediating an inflammatory microenvironment. Fibroblasts also play a central role in modifying the architecture and stiffness of the extracellular matrix (ECM). Resolving the early changes in the metastatic niche could help identify approaches to inhibit metastatic progression. Here, we demonstrate in mouse models of spontaneous breast cancer pulmonary metastasis that fibrotic changes and rewiring of lung fibroblasts occurred at premetastatic stages, suggesting systemic influence by the primary tumor. Activin A (ActA), a TGF beta superfamily member, was secreted from breast tumors and its levels in the blood were highly elevated in tumor-bearing mice. ActA upregulated the expression of profibrotic factors in lung fibroblasts, leading to enhanced collagen deposition in the lung premetastatic niche. ActAsignaling was functionally important for lung metastasis, as genetic targeting of ActA in breast cancer cells significantly attenuated lung metastasis and improved survival. Moreover, high levels of ActA in human patients with breast cancer were associated with lung metastatic relapse and poor survival. This study uncovers a novel mechanismby which breast cancer cells systemically rewire the stromal microenvironment in the metastatic niche to facilitate pulmonary metastasis.
   Significance: ActA mediates cross-talk between breast cancer cells and cancer-associated fibroblasts in the lung metastatic niche that enhances fibrosis and metastasis, implicating ActA as a potential therapeutic target to inhibit metastatic relapse.
   [GRAPHICS]
   .
C1 [Cohen, Noam; Mundhe, Dhanashree; Deasy, Sarah K.; Adler, Omer; Ershaid, Nour; Shami, Tamar; Erez, Neta] Tel Aviv Univ, Sackler Fac Med, Dept Pathol, Tel Aviv, Israel.
   [Levi-Galibov, Oshrat; Wassermann, Rina; Scherz-Shouval, Ruth] Weizmann Inst Sci, Dept Biomol Sci, Rehovot, Israel.
   [Erez, Neta] Tel Aviv Univ, Fac Med, Dept Pathol, IL-69978 Tel Aviv, Israel.
C3 Tel Aviv University; Sackler Faculty of Medicine; Weizmann Institute of
   Science; Tel Aviv University
RP Erez, N (corresponding author), Tel Aviv Univ, Fac Med, Dept Pathol, IL-69978 Tel Aviv, Israel.
EM netaerez@tauex.tau.ac.il
RI Erez, Neta/G-8584-2012
OI Deasy Spaeh, Sarah/0000-0002-0103-964X; scherz-shouval,
   ruth/0000-0002-4570-121X; Ershaid, Nour/0000-0002-6422-7728; Adler,
   Omer/0009-0002-4346-801X; Erez, Neta/0000-0001-6506-9074; Mundhe,
   Dhanashree/0000-0002-4472-6706
FU The publication costs of this article were defrayed in part by the
   payment of publication fees. Therefore, and solely to indicate this
   fact, this article is hereby marked "advertisement" in accordance with
   18 USC section 1734.
FX This study was supported by grants (to N. Erez) from the European
   Research Council (ERC) under the European Union & apos;s Horizon 2020
   Research and Innovation Program (grant agreement no. 637069 MetCAF), The
   Department of Defense (DoD) Breast Cancer Research Program (BCRP)
   Breakthrough Award, the Israel Cancer Association (ICA), the Israel
   Science Foundation (#1060/18), The Israel Cancer Research Fund (ICRF
   Project grant), and The Emerson Collective.r The publication costs of
   this article were defrayed in part by the payment of publication fees.
   Therefore, and solely to indicate this fact, this article is hereby
   marked "advertisement" in accordance with 18 USC section 1734.
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NR 50
TC 11
Z9 11
U1 1
U2 11
PU AMER ASSOC CANCER RESEARCH
PI PHILADELPHIA
PA 615 CHESTNUT ST, 17TH FLOOR, PHILADELPHIA, PA 19106-4404 USA
SN 0008-5472
EI 1538-7445
J9 CANCER RES
JI Cancer Res.
PD OCT 13
PY 2023
VL 83
IS 20
BP 3354
EP 3367
DI 10.1158/0008-5472.CAN-22-3707
PG 14
WC Oncology
WE Science Citation Index Expanded (SCI-EXPANDED)
SC Oncology
GA X8TP3
UT WOS:001101112600005
PM 37548552
DA 2025-03-13
ER

PT J
AU Affinito, A
   Quintavalle, C
   Chianese, RV
   Roscigno, G
   Fiore, D
   D'Argenio, V
   Thomas, G
   Savarese, A
   Ingenito, F
   Cocca, L
   Nuzzo, S
   Berezovski, MV
   Stoppelli, MP
   Condorelli, G
AF Affinito, Alessandra
   Quintavalle, Cristina
   Chianese, Rosario Vincenzo
   Roscigno, Giuseppina
   Fiore, Danilo
   D'Argenio, Valeria
   Thomas, Guglielmo
   Savarese, Alessia
   Ingenito, Francesco
   Cocca, Lorenza
   Nuzzo, Silvia
   Berezovski, Maxim V.
   Stoppelli, Maria Patrizia
   Condorelli, Gerolama
TI MCT4-driven CAF-mediated metabolic reprogramming in breast cancer
   microenvironment is a vulnerability targetable by miR-425-5p
SO CELL DEATH DISCOVERY
LA English
DT Article
ID HYPOXIA-INDUCIBLE FACTOR-1-ALPHA; OXIDATIVE STRESS; LACTATE SHUTTLE;
   EXPRESSION; MCT4; FIBROBLASTS; TRANSPORTER
AB Multiple oncogenic alterations contribute to breast cancer development. Metabolic reprogramming, deeply contributing to tumor microenvironment (TME) education, is now widely recognized as a hallmark of cancer. The reverse Warburg effect induces cancer-associated fibroblasts (CAFs) to produce and secrete L-lactate, enhancing malignant characteristics such as neoangiogenesis, metastatic dissemination, and treatment resistance. Monocarboxylate transporter (MCT) 4 is involved in lactate efflux from CAFs into stromal and epithelial cells. Here, we first assess the expression of miR-425-5p and its target MCT4 in breast cancer CAFs and normal fibroblasts. We analyzed the metabolic changes induced by miR-425-5p in CAFs and its role in the education of breast cancer epithelial cells. We show that miR-425-5p-induced MCT4 knockdown decreased lactate extrusion from CAFs and its availability in the TME. miR-425-5p overexpression induced profound metabolic transformation in CAFs, ultimately influencing breast cancer metabolism. Furthermore, miR-425-5p impaired the capacity of CAFs to sustain vessel formation and breast cancer cell migration, viability, and proliferation. These findings emphasize the key role of miR-425-5p in breast cancer metabolism and aggressiveness, and its possible importance for breast cancer therapy and monitoring.
C1 [Affinito, Alessandra; Chianese, Rosario Vincenzo; Roscigno, Giuseppina; Fiore, Danilo; Savarese, Alessia; Ingenito, Francesco; Cocca, Lorenza; Condorelli, Gerolama] Federico II Univ Naples, Dept Mol Med & Med Biotechnol, Naples, Italy.
   [Affinito, Alessandra] ASSI Ingn, Naples, Italy.
   [Quintavalle, Cristina; Fiore, Danilo; Condorelli, Gerolama] Gaetano Salvatore IEOS CNR, Inst Expt Endocrinol & Oncol, Naples, Italy.
   [D'Argenio, Valeria] San Raffaele Open Univ, Dept Human Sci & Qual Life Promot, Rome, Italy.
   [D'Argenio, Valeria] CEINGE Biotecnol Avanzate Franco Salvatore, Naples, Italy.
   [Thomas, Guglielmo] Mediterranea Cardioctr, Naples, Italy.
   [Nuzzo, Silvia] IRCCS SYNLAB SDN, Naples, Italy.
   [Berezovski, Maxim V.] Univ Ottawa, Dept Chem & Biomol Sci, Ottawa, ON, Canada.
   [Berezovski, Maxim V.] Univ Ottawa, John L Holmes Mass Spectrometry Facil, Ottawa, ON, Canada.
   [Stoppelli, Maria Patrizia] IGB CNR, Naples, Italy.
C3 University of Naples Federico II; University of Ottawa; University of
   Ottawa; Consiglio Nazionale delle Ricerche (CNR); Istituto di Genetica e
   Biofisica "Adriano Buzzati-Traverso" (IGB-CNR)
RP Condorelli, G (corresponding author), Federico II Univ Naples, Dept Mol Med & Med Biotechnol, Naples, Italy.; Condorelli, G (corresponding author), Gaetano Salvatore IEOS CNR, Inst Expt Endocrinol & Oncol, Naples, Italy.
EM gecondor@unina.it
RI Nuzzo, Silvia/AAB-9550-2022; Quintavalle, Cristina/O-1317-2015; Fiore,
   Danilo/A-6002-2019; Affinito, Alessandra/Q-7859-2018; D'Argenio,
   Valeria/K-9345-2016
OI STOPPELLI, MARIA/0000-0003-2402-1087; Affinito,
   Alessandra/0000-0002-3887-6513; Nuzzo, Silvia/0000-0002-6537-7867;
   D'Argenio, Valeria/0000-0001-9273-3698
FU H2020-MSCA-RISE-2019 cONCReTE 872391, H2020-MSCA-RISE-2019 PRISAR2
   872860; PNRR-MUR Next Generation EU cod. CN00000041; and
   NextGenerationEU MIUR PRIN 2022F3ZKJF [H2020-MSCA-RISE-2019 cONCReTE
   872391, H2020-MSCA-RISE-2019 PRISAR2 872860, CN00000041- CUP
   E63C22000940007]; NextGenerationEU MIUR PRIN [2022F3ZKJF, 2022-M5LBKP,
   H2020-MSCA-ITN -2019 PAVE 861190]; Italian Ministry of University and
   Research (MIUR)
FX This research was funded by: H2020-MSCA-RISE-2019 cONCReTE 872391,
   H2020-MSCA-RISE-2019 PRISAR2 872860, PNRR-MUR NextGenerationEU cod.
   CN00000041- CUP E63C22000940007, and NextGenerationEU MIUR PRIN
   2022F3ZKJF to G.C.; NextGenerationEU MIUR PRIN 2022-M5LBKP and
   NextGenerationEU cod. P2022N28FJ PRIN-PNRR to C.Q.; F.I. was supported
   by H2020-MSCA-ITN -2019 PAVE 861190. D.F. was supported by the Rita-Levi
   Montalcini grant from the Italian Ministry of University and Research
   (MIUR). We are thankful to Gennaro Cito (CNR-IEOS, Naples, Italy) and
   Mariarosaria Montagna (CNR-IEOS, Naples, Italy) for technical support.
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NR 71
TC 9
Z9 9
U1 2
U2 9
PU SPRINGERNATURE
PI LONDON
PA CAMPUS, 4 CRINAN ST, LONDON, N1 9XW, ENGLAND
EI 2058-7716
J9 CELL DEATH DISCOV
JI Cell Death Discov.
PD MAR 14
PY 2024
VL 10
IS 1
AR 140
DI 10.1038/s41420-024-01910-x
PG 13
WC Cell Biology
WE Science Citation Index Expanded (SCI-EXPANDED)
SC Cell Biology
GA LF2D3
UT WOS:001185292200005
PM 38485929
OA Green Published, gold
DA 2025-03-13
ER

PT J
AU Dai, HJ
   Xu, WT
   Wang, LL
   Li, X
   Sheng, XA
   Zhu, L
   Li, Y
   Dong, XR
   Zhou, WH
   Han, CY
   Mao, Y
   Yao, LL
AF Dai, Huijuan
   Xu, Wenting
   Wang, Lulu
   Li, Xiao
   Sheng, Xiaonan
   Zhu, Lei
   Li, Ye
   Dong, Xinrui
   Zhou, Weihang
   Han, Chenyu
   Mao, Yan
   Yao, Linli
TI Loss of SPRY2 contributes to cancer-associated fibroblasts activation
   and promotes breast cancer development
SO BREAST CANCER RESEARCH
LA English
DT Article
DE Microenvironment; Fibroblast; LDHA; Glycolysis; Stemness
ID TUMOR-SUPPRESSOR; SPROUTY; METABOLISM; PROTEINS; INVASION
AB The communication between tumor cells and tumor microenvironment plays a critical role in cancer development. Cancer-associated fibroblasts (CAFs) are the major components of the tumor microenvironment and take part in breast cancer formation and progression. Here, by comparing the gene expression patterns in CAFs and normal fibroblasts, we found SPRY2 expression was significantly decreased in CAFs and decreased SPRY2 expression was correlated with worse prognosis in breast cancer patients. SPRY2 knockdown in fibroblasts promoted tumor growth and distant metastasis of breast cancer in mice. Loss of stromal SPRY2 expression promoted CAF activation dependent on glycolytic metabolism. Mechanically, SPRY2 suppressed Y10 phosphorylation of LDHA and LDHA activity by interfering with the interaction between LDHA and SRC. Functionally, SPRY2 knockdown in fibroblasts enhanced the stemness of tumor cell dependent on glycolysis in fibroblasts. Collectively, this work identified SPRY2 as a negative regulator of CAF activation, and SPRY2 in CAFs may potentially be therapeutically targeted in breast cancer treatment.
C1 [Zhu, Lei; Yao, Linli] Shanghai Jiao Tong Univ, Ren Ji Hosp, Shanghai Canc Inst, Sch Med,State Key Lab Syst Med Canc, 800 Dongchuan Rd, Shanghai 200240, Peoples R China.
   [Dai, Huijuan; Sheng, Xiaonan; Li, Ye; Dong, Xinrui; Zhou, Weihang] Shanghai Jiao Tong Univ, Renji Hosp, Sch Med, Dept Breast Surg, Shanghai, Peoples R China.
   [Xu, Wenting] Shanghai Jiao Tong Univ, Int Peace Matern & Child Hlth Hosp, Sch Med, Dept Pathol,China Welf Inst, 910 Hengshan Rd, Shanghai 200030, Peoples R China.
   [Wang, Lulu] Capital Med Univ, Sch Basic Med Sci, Dept Human Anat, Beijing, Peoples R China.
   [Wang, Lulu] Beijing Key Lab Canc Invas & Metastasis Res, Beijing, Peoples R China.
   [Li, Xiao] Shanghai Jiao Tong Univ, Shanghai Peoples Hosp 6, Sch Med, Dept Obstet & Gynecol, Shanghai, Peoples R China.
   [Han, Chenyu] Fudan Univ, Zhongshan Hosp, Dept Endocrinol, Qingpu Branch, 1158 Gongyuan Rd, Shanghai 201700, Peoples R China.
   [Mao, Yan] Qingdao Univ, Affiliated Hosp, Breast Dis Ctr, 59 Haier Rd, Qingdao 266003, Shandong, Peoples R China.
C3 Shanghai Jiao Tong University; Shanghai Jiao Tong University; Shanghai
   Jiao Tong University; Capital Medical University; Shanghai Jiao Tong
   University; Fudan University; Qingdao University
RP Yao, LL (corresponding author), Shanghai Jiao Tong Univ, Ren Ji Hosp, Shanghai Canc Inst, Sch Med,State Key Lab Syst Med Canc, 800 Dongchuan Rd, Shanghai 200240, Peoples R China.; Han, CY (corresponding author), Fudan Univ, Zhongshan Hosp, Dept Endocrinol, Qingpu Branch, 1158 Gongyuan Rd, Shanghai 201700, Peoples R China.; Mao, Y (corresponding author), Qingdao Univ, Affiliated Hosp, Breast Dis Ctr, 59 Haier Rd, Qingdao 266003, Shandong, Peoples R China.
EM mynarrowgate@126.com; maoyan1011@qdu.edu.cn; llyao@shsci.org
RI DONG, Xinrui/MIP-4924-2025
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NR 47
TC 3
Z9 3
U1 1
U2 12
PU BMC
PI LONDON
PA CAMPUS, 4 CRINAN ST, LONDON N1 9XW, ENGLAND
SN 1465-5411
EI 1465-542X
J9 BREAST CANCER RES
JI Breast Cancer Res.
PD JUL 28
PY 2023
VL 25
IS 1
AR 90
DI 10.1186/s13058-023-01683-8
PG 16
WC Oncology
WE Science Citation Index Expanded (SCI-EXPANDED)
SC Oncology
GA N5NE7
UT WOS:001037469700001
PM 37507768
OA Green Published, gold
DA 2025-03-13
ER

PT J
AU Tao, S
   Li, H
   Ma, XZ
   Ma, YF
   He, JL
   Gao, YL
   Li, JP
AF Tao, Shuang
   Li, Hong
   Ma, Xiuzhen
   Ma, Yunfei
   He, Jiale
   Gao, Yali
   Li, Jinping
TI Elevating microRNA-1-3p shuttled by cancer-associated
   fibroblasts-derived extracellular vesicles suppresses breast cancer
   progression and metastasis by inhibiting GLIS1
SO CANCER GENE THERAPY
LA English
DT Article
ID EPITHELIAL-MESENCHYMAL TRANSITION; MIR-1-3P SUPPRESSES;
   CELL-PROLIFERATION; TUMOR-METASTASIS; BETA-CATENIN; INVASION;
   ACTIVATION; BIOMARKERS; RESISTANCE; PATHWAY
AB Cancer-associated fibroblasts (CAFs) play supporting roles in tumor progression by releasing microvesicles that transmit oncogenic cargoes. Indeed, extracellular vesicles (EVs) have emerged as important vehicles to deliver proteins, messenger RNAs (mRNAs), and microRNAs (miRs) between cells. In this study, we aimed to outline the role and function of CAFs-derived EVs carrying miR-1-3p in breast cancer. We first experimentally determined downregulated miR-1-3p in breast cancer tissues. EVs were isolated from CAFs extracted from breast cancer tissues, which showed downregulated miR-1-3p expression relative to EVs derived from normal fibroblasts (NFs). In a co-culture system, miR-1-3p cargo was transported into breast cancer cells via CAF-derived EVs. In gain-of-function experiments, the elevation of miR-1-3p in breast cancer cells inhibited cell viability, invasion, migration, and epithelial-to-mesenchymal transition, and suppressed tumor formation and metastasis. Furthermore, EVs derived from CAFs transfected with miR-1-3p mimic were more effective in transferring miR-1-3p to suppress cancer progression and metastasis. Kruppel-like zinc-finger protein Gli-similar 1 (GLIS1) was predicted to be a putative target of miR-1-3p, which was subsequently confirmed by dual-luciferase reporter assay. We then demonstrated that overexpression of GLIS1 neutralized the effects of miR-1-3 on the development of breast cancer in vitro. These findings shed light on the underlying mechanism by which CAFs-derived EVs carrying miR-1-3p mediate the progression and metastasis of breast cancer, and highlight the potential of miR-1-3p shuttled by CAFs-derived EVs serving as a therapeutic target for breast cancer.
C1 [Tao, Shuang] Changzhou 7 Peoples Hosp, Dept Breast Surg, Changzhou 213000, Peoples R China.
   [Li, Hong; Ma, Xiuzhen; Li, Jinping] Ningxia Med Univ, Gen Hosp, Dept Surg Oncol, Yinchuan 750004, Ningxia, Peoples R China.
   [Ma, Yunfei; He, Jiale; Gao, Yali] Ningxia Med Univ, Yinchuan 750004, Ningxia, Peoples R China.
C3 Ningxia Medical University; Ningxia Medical University
RP Li, JP (corresponding author), Ningxia Med Univ, Gen Hosp, Dept Surg Oncol, Yinchuan 750004, Ningxia, Peoples R China.
EM lijinping@nxmu.edu.cn
RI ma, xiuzhen/LTF-2461-2024; Gao, Yali/AAQ-7570-2020
FU National Natural Science Foundation of China [81760482, 82060479];
   Natural Science Foundation of Ningxia [2020AAC03417, 2018AAC03165];
   Changzhou Sci Tech Program [CJ20200068]
FX This work was supported by the National Natural Science Foundation of
   China (No. 81760482, 82060479), Natural Science Foundation of Ningxia
   (2020AAC03417, 2018AAC03165) and Changzhou Sci & Tech Program
   (CJ20200068).
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NR 37
TC 33
Z9 33
U1 1
U2 7
PU SPRINGERNATURE
PI LONDON
PA CAMPUS, 4 CRINAN ST, LONDON, N1 9XW, ENGLAND
SN 0929-1903
EI 1476-5500
J9 CANCER GENE THER
JI Cancer Gene Ther.
PD JUN
PY 2021
VL 28
IS 6
BP 634
EP 648
DI 10.1038/s41417-020-00244-x
EA NOV 2020
PG 15
WC Biotechnology & Applied Microbiology; Oncology; Genetics & Heredity;
   Medicine, Research & Experimental
WE Science Citation Index Expanded (SCI-EXPANDED)
SC Biotechnology & Applied Microbiology; Oncology; Genetics & Heredity;
   Research & Experimental Medicine
GA SS2FC
UT WOS:000587147300002
PM 33154575
DA 2025-03-13
ER

PT J
AU Ye, FZ
   Liang, YR
   Wang, YJ
   Le Yang, R
   Luo, D
   Li, YM
   Jin, YH
   Han, DW
   Chen, B
   Zhao, WJ
   Wang, LJ
   Chen, X
   Ma, TT
   Kong, XL
   Yang, QF
AF Ye, Fangzhou
   Liang, Yiran
   Wang, Yajie
   Le Yang, Robert
   Luo, Dan
   Li, Yaming
   Jin, Yuhan
   Han, Dianwen
   Chen, Bing
   Zhao, Wenjing
   Wang, Lijuan
   Chen, Xi
   Ma, Tingting
   Kong, Xiaoli
   Yang, Qifeng
TI Cancer-associated fibroblasts facilitate breast cancer progression
   through exosomal circTBPL1-mediated intercellular communication
SO CELL DEATH & DISEASE
LA English
DT Article
ID TUMOR-SUPPRESSOR; METASTASIS; MICROENVIRONMENT; PROLIFERATION;
   ACTIVATION; CARCINOMA; PROMOTES; INVASION; INSIGHTS; TBPL1
AB Breast cancer is the major common malignancy worldwide among women. Previous studies reported that cancer-associated fibroblasts (CAFs) showed pivotal roles in regulating tumor progression via exosome-mediated cellular communication. However, the detailed mechanism underlying the exosomal circRNA from CAFs in breast cancer progression remains ambiguous. Here, exosomal circRNA profiling of breast cancer-derived CAFs and normal fibroblasts (NFs) was detected by high-throughput sequencing, and upregulated circTBPL1 expression was identified in CAF exosomes. The exosomal circTBPL1 from CAFs could be transferred to breast cancer cells and promoted cell proliferation, migration, and invasion. Consistently, circTBPL1 knockdown in CAFs attenuated their tumor-promoting ability. Further exploration identified miR-653-5p as an inhibitory target of circTBPL1, and ectopic expression of miR-653-5p could partially reverse the malignant phenotypes induced by circTBPL1 overexpression in breast cancer. Additionally, TPBG was selected as a downstream target gene, and circTBPL1 could protect TPBG from miR-653-5p-mediated degradation, leading to enhanced breast cancer progression. Significantly, the accelerated tumor progression triggered by exosomal circTBPL1 from CAFs was confirmed in xenograft models. Taken together, these results revealed that exosomal circTBPL1 derived from CAFs contributed to cancer progression via miR-653-5p/TPBG pathway, indicating the potential of exosomal circTBPL1 as a biomarker and novel therapeutic target for breast cancer.
C1 [Ye, Fangzhou; Liang, Yiran; Wang, Yajie; Li, Yaming; Jin, Yuhan; Han, Dianwen; Chen, Xi; Ma, Tingting; Kong, Xiaoli; Yang, Qifeng] Shandong Univ, Qilu Hosp, Dept Breast Surg, Gen Surg, Jinan 250012, Shandong, Peoples R China.
   [Le Yang, Robert] Shandong Expt High Sch, Jinan 250001, Shandong, Peoples R China.
   [Luo, Dan; Chen, Bing; Zhao, Wenjing; Wang, Lijuan; Yang, Qifeng] Shandong Univ, Qilu Hosp, Pathol Tissue Bank, Jinan 250012, Shandong, Peoples R China.
   [Yang, Qifeng] Shandong Univ, Res Inst Breast Canc, Jinan 250012, Shandong, Peoples R China.
C3 Shandong University; Shandong University; Shandong University
RP Yang, QF (corresponding author), Shandong Univ, Qilu Hosp, Dept Breast Surg, Gen Surg, Jinan 250012, Shandong, Peoples R China.; Yang, QF (corresponding author), Shandong Univ, Qilu Hosp, Pathol Tissue Bank, Jinan 250012, Shandong, Peoples R China.; Yang, QF (corresponding author), Shandong Univ, Res Inst Breast Canc, Jinan 250012, Shandong, Peoples R China.
EM qifengy_sdu@163.com
RI Li, Long-Ke/S-7231-2016; liang, yiran/KDO-6280-2024
OI wang, haoyu/0009-0001-2467-5331
FU National Key Research and Development Program [2020YFA0712400]; National
   Natural Science Foundation of China [81874119, 82002785, 81902695,
   82002784, 81902697]; Natural Science Foundation of Shandong Province
   [ZR2020QH258]
FX This work was supported by the National Key Research and Development
   Program (No. 2020YFA0712400), National Natural Science Foundation of
   China (No. 81874119; No. 82002785; No. 81902695; No. 82002784; No.
   81902697), and Natural Science Foundation of Shandong Province (No.
   ZR2020QH258).
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NR 60
TC 22
Z9 23
U1 2
U2 12
PU SPRINGERNATURE
PI LONDON
PA CAMPUS, 4 CRINAN ST, LONDON, N1 9XW, ENGLAND
SN 2041-4889
J9 CELL DEATH DIS
JI Cell Death Dis.
PD JUL 26
PY 2023
VL 14
IS 7
AR 471
DI 10.1038/s41419-023-05986-8
PG 17
WC Cell Biology
WE Science Citation Index Expanded (SCI-EXPANDED)
SC Cell Biology
GA N5YP6
UT WOS:001037767700003
PM 37495592
OA Green Published, gold
DA 2025-03-13
ER

PT J
AU Zhan, YX
   Du, JX
   Min, ZH
   Ma, L
   Zhang, W
   Zhu, W
   Liu, YL
AF Zhan, Yanxia
   Du, Junxian
   Min, Zhihui
   Ma, Li
   Zhang, Wei
   Zhu, Wei
   Liu, Yonglei
TI Carcinoma-associated fibroblasts derived exosomes modulate breast cancer
   cell stemness through exonic circHIF1A by miR-580-5p in hypoxic stress
SO CELL DEATH DISCOVERY
LA English
DT Article
ID COLORECTAL-CANCER; CIRCULAR RNA; PROMOTE
AB Hypoxia is a common phenomenon in solid tumors. The roles of exosomes from hypoxic breast cancer stroma are less studied. So, the study was aimed to investigate the role of exosomes from hypoxic cancer-associated fibroblasts (CAFs) cells in breast cancer. The circRNA array analysis was performed to screen differential expressed circRNAs between hypoxic and normoxic CAFs exosomes. Candidate circHIF1A (circ_0032138) was screened out and it was confirmed that circHIF1A was up-regulated in the exosomes from hypoxic CAFs and their exosomes. Through investigating cellular functions including cell proliferation and stem cell features, it was demonstrated that hypoxic CAFs exosomes transferred circHIF1A into breast cancer cells, which played an important role in cancer stem cell properties sponging miR-580-5p by regulating CD44 expression. In a summary, circHIF1A from hypoxic CAFs exosomes played an important role in stem cell properties of breast cancer. CircHIF1A may act as a target molecule of breast cancer therapy.
C1 [Zhan, Yanxia] Fudan Univ, Zhongshan Hosp, Dept Hematol, Shanghai, Peoples R China.
   [Du, Junxian; Min, Zhihui; Ma, Li; Zhang, Wei] Fudan Univ, Zhongshan Hosp, Res Ctr, Shanghai, Peoples R China.
   [Du, Junxian; Zhu, Wei] Fudan Univ, Zhongshan Hosp, Gen Surg, Shanghai, Peoples R China.
   [Liu, Yonglei] Fudan Univ, Zhongshan Hosp Qingpu Branch, Res Ctr, Shanghai, Peoples R China.
C3 Fudan University; Fudan University; Fudan University; Fudan University
RP Zhu, W (corresponding author), Fudan Univ, Zhongshan Hosp, Gen Surg, Shanghai, Peoples R China.; Liu, YL (corresponding author), Fudan Univ, Zhongshan Hosp Qingpu Branch, Res Ctr, Shanghai, Peoples R China.
EM drzhu@163.com; yl_liu9@yeah.net
RI cai, wen/JWP-4797-2024; wei, li/JWP-9848-2024
FU Shanghai Qingpu District Health Commission [W2019-42]; Hospital Key
   Project [QYZ2019-05]; Shanghai Science and Technology Committee
   [19140901000]; National Natural Science Foundation of China [81502571]
FX This study was supported by Shanghai Qingpu District Health Commission
   (W2019-42), Hospital Key Project (No. QYZ2019-05), Shanghai Science and
   Technology Committee (No. 19140901000), and National Natural Science
   Foundation of China (No. 81502571).
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NR 29
TC 57
Z9 62
U1 2
U2 21
PU SPRINGERNATURE
PI LONDON
PA CAMPUS, 4 CRINAN ST, LONDON, N1 9XW, ENGLAND
EI 2058-7716
J9 CELL DEATH DISCOV
JI Cell Death Discov.
PD JUN 12
PY 2021
VL 7
IS 1
AR 141
DI 10.1038/s41420-021-00506-z
PG 15
WC Cell Biology
WE Science Citation Index Expanded (SCI-EXPANDED)
SC Cell Biology
GA SR1YF
UT WOS:000660839400001
PM 34120145
OA Green Published, gold
DA 2025-03-13
ER

PT J
AU Wang, SW
   Xu, KL
   Ruan, SQ
   Zhao, LL
   Chen, LR
AF Wang, Shan-Wei
   Xu, Kan-Lun
   Ruan, Shu-Qin
   Zhao, Li-Li
   Chen, Li-Rong
TI Overexpression of Caveolin-1 in Cancer-Associated Fibroblasts Predicts
   Good Outcome in Breast Cancer
SO BREAST CARE
LA English
DT Article
DE Breast cancer; Cancer-associated fibroblasts; Biomarker; Gene; Prognosis
ID STROMAL FIBROBLASTS; BASAL-LIKE; EXPRESSION; PROGRESSION; TUMORIGENESIS;
   CARCINOMAS
AB Background: The aim of this study was to investigate the expression of caveolin-1 (Cav-1) in cancer-associated fibroblasts (CAFs) and to explore its correlation with clinicopathologic parameters and prognosis. Materials and Methods: Cav-1 expression was detected in the stroma of 143 patients with breast cancer, 10 patients with ductal carcinoma in situ (DCIS), and 10 normal breast tissue samples. Results: Overexpression of stromal Cav-1 in breast cancer was associated with histological type, low histological grade, estrogen receptor (ER) negativity, and molecular subtypes. The expression rate of stronnal Cav-1 in breast cancer (65.7%, 94/143) was significantly higher than that of DCIS (0%, 0/10) and normal breast tissue (0%, 0/10) (p = 0.000). A positive correlation was found between stromal Cav-1 and ER (p = 0.046, rs = 0.218). Stromal Cav-1 expression in lumina! B was significantly higher than in basal-like type (p = 0.048). Furthermore, stromal expression of Cav-1 was significantly correlated with the 5-year survival rate (p = 0.029), and it was an independent prognostic factor (p = 0.009). Conclusion: Cav-1 expression in CAFs was correlated with histological type, histological grade, ER status, and molecular subtypes in breast cancer. Stromal Cav-1 expression was an independent prognostic factor, and the absence or reduction of Cav-1 expression in stromal CAFs of invasive breast cancer predicts poor prognostic outcome.
C1 [Wang, Shan-Wei; Ruan, Shu-Qin; Zhao, Li-Li] Zhejiang Univ, Sch Med, Affiliated Hosp 2, Key Lab Canc Prevent & Intervent,China Natl Minis, Hangzhou 310009, Zhejiang, Peoples R China.
   [Wang, Shan-Wei] Xian Med Coll, Sch Basic Med, Dept Pathol Anat, Xian, Peoples R China.
   [Xu, Kan-Lun; Chen, Li-Rong] Zhejiang Univ, Sch Med, Affiliated Hosp 2, Dept Pathol, Hangzhou 310009, Zhejiang, Peoples R China.
C3 Zhejiang University; Xi'an Medical University; Zhejiang University
RP Chen, LR (corresponding author), Zhejiang Univ, Sch Med, Affiliated Hosp 2, Dept Pathol, Hangzhou 310009, Zhejiang, Peoples R China.
EM Chenlr1999@163.com
RI Wang, Shanwei/AFL-9959-2022; Zhao, Lili/JEO-7007-2023
FU Institute of Medical Oncology
FX We thank the Institute of Medical Oncology, and Zhejiang University
   lecturer Zhou Lun for providing support and assistance.
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NR 17
TC 26
Z9 28
U1 0
U2 9
PU KARGER
PI BASEL
PA ALLSCHWILERSTRASSE 10, CH-4009 BASEL, SWITZERLAND
SN 1661-3791
EI 1661-3805
J9 BREAST CARE
JI Breast Care
PY 2012
VL 7
IS 6
BP 477
EP 483
DI 10.1159/000345464
PG 7
WC Oncology; Obstetrics & Gynecology
WE Science Citation Index Expanded (SCI-EXPANDED)
SC Oncology; Obstetrics & Gynecology
GA 079WX
UT WOS:000314204000008
PM 24715830
OA Green Published, Bronze
DA 2025-03-13
ER

PT J
AU Salimifard, S
   Masjedi, A
   Hojjat-Farsangi, M
   Ghalamfarsa, G
   Irandoust, M
   Azizi, G
   Mohammadi, H
   Keramati, MR
   Jadidi-Niaragh, F
AF Salimifard, Sevda
   Masjedi, Ali
   Hojjat-Farsangi, Mohammad
   Ghalamfarsa, Ghasem
   Irandoust, Mahzad
   Azizi, Gholamreza
   Mohammadi, Hamed
   Keramati, Mohammad Reza
   Jadidi-Niaragh, Farhad
TI Cancer associated fibroblasts as novel promising therapeutic targets in
   breast cancer
SO PATHOLOGY RESEARCH AND PRACTICE
LA English
DT Review
DE Breast cancer; Cancer associated fibroblast; Tumor microenvironment;
   Fibroblast; Cancer therapy
ID REGULATORY T-CELLS; TUMOR MICROENVIRONMENT; STROMAL FIBROBLASTS;
   COLORECTAL-CANCER; GENE-EXPRESSION; POOR-PROGNOSIS; COLON-CANCER;
   TGF-BETA; MESENCHYMAL TRANSITION; PRIMARY CULTURE
AB Breast cancer is one of the most important women-related malignancies, which is incurable (particularly in advanced stages) and tumor microenvironment is a number one accused part in the inefficiency of current anti-breast cancer therapeutic strategies. The tumor microenvironment is composed of various cellular and acellular components, which provide an optimum condition for freely expanding cancer cells in various cancer types, particularly breast cancer. Cancer-associated fibroblasts (CAFs) are one of the main cell types in the breast tumor region, which can promote various tumor-promoting processes such as expansion, angiogenesis, metastasis and drug resistance. CAFs directly (by cell-to-cell communication) and indirectly (through secreting soluble factors) can exert their tumorigenic functions. We try to elucidate the immunobiology of CAFs, their origin, function, and heterogeneity in association with their role in various cancer-promoting processes in breast cancer. Based on current knowledge, we believe that the origin of CAFs, their subsets, and their specific expressed biomarkers determine their pro- or anti-tumor functions. Therefore, targeting CAF without considering their specific functions may lead to a deleterious outcome. We propose to find and characterize each subtype of CAFs in association with its specific function in different stages of breast cancer to develop novel promising therapeutic approaches against the right CAF subtype.
C1 [Salimifard, Sevda; Keramati, Mohammad Reza] Mashhad Univ Med Sci, Sch Allied Med, Dept Hematol & Blood Transfus, Mashhad, Razavi Khorasan, Iran.
   [Masjedi, Ali] Tabriz Univ Med Sci, Drug Appl Res Ctr, Tabriz, Iran.
   [Masjedi, Ali] Tabriz Univ Med Sci, Student Res Comm, Tabriz, Iran.
   [Hojjat-Farsangi, Mohammad] Karolinska Inst, Dept Oncol Pathol, Bioclinicum, Stockholm, Sweden.
   [Hojjat-Farsangi, Mohammad] Bushehr Univ Med Sci, Persian Gulf Marine Biotechnol Med Res Ctr, Bushehr, Iran.
   [Ghalamfarsa, Ghasem] Yasuj Univ Med Sci, Cellular & Mol Res Ctr, Yasuj, Iran.
   [Irandoust, Mahzad] Tabriz Univ Med Sci, Stem Cell Res Ctr, Tabriz, Iran.
   [Azizi, Gholamreza; Mohammadi, Hamed] Alborz Univ Med Sci, Noncommunicable Dis Res Ctr, Karaj, Iran.
   [Jadidi-Niaragh, Farhad] Tabriz Univ Med Sci, Immunol Res Ctr, Tabriz, Iran.
   [Jadidi-Niaragh, Farhad] Tabriz Univ Med Sci, Fac Med, Dept Immunol, Tabriz, Iran.
C3 Mashhad University of Medical Sciences; Tabriz University of Medical
   Science; Tabriz University of Medical Science; Karolinska Institutet;
   Yasouj University; Tabriz University of Medical Science; Tabriz
   University of Medical Science; Tabriz University of Medical Science
RP Keramati, MR (corresponding author), Mashhad Univ Med Sci, Sch Allied Med, Dept Hematol & Blood Transfus, Mashhad, Razavi Khorasan, Iran.; Jadidi-Niaragh, F (corresponding author), Tabriz Univ Med Sci, Immunol Res Ctr, Tabriz, Iran.
EM Keramatimr@mums.ac.ir; jadidif@tbzmed.ac.ir
RI Jadidi-Niaragh, Farhad/D-3985-2017; Masjedi, Ali/AAB-6293-2019;
   Ghalamfarsa, Ghasem/M-5790-2017; Azizi, Gholamreza/B-9477-2018; Hojat
   Farsangi, Mohammad/E-8171-2018; Mohammadi, Hamed/J-8382-2016
OI Hojat Farsangi, Mohammad/0000-0002-0589-5523; Masjedi,
   Ali/0000-0002-7692-0925; Mohammadi, Hamed/0000-0002-0736-6211
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NR 136
TC 41
Z9 43
U1 0
U2 40
PU ELSEVIER GMBH
PI MUNICH
PA HACKERBRUCKE 6, 80335 MUNICH, GERMANY
SN 0344-0338
EI 1618-0631
J9 PATHOL RES PRACT
JI Pathol. Res. Pract.
PD MAY
PY 2020
VL 216
IS 5
AR 152915
DI 10.1016/j.prp.2020.152915
PG 11
WC Pathology
WE Science Citation Index Expanded (SCI-EXPANDED)
SC Pathology
GA LG6EA
UT WOS:000528190500002
PM 32146002
DA 2025-03-13
ER

PT J
AU Simpkins, SA
   Hanby, AM
   Holliday, DL
   Speirs, V
AF Simpkins, Samantha A.
   Hanby, Andrew M.
   Holliday, Deborah L.
   Speirs, Valerie
TI Clinical and functional significance of loss of caveolin-1 expression in
   breast cancer-associated fibroblasts
SO JOURNAL OF PATHOLOGY
LA English
DT Article
DE caveolin-1; stroma; invasion; breast
ID EARLY TUMOR RECURRENCE; PROGNOSTIC-SIGNIFICANCE; STROMAL CELLS;
   MICROENVIRONMENT; CARCINOMA
AB Loss of caveolin-1 (Cav-1) expression in breast cancer-associated fibroblasts (CAFs) is predictive of poor prognosis in breast cancer, but its function has not been established. Our study tested the hypotheses that loss of Cav-1 expression in breast fibroblasts was associated with poor prognosis in breast cancer, through promotion of breast cancer cell invasion. Cav-1 stromal expression was immunohistochemically assessed in 358 breast cancers. Cav-1 expression in primary breast fibroblasts was analysed by western blot. Modified Boyden chamber assays determined fibroblast ability to promote invasion of breast cancer cells. The impact of siRNA silencing of Cav-1 in fibroblasts was evaluated using invasion assays and 3D co-culture assays. Loss of Cav-1 expression in breast stroma was significantly associated with decreased breast cancer-specific and disease-free survival (p = 0.01). Mean survival was 72 months (Cav-1+ group) versus 29.5 months (Cav-1- group). This was confirmed in multivariate analysis. Cav-1 expression was significantly decreased in CAFs compared to normal fibroblasts (p = 0.01) and was associated with increased invasion-promoting capacity. Cav-1 siRNA-treated fibroblasts promoted significantly increased invasion of MDA-MB-468 and T47D breast cancer cells from 27% (control) to 67% (p = 0.006) and from 37% to 56%, respectively (p = 0.01). 3D co-cultures of MDA-MB-468 cells with myoepithelial cells led to the formation of organized cohesive structures when cultured with conditioned media from fibroblasts but resulted in a disorganized appearance in the presence of conditioned media from Cav-1 siRNA-treated fibroblasts, accompanied by loss of E-cadherin expression in tumour cells. Our data confirm that loss of stromal Cav-1 in breast cancer predicts poor outcome. At a functional level, Cav-1-deficient CAFs are capable of significantly increasing the invasive capacity of breast cancer cells. Copyright (C) 2012 Pathological Society of Great Britain and Ireland. Published by John Wiley & Sons, Ltd.
C1 [Simpkins, Samantha A.; Hanby, Andrew M.; Holliday, Deborah L.; Speirs, Valerie] Univ Leeds, Leeds Inst Mol Med, Leeds LS9 7TF, W Yorkshire, England.
C3 University of Leeds
RP Speirs, V (corresponding author), St James Univ Hosp, Leeds Inst Mol Med, Wellcome Trust Brenner Bldg, Leeds LS9 7TF, W Yorkshire, England.
EM v.speirs@leeds.ac.uk
RI Speirs, Valerie/ABE-7377-2021
FU Wolfson Foundation; Wellcome Trust; Breast Cancer Campaign
FX This study was supported by the Wolfson Foundation (SAS), the Wellcome
   Trust (DLH, SAS, VS), and the Breast Cancer Campaign (AMH, DLH, VS).
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NR 29
TC 81
Z9 86
U1 1
U2 14
PU WILEY
PI HOBOKEN
PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA
SN 0022-3417
EI 1096-9896
J9 J PATHOL
JI J. Pathol.
PD AUG
PY 2012
VL 227
IS 4
BP 490
EP 498
DI 10.1002/path.4034
PG 9
WC Oncology; Pathology
WE Science Citation Index Expanded (SCI-EXPANDED)
SC Oncology; Pathology
GA 971UJ
UT WOS:000306229100013
PM 22488553
DA 2025-03-13
ER

PT J
AU Magagna, I
   Gourdin, N
   Kieffer, Y
   Licaj, M
   Mhaidly, R
   Andre, P
   Morel, A
   Vincent-Salomon, A
   Paturel, C
   Mechta-Grigoriou, F
AF Magagna, Ilaria
   Gourdin, Nicolas
   Kieffer, Yann
   Licaj, Monika
   Mhaidly, Rana
   Andre, Pascale
   Morel, Ariane
   Vincent-Salomon, Anne
   Paturel, Carine
   Mechta-Grigoriou, Fatima
TI CD73-Mediated Immunosuppression Is Linked to a Specific Fibroblast
   Population That Paves the Way for New Therapy in Breast Cancer
SO CANCERS
LA English
DT Article
DE breast cancer; CAF subsets; Tregs; immunosuppression; anti-CD73 antibody
ID PROMOTE TUMOR-GROWTH; REGULATORY T-CELLS; STROMAL FIBROBLASTS;
   IMMUNE-RESPONSES; CD73; ADENOSINE; EXPRESSION; RESISTANCE; CARCINOMA;
   PD-1
AB Simple Summary Recent findings have revealed the contribution of cancer-associated fibroblasts (CAF) in immune escape in breast cancer. Still, how to specifically target immunosuppressive CAF remains an unmet medical question. Here, we provide a promising therapeutic strategy by highlighting the role of CD73 in immunosuppressive CAF. By studying cohorts of breast cancer patients and performing functional assays, our study uncovers how CD73 contributes to immunosuppression by acting in a specific CAF subpopulation (referred to as CAF-S1) in breast cancer. In addition, we validate that using an anti-CD73 antibody significantly reduces CAF-S1-mediated immunosuppression, thereby highlighting a new interesting therapeutic strategy for breast cancer patients. Background: Cancer-associated fibroblasts (CAF) are heterogeneous with multiple functions in breast cancer. Recently, we identified a specific CAF subpopulation (referred to as CAF-S1), which promotes immunosuppression and immunotherapy resistance. Methods and Results: Here, by studying a large collection of human samples, we highlight the key function of CD73/NT5E in CAF-S1-mediated immunosuppression in breast cancer. We first reveal that CD73 protein level specifically accumulates in CAF-S1 in breast cancer patients. Interestingly, infiltration of regulatory T lymphocytes (Tregs) is significantly correlated with CD73 expression in stroma but not in epithelium, indicating that CD73 contributes to immunosuppression when expressed in CAF-S1 and not in tumor cells. By performing functional assays based on relevant systems using primary CAF-S1 isolated from patients, we demonstrate that CAF-S1 increase the content in both PD-1+ and CTLA-4+ Tregs. Importantly, the use of a blocking anti-CD73 antibody on CAF-S1 reduces CAF-S1-mediated immunosuppression by preventing expression of these immune checkpoints on Tregs. Conclusions: Our data support the potential clinical benefit of using both anti-CD73 and immune-checkpoint inhibitors in breast cancer patients for inhibiting CAF-S1-mediated immunosuppression and enhancing anti-tumor immune response.
C1 [Magagna, Ilaria; Kieffer, Yann; Licaj, Monika; Mhaidly, Rana; Mechta-Grigoriou, Fatima] PSL Res Univ, Inst Curie, Equipe Labellisee Ligue Natl Canc Stress & Canc L, 26 Rue Ulm, F-75005 Paris, France.
   [Magagna, Ilaria; Kieffer, Yann; Licaj, Monika; Mhaidly, Rana; Mechta-Grigoriou, Fatima] INSERM, U830, F-75005 Paris, France.
   [Magagna, Ilaria; Gourdin, Nicolas; Andre, Pascale; Morel, Ariane; Paturel, Carine] Innate Pharma, 117 Ave De Luminy,BP 30191, F-13276 Marseille, France.
   [Vincent-Salomon, Anne] Inst Curie, Dept Diagnost & Theranost Med, Hosp Grp, F-75005 Paris, France.
C3 UNICANCER; Universite PSL; Institut Curie; Universite PSL; UNICANCER;
   Institut Curie; Institut National de la Sante et de la Recherche
   Medicale (Inserm); UNICANCER; Universite PSL; Institut Curie
RP Mechta-Grigoriou, F (corresponding author), PSL Res Univ, Inst Curie, Equipe Labellisee Ligue Natl Canc Stress & Canc L, 26 Rue Ulm, F-75005 Paris, France.; Mechta-Grigoriou, F (corresponding author), INSERM, U830, F-75005 Paris, France.
EM ilaria.magagna@curie.fr; nicolas.gourdin@innate-pharma.fr;
   yann.kieffer@curie.fr; monika.licaj@curie.fr; rana.mhaidly@curie.fr;
   pascale.andre@innate-pharma.fr; ariane.morel@innate-pharma.fr;
   anne.salomon@curie.fr; carine.paturel@innate-pharma.fr;
   fatima.mechta-grigoriou@curie.fr
RI ; Mechta-Grigoriou, Fatima/C-5253-2017
OI KIEFFER, Yann/0000-0003-2722-3071; Vincent-Salomon,
   Anne/0000-0001-5754-5771; Mechta-Grigoriou, Fatima/0000-0002-3751-6989
FU Institut National du Cancer, INCa [INCa-DGOS-9963, INCa-11692]; SIRIC
   [INCa-DGOS-4654]; Inserm [PC201317]; Institut Curie (Incentive and
   Cooperative Program Tumor Micro-environment PIC TME/T-MEGA, PIC3i CAFi);
   ICGex [ANR-10-EQPX-03]; INCa [STROMAE INCa-DGOS-9963, CaLYS INCa-11692,
   INCa-DGOSInserm-12554]; Foundation ARC; Foundation "Chercher et
   Trouver"; Ligue Nationale Contre le Cancer (Labelisation)
FX INCa-DGOS-4654 Y.K. was supported by the Institut National du Cancer,
   INCa (INCa-DGOS-9963; INCa-11692) and SIRIC (INCa-DGOS-4654). The
   experimental work was supported by grants from the Ligue Nationale
   Contre le Cancer (Labelisation), Inserm (PC201317), Institut Curie
   (Incentive and Cooperative Program Tumor Micro-environment PIC
   TME/T-MEGA, PIC3i CAFi), ICGex (ANR-10-EQPX-03), SIRIC (INCa-DGOS-4654),
   INCa (STROMAE INCa-DGOS-9963, CaLYS INCa-11692, INCa-DGOSInserm-12554),
   SIGN'it 2019 from the Foundation ARC and the Foundation "Chercher et
   Trouver".
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NR 64
TC 23
Z9 23
U1 0
U2 20
PU MDPI
PI BASEL
PA ST ALBAN-ANLAGE 66, CH-4052 BASEL, SWITZERLAND
EI 2072-6694
J9 CANCERS
JI Cancers
PD DEC
PY 2021
VL 13
IS 23
AR 5878
DI 10.3390/cancers13235878
PG 21
WC Oncology
WE Science Citation Index Expanded (SCI-EXPANDED)
SC Oncology
GA YG7CC
UT WOS:000742640700001
PM 34884993
OA Green Published, gold
DA 2025-03-13
ER

PT J
AU Roscigno, G
   Cirella, A
   Affinito, A
   Quintavalle, C
   Scognamiglio, I
   Palma, F
   Ingenito, F
   Nuzzo, S
   De Micco, F
   Cuccuru, A
   Thomas, R
   Condorelli, G
AF Roscigno, Giuseppina
   Cirella, Assunta
   Affinito, Alessandra
   Quintavalle, Cristina
   Scognamiglio, Iolanda
   Palma, Francesco
   Ingenito, Francesco
   Nuzzo, Silvia
   De Micco, Francesca
   Cuccuru, Antonio
   Thomas, Renato
   Condorelli, Gerolama
TI miR-216a Acts as a Negative Regulator of Breast Cancer by Modulating
   Stemness Properties and Tumor Microenvironment
SO INTERNATIONAL JOURNAL OF MOLECULAR SCIENCES
LA English
DT Article
DE Breast cancer; cancer stem cells; microRNA; tumor microenvironment
ID STROMAL FIBROBLASTS; UP-REGULATION; CELLS; IL-6; MAPK; GLIOBLASTOMA;
   INFLAMMATION; MICRORNAS; CARCINOMA; PATHWAYS
AB Breast cancer is the most frequent malignancy in females in terms of both incidence and mortality. Underlying the high mortality rate is the presence of cancer stem cells, which divide indefinitely and are resistant to conventional chemotherapies, so causing tumor relapse. In the present study, we identify miR-216a-5p as a downregulated microRNA in breast cancer stem cells vs. the differentiated counterpart. We demonstrate that overexpression of miR-216a-5p impairs stemness markers, mammosphere formation, ALDH activity, and the level of Toll-like receptor 4 (TLR4), which plays a significant role in breast cancer progression and metastasis by leading to the release of pro-inflammatory molecules, such as interleukin 6 (IL-6). Indeed, miR-216a regulates the crosstalk between cancer cells and the cells of the microenvironment, in particular cancer-associated fibroblasts (CAFs), through regulation of the TLR4/IL6 pathway. Thus, miR-216a has an important role in the regulation of stem phenotype, decreasing stem-like properties and affecting the cross-talk between cancer cells and the tumor microenvironment.
C1 [Roscigno, Giuseppina; Cirella, Assunta; Scognamiglio, Iolanda; Condorelli, Gerolama] Federico II Univ Naples, Dept Mol Med & Med Biotechnol, I-80131 Naples, Italy.
   [Affinito, Alessandra; Quintavalle, Cristina; Palma, Francesco; Ingenito, Francesco] Percuros BV, NL-2333 CL Leiden, Netherlands.
   [Quintavalle, Cristina; Condorelli, Gerolama] CNR Consiglio Nazl Ric, IEOS Ist Endocrinol & Oncol Sperimentale G Salvat, I-80131 Naples, Italy.
   [Nuzzo, Silvia] SYNLAB Ist Diagnost Nucl, IRCCS SDN Ist Ricovero & Cura Carattere Sci, I-80143 Naples, Italy.
   [De Micco, Francesca; Cuccuru, Antonio; Thomas, Renato] Mediterranea Cardioctr, I-80122 Naples, Italy.
C3 University of Naples Federico II; Consiglio Nazionale delle Ricerche
   (CNR)
RP Condorelli, G (corresponding author), Federico II Univ Naples, Dept Mol Med & Med Biotechnol, I-80131 Naples, Italy.; Condorelli, G (corresponding author), CNR Consiglio Nazl Ric, IEOS Ist Endocrinol & Oncol Sperimentale G Salvat, I-80131 Naples, Italy.
EM giusy_roscigno@yahoo.it; ass.cirella@outlook.com; aleaffi4@gmail.com;
   cristinaquintavalle@gmail.com; iolanda.scognamiglio@gmail.com;
   frapalma9@gmail.com; francesco.ingenito@outlook.it;
   nuzzo.silvia@gmail.com; demiccofrancesca@hotmail.it;
   amalianto@libero.it; senologia@clinicamediterranea.it; gecondor@unina.it
RI Condorelli, Gerolama/AAC-3472-2022; Nuzzo, Silvia/AAB-9550-2022;
   Quintavalle, Cristina/AHH-9379-2022; Quintavalle, Cristina/O-1317-2015;
   Affinito, Alessandra/Q-7859-2018
OI Quintavalle, Cristina/0000-0002-7432-9170; CIRELLA,
   ASSUNTA/0000-0001-8493-7113; Scognamiglio, Iolanda/0000-0003-0276-3207;
   Affinito, Alessandra/0000-0002-3887-6513; Nuzzo,
   Silvia/0000-0002-6537-7867
FU Associazione Italiana Ricerca sul Cancro (AIRC) [18473]; POR Campania
   FESR 2014-2020 "SATIN"; Fondazione Umberto Veronesi; MSCA IF [838988];
   Earlier foundation;  [H2020-MSCA-RISE-2019 cONCReTE 872391]; 
   [H2020-MSCA-RISE-2019 PRISAR2 872860];  [H2020-MSCA-RISE-2017 CANCER
   777682];  [MSCA-ITN-ETN CAST 857894];  [MSCA-ITN-ETN PAVE 861190]; Marie
   Curie Actions (MSCA) [838988] Funding Source: Marie Curie Actions (MSCA)
FX This research was funded by Associazione Italiana Ricerca sul Cancro
   (AIRC) (IG 2016 N. 18473, to G.C.); POR Campania FESR 2014-2020 "SATIN"
   to G.C., Earlier foundation to GC; H2020-MSCA-RISE-2019 cONCReTE 872391,
   H2020-MSCA-RISE-2019 PRISAR2 872860, H2020-MSCA-RISE-2017 CANCER 777682,
   MSCA-ITN-ETN CAST 857894, MSCA-ITN-ETN PAVE 861190. G.R. was supported
   by Fondazione Umberto Veronesi; C.Q. is recipient of a MSCA IF N.
   838988.
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NR 51
TC 14
Z9 16
U1 1
U2 5
PU MDPI
PI BASEL
PA ST ALBAN-ANLAGE 66, CH-4052 BASEL, SWITZERLAND
SN 1661-6596
EI 1422-0067
J9 INT J MOL SCI
JI Int. J. Mol. Sci.
PD APR
PY 2020
VL 21
IS 7
AR 2313
DI 10.3390/ijms21072313
PG 16
WC Biochemistry & Molecular Biology; Chemistry, Multidisciplinary
WE Science Citation Index Expanded (SCI-EXPANDED)
SC Biochemistry & Molecular Biology; Chemistry
GA LR3DN
UT WOS:000535574200055
PM 32230799
OA Green Published, gold
DA 2025-03-13
ER

PT J
AU Gao, Y
   Li, XJ
   Zeng, C
   Liu, CL
   Hao, Q
   Li, WN
   Zhang, K
   Zhang, WQ
   Wang, SN
   Zhao, HD
   Fan, D
   Li, M
   Zhang, YQ
   Zhang, W
   Zhang, C
AF Gao, Yuan
   Li, Xiaoju
   Zeng, Cheng
   Liu, Chenlin
   Hao, Qiang
   Li, Weina
   Zhang, Kuo
   Zhang, Wangqian
   Wang, Shuning
   Zhao, Huadong
   Fan, Dong
   Li, Meng
   Zhang, Yingqi
   Zhang, Wei
   Zhang, Cun
TI CD63<SUP>+</SUP>Cancer-Associated Fibroblasts Confer Tamoxifen
   Resistance to Breast Cancer Cells through Exosomal miR-22
SO ADVANCED SCIENCE
LA English
DT Article
DE breast cancer; cancer-associated fibroblasts; exosomes; miR-22;
   tamoxifen
ID ESTROGEN-RECEPTOR-ALPHA; GENE-EXPRESSION; INHIBITOR; PTEN; MECHANISMS;
   SUPPRESSOR; THERAPY; MIRNAS; GROWTH; NICHE
AB Tamoxifen remains the most effective treatment for estrogen receptor alpha (ER alpha)-positive breast cancer. However, many patients still develop resistance to tamoxifen in association with metastatic recurrence, which presents a tremendous clinical challenge. To better understand tamoxifen resistance from the perspective of the tumor microenvironment, the whole microenvironment landscape is charted by single-cell RNA sequencing and a new cancer-associated fibroblast (CAF) subset, CD63(+)CAFs, is identified that promotes tamoxifen resistance in breast cancer. Furthermore, it is discovered that CD63(+)CAFs secrete exosomes rich in miR-22, which can bind its targets, ER alpha and PTEN, to confer tamoxifen resistance on breast cancer cells. Additionally, it is found that the packaging of miR-22 into CD63(+)CAF-derived exosomes is mediated by SFRS1. Furthermore, CD63 induces STAT3 activation to maintain the phenotype and function of CD63(+)CAFs. Most importantly, the pharmacological blockade of CD63(+)CAFs with a CD63-neutralizing antibody or cRGD-miR-22-sponge nanoparticles enhances the therapeutic effect of tamoxifen in breast cancer. In summary, the study reveals a novel subset of CD63(+)CAFs that induces tamoxifen resistance in breast cancer via exosomal miR-22, suggesting that CD63(+)CAFs may be a novel therapeutic target to enhance tamoxifen sensitivity.
C1 [Gao, Yuan; Li, Xiaoju; Zeng, Cheng; Liu, Chenlin; Hao, Qiang; Li, Weina; Zhang, Kuo; Zhang, Wangqian; Wang, Shuning; Li, Meng; Zhang, Yingqi; Zhang, Wei; Zhang, Cun] Fourth Mil Med Univ, Sch Pharm, Ctr Biotechnol, State Key Lab Canc Biol, Xian 710032, Peoples R China.
   [Zeng, Cheng] Fourth Mil Med Univ, Sch Pharm, Inst Mat Med, Xian 710032, Peoples R China.
   [Zhao, Huadong; Fan, Dong] Fourth Mil Med Univ, Tangdu Hosp, Dept Gen Surg, Xian 710038, Peoples R China.
C3 Air Force Military Medical University; Air Force Military Medical
   University; Air Force Military Medical University
RP Zhang, YQ; Zhang, W; Zhang, C (corresponding author), Fourth Mil Med Univ, Sch Pharm, Ctr Biotechnol, State Key Lab Canc Biol, Xian 710032, Peoples R China.
EM zhangyqh@fmmu.edu.cn; zhangw90@fmmu.edu.cn; zhangcun@fmmu.edu.cn
RI li, fei/HJO-9520-2023; zhang, cun/KYQ-2883-2024
OI Gao, Yuan/0000-0002-0507-6499; Zeng, Cheng/0000-0002-7327-7807
FU National Natural Science Foundation of China (NSFC) [81902678, 81672864,
   81802632, 81702590]; Key Research and Development Program of Shaanxi
   Province [2017ZDCXL-SF-01-03]
FX This study was supported by grants from the National Natural Science
   Foundation of China (NSFC), Nos. 81902678, 81672864, 81802632, 81702590;
   and the Key Research and Development Program of Shaanxi Province (No.
   2017ZDCXL-SF-01-03).
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NR 60
TC 111
Z9 118
U1 1
U2 43
PU WILEY
PI HOBOKEN
PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA
EI 2198-3844
J9 ADV SCI
JI Adv. Sci.
PD NOV
PY 2020
VL 7
IS 21
AR 2002518
DI 10.1002/advs.202002518
EA SEP 2020
PG 17
WC Chemistry, Multidisciplinary; Nanoscience & Nanotechnology; Materials
   Science, Multidisciplinary
WE Science Citation Index Expanded (SCI-EXPANDED)
SC Chemistry; Science & Technology - Other Topics; Materials Science
GA OP9BG
UT WOS:000572374200001
PM 33173749
OA gold, Green Published
DA 2025-03-13
ER

PT J
AU Kalpana, G
   Figy, C
   Yeung, M
   Yeung, KC
AF Kalpana, Gardiyawasam
   Figy, Christopher
   Yeung, Miranda
   Yeung, Kam C.
TI Reduced RhoA expression enhances breast cancer metastasis with a
   concomitant increase in CCR5 and CXCR4 chemokines signaling
SO SCIENTIFIC REPORTS
LA English
DT Article
ID NF-KAPPA-B; TUMOR PROGRESSION; BLOOD-VESSELS; UP-REGULATION; GTPASES;
   CELL; ACTIVATION; MUTATIONS; PROTEIN; DISSEMINATION
AB The role of RhoA GTPases in breast cancer tumorigenesis and metastasis is unclear. Early studies within which mutations in RhoA were designed based on cancer-associated mutations in Ras supported an oncogene role for RhoA. However, recent whole-genome sequencing studies of cancers raised the possibility that RhoA may have a tumor suppression function. Here, using a syngeneic triple negative breast cancer murine model we investigated the physiological effects of reduced RhoA expression on breast cancer tumorigenesis and metastasis. RhoA knockdown had no effect on primary tumor formation and tumor proliferation, concurring with our in vitro findings where reduced RhoA had no effect on breast cancer cell proliferation and clonogenic growth. In contrast, primary tumors with RhoA knockdown efficiently invaded sentinel lymph nodes and significantly metastasized to lungs compared to control tumors. Mechanistically, the current study demonstrated that this is achieved by promoting a pro-tumor microenvironment, with increased cancer-associated fibroblasts and macrophage infiltration, and by modulating the CCL5-CCR5 and CXCL12-CXCR4 chemokine axes in the primary tumor. To our knowledge, this is the first such mechanistic study in breast cancer showing the ability of RhoA to suppress chemokine receptor expression in breast tumor cells. Our work suggests a physiological lung and lymph node metastasis suppressor role for RhoA GTPase in breast cancer.
C1 [Kalpana, Gardiyawasam; Figy, Christopher; Yeung, Miranda; Yeung, Kam C.] Univ Toledo, Dept Canc Biol, Coll Med & Life Sci, Hlth Sci Campus, Toledo, OH 43614 USA.
C3 University System of Ohio; University of Toledo; University of Toledo
   Health Science Campus
RP Yeung, KC (corresponding author), Univ Toledo, Dept Canc Biol, Coll Med & Life Sci, Hlth Sci Campus, Toledo, OH 43614 USA.
EM kam.yeung@utoledo.edu
FU URFO Biomedical Research Award from University of Toledo; Fully Honest
   Corp Research Grant
FX We thank Dr. Ivana de la Serna for providing the PD0325901 drug and for
   critical reading of the manuscript. The human RhoA shRNA expressing
   lentivirus was a kind gift of Dr. Rafael Garcia-Mata. UT Foundation, a
   gift from Clement Lam to KCY, Fully Honest Corp Research Grant and a
   URFO Biomedical Research Award from University of Toledo supported this
   work.
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NR 55
TC 34
Z9 38
U1 0
U2 7
PU NATURE PORTFOLIO
PI BERLIN
PA HEIDELBERGER PLATZ 3, BERLIN, 14197, GERMANY
SN 2045-2322
J9 SCI REP-UK
JI Sci Rep
PD NOV 8
PY 2019
VL 9
AR 16351
DI 10.1038/s41598-019-52746-w
PG 12
WC Multidisciplinary Sciences
WE Science Citation Index Expanded (SCI-EXPANDED)
SC Science & Technology - Other Topics
GA JL2OO
UT WOS:000495371900027
PM 31705019
OA gold, Green Published
DA 2025-03-13
ER

PT J
AU Koyama, Y
   Okazaki, H
   Shi, Y
   Mezawa, Y
   Wang, ZX
   Sakimoto, M
   Ishizuka, A
   Ito, Y
   Koyama, T
   Daigo, Y
   Takano, A
   Miyagi, Y
   Yokose, T
   Yamashita, T
   Sugahara, K
   Hino, O
   Yang, LY
   Maruyama, R
   Katakura, A
   Yasukawa, T
   Orimo, A
AF Koyama, Yu
   Okazaki, Hiroya
   Shi, Yang
   Mezawa, Yoshihiro
   Wang, Zixu
   Sakimoto, Mizuki
   Ishizuka, Akane
   Ito, Yasuhiko
   Koyama, Takumi
   Daigo, Yataro
   Takano, Atsushi
   Miyagi, Yohei
   Yokose, Tomoyuki
   Yamashita, Toshinari
   Sugahara, Keisuke
   Hino, Okio
   Yang, Liying
   Maruyama, Reo
   Katakura, Akira
   Yasukawa, Takehiro
   Orimo, Akira
TI Increased RUNX3 expression mediates tumor-promoting ability of human
   breast cancer-associated fibroblasts
SO CANCER MEDICINE
LA English
DT Article
DE breast cancer; CAFs; cancer-associated fibroblasts; RUNX3; tumor
   microenvironment
ID GENE-EXPRESSION; STROMAL FIBROBLASTS; BETA; TRANSCRIPTION; FAMILY;
   GROWTH; CARCINOMAS
AB Background Cancer-associated fibroblasts (CAFs) are a major stromal component of human breast cancers and often promote tumor proliferation, progression and malignancy. We previously established an experimental CAF (exp-CAF) cell line equipped with a potent tumor-promoting ability. It was generated through prolonged incubation of immortalized human mammary fibroblasts with human breast cancer cells in a tumor xenograft mouse model.Results Herein, we found that the exp-CAFs highly express Runt-related transcription factor 3 (RUNX3), while counterpart fibroblasts do not. In breast cancer patients, the proportion of RUNX3-positive stromal fibroblast-like cells tends to be higher in cancerous regions than in non-cancerous regions. These findings suggest an association of RUNX3 with CAF characteristics in human breast cancers. To investigate the functional role of RUNX3 in CAFs, the exp-CAFs with or without shRNA-directed knockdown of RUNX3 were implanted with breast cancer cells subcutaneously in immunodeficient mice. Comparison of the resulting xenograft tumors revealed that tumor growth was significantly attenuated when RUNX3 expression was suppressed in the fibroblasts. Consistently, Ki-67 and CD31 immunohistochemical staining of the tumor sections indicated reduction of cancer cell proliferation and microvessel formation in the tumors formed with the RUNX3-suppressed exp-CAFs.Conclusion These results suggest that increased RUNX3 expression could contribute to the tumor-promoting ability of CAFs through mediating cancer cell growth and neoangiogenesis in human breast tumors.
C1 [Koyama, Yu; Okazaki, Hiroya; Sugahara, Keisuke; Katakura, Akira] Tokyo Dent Coll, Dept Oral Pathobiol Sci & Surg, Tokyo, Japan.
   [Koyama, Yu; Okazaki, Hiroya; Shi, Yang; Mezawa, Yoshihiro; Wang, Zixu; Sakimoto, Mizuki; Ishizuka, Akane; Ito, Yasuhiko; Koyama, Takumi; Hino, Okio; Yasukawa, Takehiro; Orimo, Akira] Juntendo Univ, Fac Med, Dept Pathol & Oncol, Tokyo, Japan.
   [Shi, Yang; Mezawa, Yoshihiro; Wang, Zixu; Ishizuka, Akane; Yasukawa, Takehiro] Juntendo Univ, Grad Sch Med, Dept Mol Pathogenesis, Tokyo, Japan.
   [Daigo, Yataro; Takano, Atsushi] Univ Tokyo, Res Hosp, Inst Med Sci, Ctr Antibody & Vaccine Therapy, Tokyo, Japan.
   [Daigo, Yataro; Takano, Atsushi] Shiga Univ Med Sci, Dept Med Oncol, Otsu, Japan.
   [Daigo, Yataro; Takano, Atsushi] Shiga Univ Med Sci, Canc Ctr, Otsu, Japan.
   [Daigo, Yataro; Takano, Atsushi] Shiga Univ Med Sci, Ctr Adv Med Canc, Otsu, Japan.
   [Miyagi, Yohei] Kanagawa Canc Ctr Res Inst, Mol Pathol & Genet Div, Yokohama, Japan.
   [Yokose, Tomoyuki] Kanagawa Canc Ctr, Dept Pathol, Yokohama, Japan.
   [Yamashita, Toshinari] Kanagawa Canc Ctr, Dept Breast Surg & Oncol, Yokohama, Japan.
   [Yang, Liying; Maruyama, Reo] Japanese Fdn Canc Res, Canc Inst, Project Canc Epigen, Tokyo, Japan.
   [Ito, Yasuhiko] Juntendo Univ, Grad Sch Med, Dept Immunol Diag, Tokyo, Japan.
   [Yasukawa, Takehiro; Orimo, Akira] Juntendo Univ, Fac Med, Dept Pathol & Oncol, 2-1-1 Hongo, Bunkyo Ku, Tokyo 1138421, Japan.
C3 Tokyo Dental College; Juntendo University; Juntendo University;
   University of Tokyo; Shiga University of Medical Science; Shiga
   University of Medical Science; Shiga University of Medical Science;
   Kanagawa Prefectural Cancer Center; Kanagawa Prefectural Cancer Center;
   Kanagawa Prefectural Cancer Center; Japanese Foundation for Cancer
   Research; Juntendo University; Juntendo University
RP Yasukawa, T; Orimo, A (corresponding author), Juntendo Univ, Fac Med, Dept Pathol & Oncol, 2-1-1 Hongo, Bunkyo Ku, Tokyo 1138421, Japan.
EM t.yasukawa.vb@juntendo.ac.jp; aorimo@juntendo.ac.jp
RI Yasukawa, Takehiro/AAP-1335-2020
OI Yasukawa, Takehiro/0000-0001-9531-8780; Okazaki,
   Hiroya/0009-0004-4952-8145; Daigo, Yataro/0000-0002-0915-3025
FU We thank Ms. Chie Kataoka for assisting figure organization. Dr.
   Yoshiaki Ito for providing human RUNX3 cDNA, Ms Naomi Ohtsuji for
   preparation of paraffin sections and assistance of immunohistochemistry,
   Dr. Toshiyuki Kobayashi, Mrs. Masaaki Abe and Tetsuy; Grants-in-Aid for
   Scientific Research [22H04923, 23K14603, 23K27506, 22K17217, 22K20837,
   21K07127] Funding Source: KAKEN
FX We thank Ms. Chie Kataoka for assisting figure organization. Dr.
   Yoshiaki Ito for providing human RUNX3 cDNA, Ms Naomi Ohtsuji for
   preparation of paraffin sections and assistance of immunohistochemistry,
   Dr. Toshiyuki Kobayashi, Mrs. Masaaki Abe and Tetsuya Takagaki for
   technical and general assistance, Ms. Wali Nadila and Dr Katsumi
   Miyahara for immunofluorescence. We also thank the Laboratory of
   Molecular and Biochemical Research, Biomedical Research Core Facilities
   at Juntendo University and Oral health research center, Tokyo Dental
   College, for technical assistance.
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NR 35
TC 2
Z9 3
U1 0
U2 6
PU WILEY
PI HOBOKEN
PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA
SN 2045-7634
J9 CANCER MED-US
JI Cancer Med.
PD SEP
PY 2023
VL 12
IS 17
BP 18062
EP 18077
DI 10.1002/cam4.6421
EA AUG 2023
PG 16
WC Oncology
WE Science Citation Index Expanded (SCI-EXPANDED)
SC Oncology
GA U2CD8
UT WOS:001063737800001
PM 37641472
OA Green Published, gold
DA 2025-03-13
ER

PT J
AU Buchsbaum, RJ
   Oh, SY
AF Buchsbaum, Rachel J.
   Oh, Sun Young
TI Breast Cancer-Associated Fibroblasts: Where We Are and Where We Need to
   Go
SO CANCERS
LA English
DT Review
DE breast cancer; tumor microenvironment; cancer-associated fibroblasts
ID EPITHELIAL-MESENCHYMAL TRANSITION; STROMAL CAVEOLIN-1 EXPRESSION;
   INVASIVE DUCTAL CARCINOMA; NORMAL MAMMARY FIBROBLASTS; HEPATOCYTE
   GROWTH-FACTOR; EARLY TUMOR RECURRENCE; GENE-EXPRESSION; OXIDATIVE
   STRESS; TGF-BETA; IN-VITRO
AB Cancers are heterogeneous tissues comprised of multiple components, including tumor cells and microenvironment cells. The tumor microenvironment has a critical role in tumor progression. The tumor microenvironment is comprised of various cell types, including fibroblasts, macrophages and immune cells, as well as extracellular matrix and various cytokines and growth factors. Fibroblasts are the predominant cell type in the tumor microenvironment. However, neither the derivation of tissue-specific cancer-associated fibroblasts nor markers of tissue-specific cancer-associated fibroblasts are well defined. Despite these uncertainties it is increasingly apparent that cancer-associated fibroblasts have a crucial role in tumor progression. In breast cancer, there is evolving evidence showing that breast cancer-associated fibroblasts are actively involved in breast cancer initiation, proliferation, invasion and metastasis. Breast cancer-associated fibroblasts also play a critical role in metabolic reprogramming of the tumor microenvironment and therapy resistance. This review summarizes the current understanding of breast cancer-associated fibroblasts.
C1 [Buchsbaum, Rachel J.] Mol Oncol Res Inst, Tufts Med Ctr, Div Hematol Oncol, Boston, MA 02111 USA.
   [Buchsbaum, Rachel J.] Tufts Med Ctr, Dept Med, Boston, MA 02111 USA.
   [Oh, Sun Young] Montefiore Med Ctr, Dept Med, Div Med Oncol, New York, NY 10467 USA.
C3 Tufts Medical Center; Tufts Medical Center; Montefiore Medical Center
RP Buchsbaum, RJ (corresponding author), Mol Oncol Res Inst, Tufts Med Ctr, Div Hematol Oncol, Boston, MA 02111 USA.; Buchsbaum, RJ (corresponding author), Tufts Med Ctr, Dept Med, Boston, MA 02111 USA.
EM rbuchsbaum@tuftsmedicalcenter.org; suyoung@montefiore.org
OI Buchsbaum, Rachel/0000-0003-2502-9240
FU Diane Connolly-Zaniboni Research Scholarship in Breast Cancer (RJB)
   [NIH-T32 CA009429]
FX This work was supported by the Diane Connolly-Zaniboni Research
   Scholarship in Breast Cancer (RJB) and NIH-T32 CA009429 (SYO).
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NR 131
TC 142
Z9 160
U1 0
U2 36
PU MDPI
PI BASEL
PA ST ALBAN-ANLAGE 66, CH-4052 BASEL, SWITZERLAND
EI 2072-6694
J9 CANCERS
JI Cancers
PD FEB
PY 2016
VL 8
IS 2
AR 19
DI 10.3390/cancers8020019
PG 19
WC Oncology
WE Science Citation Index Expanded (SCI-EXPANDED)
SC Oncology
GA EO7QH
UT WOS:000396884700007
PM 26828520
OA Green Published, Green Submitted, gold
DA 2025-03-13
ER

PT J
AU Zheng, J
   Hao, H
AF Zheng, Jian
   Hao, Hua
TI The importance of cancer-associated fibroblasts in targeted therapies
   and drug resistance in breast cancer
SO FRONTIERS IN ONCOLOGY
LA English
DT Review
DE cancer-associated fibroblasts; breast cancer; mechanism; targeted
   therapy; immunotherapy; drug resistance; prognosis
ID INVASIVE DUCTAL CARCINOMA; TUMOR MICROENVIRONMENT; TGF-BETA;
   PROGNOSTIC-SIGNIFICANCE; MESENCHYMAL TRANSITION; EXTRACELLULAR-MATRIX;
   RECEPTOR EXPRESSION; CELL-MIGRATION; PROMOTES; GROWTH
AB Cancer-associated fibroblasts (CAFs) play a substantial role in the tumor microenvironment, exhibiting a strong association with the advancement of various types of cancer, including breast, pancreatic, and prostate cancer. CAFs represent the most abundant mesenchymal cell population in breast cancer. Through diverse mechanisms, including the release of cytokines and exosomes, CAFs contribute to the progression of breast cancer by influencing tumor energy metabolism, promoting angiogenesis, impairing immune cell function, and remodeling the extracellular matrix. Moreover, CAFs considerably impact the response to treatment in breast cancer. Consequently, the development of interventions targeting CAFs has emerged as a promising therapeutic approach in the management of breast cancer. This article provides an analysis of the role of CAFs in breast cancer, specifically in relation to diagnosis, treatment, drug resistance, and prognosis. The paper succinctly outlines the diverse mechanisms through which CAFs contribute to the malignant behavior of breast cancer cells, including proliferation, invasion, metastasis, and drug resistance. Furthermore, the article emphasizes the potential of CAFs as valuable tools for early diagnosis, targeted therapy, treatment resistance, and prognosis assessment in breast cancer, thereby offering novel approaches for targeted therapy and overcoming treatment resistance in this disease.
C1 [Zheng, Jian; Hao, Hua] Tongji Univ, Yangpu Hosp, Sch Med, Dept Pathol, Shanghai, Peoples R China.
C3 Tongji University
RP Hao, H (corresponding author), Tongji Univ, Yangpu Hosp, Sch Med, Dept Pathol, Shanghai, Peoples R China.
EM haohua410@tongji.edu.cn
FU Project of Shanghai Municipal Health Commission [202140232]; Climb Plan
   of Tongji University Affiliated Yangpu Hospital [Ye2202105]; Project of
   College-level Key Discipline of Tongji University Affiliated Yangpu
   Hospital [2023YJXK01]; The "Bringing in talent scientific starting
   project" grant of Tongji University Affiliated Yangpu Hospital
FX The author(s) declare financial support was received for the research,
   authorship, and/or publication of this article. This work was supported
   by project of Shanghai Municipal Health Commission (No.202140232), Climb
   Plan of Tongji University Affiliated Yangpu Hospital (No.Ye2202105),
   Project of College-level Key Discipline of Tongji University Affiliated
   Yangpu Hospital (No.2023YJXK01) and a "Bringing in talent scientific
   starting project" grant of Tongji University Affiliated Yangpu Hospital.
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NR 192
TC 15
Z9 15
U1 3
U2 19
PU FRONTIERS MEDIA SA
PI LAUSANNE
PA AVENUE DU TRIBUNAL FEDERAL 34, LAUSANNE, CH-1015, SWITZERLAND
SN 2234-943X
J9 FRONT ONCOL
JI Front. Oncol.
PD JAN 4
PY 2024
VL 13
AR 1333839
DI 10.3389/fonc.2023.1333839
PG 19
WC Oncology
WE Science Citation Index Expanded (SCI-EXPANDED)
SC Oncology
GA FR6C1
UT WOS:001147610700001
PM 38273859
OA Green Published, gold
DA 2025-03-13
ER

PT J
AU Santolla, MF
   Talia, M
   Cirillo, F
   Scordamaglia, D
   De Rosis, S
   Spinelli, A
   Miglietta, AM
   Nardo, B
   Filippelli, G
   De Francesco, EM
   Belfiore, A
   Lappano, R
   Maggiolini, M
AF Santolla, Maria Francesca
   Talia, Marianna
   Cirillo, Francesca
   Scordamaglia, Domenica
   De Rosis, Salvatore
   Spinelli, Asia
   Miglietta, Anna Maria
   Nardo, Bruno
   Filippelli, Gianfranco
   De Francesco, Ernestina Marianna
   Belfiore, Antonino
   Lappano, Rosamaria
   Maggiolini, Marcello
TI The AGEs/RAGE Transduction Signaling Prompts IL-8/CXCR1/2-Mediated
   Interaction between Cancer-Associated Fibroblasts (CAFs) and Breast
   Cancer Cells
SO CELLS
LA English
DT Article
DE cancer-associated fibroblasts; AGEs; RAGE; IL-8; breast cancer
ID GLYCATION END-PRODUCTS; INTERLEUKIN-8; EXPRESSION; RECEPTOR; TUMOR;
   PROTEIN; GROWTH; METASTASIS; OBESITY; RAGE
AB Advanced glycation end products (AGEs) and the cognate receptor, named RAGE, are involved in metabolic disorders characterized by hyperglycemia, type 2 diabetes mellitus (T2DM) and obesity. Moreover, the AGEs/RAGE transduction pathway prompts a dysfunctional interaction between breast cancer cells and tumor stroma toward the acquisition of malignant features. However, the action of the AGEs/RAGE axis in the main players of the tumor microenvironment, named breast cancer-associated fibroblasts (CAFs), remains to be fully explored. In the present study, by chemokine array, we first assessed that interleukin-8 (IL-8) is the most up-regulated pro-inflammatory chemokine upon AGEs/RAGE activation in primary CAFs, obtained from breast tumors. Thereafter, we ascertained that the AGEs/RAGE signaling promotes a network cascade in CAFs, leading to the c-Fos-dependent regulation of IL-8. Next, using a conditioned medium from AGEs-exposed CAFs, we determined that IL-8/CXCR1/2 paracrine activation induces the acquisition of migratory and invasive features in MDA-MB-231 breast cancer cells. Altogether, our data provide new insights on the involvement of IL-8 in the AGEs/RAGE transduction pathway among the intricate connections linking breast cancer cells to the surrounding stroma. Hence, our findings may pave the way for further investigations to define the role of IL-8 as useful target for the better management of breast cancer patients exhibiting metabolic disorders.
C1 [Santolla, Maria Francesca; Talia, Marianna; Cirillo, Francesca; Scordamaglia, Domenica; De Rosis, Salvatore; Spinelli, Asia; Nardo, Bruno; Lappano, Rosamaria; Maggiolini, Marcello] Univ Calabria, Dept Pharm Hlth & Nutr Sci, I-87036 Arcavacata Di Rende, Italy.
   [Miglietta, Anna Maria; Nardo, Bruno] Reg Hosp Cosenza, Breast & Gen Surg Unit, I-87100 Cosenza, Italy.
   [Filippelli, Gianfranco] Hosp Paola, Oncol Dept, I-87100 Cosenza, Italy.
   [De Francesco, Ernestina Marianna; Belfiore, Antonino] Univ Catania, Garibaldi Nesima Hosp, Dept Clin & Expt Med, Endocrinol, I-95122 Catania, Italy.
C3 University of Calabria; University of Catania; Presidio Ospedaliero
   Garibaldi-Nesima
RP Lappano, R; Maggiolini, M (corresponding author), Univ Calabria, Dept Pharm Hlth & Nutr Sci, I-87036 Arcavacata Di Rende, Italy.
EM rosamaria.lappano@unical.it; marcello.maggiolini@unical.it
RI Santolla, Maria/AAH-5481-2020; Maggiolini, Marcello/Z-4729-2019;
   CIRILLO, FRANCESCA/K-2612-2018; De Francesco, Ernestina
   Marianna/LQK-4482-2024; BELFIORE, Antonino/B-4652-2011
OI Santolla, Maria Francesca/0000-0002-4838-5953; De Francesco, Ernestina
   Marianna/0000-0002-2810-6128; Talia, Marianna/0000-0002-3440-5618;
   Maggiolini, Marcello/0000-0002-7485-854X; BELFIORE,
   Antonino/0000-0002-6181-4193
FU Fondazione AIRC [23369, 21651, 21322]; Ministero della Salute
   [RF-2019-12368937]; Italian Minister of University and Research (MIUR)
   [3407/2018]
FX Fondazione AIRC supported A.B. (IG n. 23369), E.M.D.F. (Start-Up Grant
   21651) and M.M. (IG n. 21322). Ministero della Salute supported A.B.,
   R.L. and M.M. (project RF-2019-12368937). M.F.S. was supported by the
   Italian Minister of University and Research (MIUR, D.D. n.
   3407/2018)-PON R&I 2014-2020 "AIM Attrazione e Mobilita Internazionale".
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NR 126
TC 12
Z9 13
U1 3
U2 14
PU MDPI
PI BASEL
PA ST ALBAN-ANLAGE 66, CH-4052 BASEL, SWITZERLAND
EI 2073-4409
J9 CELLS-BASEL
JI Cells
PD AUG
PY 2022
VL 11
IS 15
AR 2402
DI 10.3390/cells11152402
PG 21
WC Cell Biology
WE Science Citation Index Expanded (SCI-EXPANDED)
SC Cell Biology
GA 3R8MA
UT WOS:000839159000001
PM 35954247
OA Green Published, gold
DA 2025-03-13
ER

PT J
AU Ren, ZJ
   Lv, MM
   Yu, Q
   Bao, J
   Lou, KX
   Li, XJ
AF Ren, Zhaojun
   Lv, Mengmeng
   Yu, Qiao
   Bao, Jun
   Lou, Kexin
   Li, Xiujuan
TI MicroRNA-370-3p shuttled by breast cancer cell-derived extracellular
   vesicles induces fibroblast activation through the CYLD/Nf-κB axis to
   promote breast cancer progression
SO FASEB JOURNAL
LA English
DT Article
DE CYLD; extracellular vesicles; fibroblasts; highly metastatic breast
   cancer cells; miR&#8208; 370&#8208; 3p; NF&#8208; &#954; B
ID DOWN-REGULATION; EXPRESSION; GROWTH; PROLIFERATION; ANGIOGENESIS;
   METASTASIS; RESISTANCE; MIGRATION
AB Breast cancer is a malignancy arising in the mammary epithelial tissues. Recent studies have indicated the abundance of microRNAs (miRNAs) in extracellular vesicles (EVs), and their interactions have been illustrated to exert crucial roles in the cell-to-cell communication. The present study focused on investigating whether EV-delivered miR-370-3p affects breast cancer. Initially, the miR-370-3p expression pattern was examined in the cancer-associated fibroblasts (CAFs), normal fibroblasts (NFs), and cancerous cells-derived EVs. The relation of miR-370-3p to CYLD was assessed using luciferase activity assay. Afterwards, based on ectopic expression and depletion experiments in the MCF-7 breast cancer cells, we evaluated stemness, migration, invasion, and sphere formation ability, and EMT, accompanied with measurement on the expression patterns of pro-inflammatory factors and nuclear factor-kappa B (NF-kappa B) signaling-related genes. Finally, tumorigenesis and proliferation were analyzed in vivo using a nude mouse xenograft model. The in vitro experiments revealed that breast cancer cell-derived EVs promoted NF activation, while activated fibroblasts contributed to enhanced stemness, migration, invasion, as well as EMT of cancerous cells. In addition, EVs could transfer miR-370-3p from breast cancer cells to NFs, and EV-encapsulated miR-370-3p was also found to facilitate fibroblast activation. Mechanistically, EV-encapsulated miR-370-3p downregulated the expression of CYLD through binding to its 3 ' UTR and activated the NF-kappa B signaling pathway, thereby promoting the cellular functions in vitro and in vivo in breast cancer. Taken together, EVs secreted by breast cancer cells could carry miR-370-3p to aggravate breast cancer through downregulating CYLD expression and activating the NF-kappa B signaling pathway.
C1 [Ren, Zhaojun; Lou, Kexin] Nanjing Med Univ, Dept Pathol, Jiangsu Canc Hosp, Nanjing, Peoples R China.
   [Ren, Zhaojun; Lv, Mengmeng; Yu, Qiao; Bao, Jun; Lou, Kexin; Li, Xiujuan] Nanjing Med Univ, Jiangsu Inst Canc Res, 42 Baziting, Nanjing 210009, Jiangsu, Peoples R China.
   [Ren, Zhaojun; Lv, Mengmeng; Yu, Qiao; Bao, Jun; Lou, Kexin; Li, Xiujuan] Nanjing Med Univ, Affiliated Canc Hosp, 42 Baziting, Nanjing 210009, Jiangsu, Peoples R China.
   [Lv, Mengmeng] Nanjing Med Univ, Jiangsu Canc Hosp, Dept Gynecol Oncol, Nanjing, Peoples R China.
   [Yu, Qiao; Li, Xiujuan] Nanjing Med Univ, Jiangsu Canc Hosp, Dept Gen Surg, 42 Baziting, Nanjing 210009, Jiangsu, Peoples R China.
   [Bao, Jun] Nanjing Med Univ, Jiangsu Canc Hosp, Dept Med Oncol, Nanjing, Peoples R China.
C3 Nanjing Medical University; Nanjing Medical University; Nanjing Medical
   University; Nanjing Medical University; Nanjing Medical University;
   Nanjing Medical University
RP Li, XJ (corresponding author), Nanjing Med Univ, Jiangsu Inst Canc Res, 42 Baziting, Nanjing 210009, Jiangsu, Peoples R China.; Li, XJ (corresponding author), Nanjing Med Univ, Affiliated Canc Hosp, 42 Baziting, Nanjing 210009, Jiangsu, Peoples R China.; Li, XJ (corresponding author), Nanjing Med Univ, Jiangsu Canc Hosp, Dept Gen Surg, 42 Baziting, Nanjing 210009, Jiangsu, Peoples R China.
EM szlxj88@163.com
RI yu, qiao/KFT-2125-2024
FU NSFC \ National Natural Science Foundation of China-Yunnan Joint Fund
   (NSFC-Yunnan Joint Fund) [81702612, 81702895]; Young Talent Program of
   Jiangsu Cancer Hospital [2017YQL-17]; Nanjing International Scientific
   and Technological Cooperation Foundation [201911036]
FX NSFC vertical bar National Natural Science Foundation of China-Yunnan
   Joint Fund (NSFC-Yunnan Joint Fund), Grant/Award Number: 81702612 &
   81702895 and 81702895; Young Talent Program of Jiangsu Cancer Hospital,
   Grant/Award Number: 2017YQL-17; Nanjing International Scientific and
   Technological Cooperation Foundation, Grant/Award Number: 201911036
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NR 41
TC 24
Z9 24
U1 0
U2 4
PU WILEY
PI HOBOKEN
PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA
SN 0892-6638
EI 1530-6860
J9 FASEB J
JI Faseb J.
PD MAR
PY 2021
VL 35
IS 3
AR e21383
DI 10.1096/fj.202001430RR
PG 14
WC Biochemistry & Molecular Biology; Biology; Cell Biology
WE Science Citation Index Expanded (SCI-EXPANDED)
SC Biochemistry & Molecular Biology; Life Sciences & Biomedicine - Other
   Topics; Cell Biology
GA QX8EV
UT WOS:000629576700004
PM 33629796
DA 2025-03-13
ER

PT J
AU Zhang, LX
AF Zhang, Luxiao
TI The Role of Mesenchymal Stem Cells in Modulating the Breast Cancer
   Microenvironment
SO CELL TRANSPLANTATION
LA English
DT Review
DE mesenchymal stem cells; breast cancer; tumor microenvironment
ID ENDOTHELIAL GROWTH-FACTOR; STROMAL CELLS; IN-VITRO; TUMOR PROGRESSION;
   UP-REGULATION; PROMOTES; DIFFERENTIATION; BONE; PROLIFERATION;
   INTERLEUKIN-6
AB The role of mesenchymal stem cells (MSCs) in the breast tumor microenvironment (TME) is significant and multifaceted. MSCs are recruited to breast tumor sites through molecular signals released by tumor sites. Once in the TME, MSCs undergo polarization and interact with various cell populations, including immune cells, cancer-associated fibroblasts (CAFs), cancer stem cells (CSCs), and breast cancer cells. In most cases, MSCs play roles in breast cancer therapeutic resistance, but there is also evidence that indicates their abilities to sensitize cancer cells to chemotherapy and radiotherapy. MSCs possess inherent regenerative and homing properties, making them attractive candidates for cell-based therapies. Therefore, MSCs can be engineered to express therapeutic molecules or deliver anti-cancer agents directly to tumor sites. Unraveling the intricate relationship between MSCs and the breast TME has the potential to uncover novel therapeutic targets and advance our understanding of breast cancer biology.
C1 [Zhang, Luxiao] Shandong First Med Univ, Dept Surg Oncol, Cent Hosp, Jinan, Peoples R China.
   [Zhang, Luxiao] Shandong First Med Univ, Dept Surg Oncol, Cent Hosp, Jinan 250001, Shan Dong, Peoples R China.
C3 Shandong First Medical University & Shandong Academy of Medical
   Sciences; Shandong First Medical University & Shandong Academy of
   Medical Sciences
RP Zhang, LX (corresponding author), Shandong First Med Univ, Dept Surg Oncol, Cent Hosp, Jinan 250001, Shan Dong, Peoples R China.
EM 463752114@qq.com
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NR 210
TC 8
Z9 8
U1 3
U2 9
PU SAGE PUBLICATIONS INC
PI THOUSAND OAKS
PA 2455 TELLER RD, THOUSAND OAKS, CA 91320 USA
SN 0963-6897
EI 1555-3892
J9 CELL TRANSPLANT
JI Cell Transplant.
PY 2023
VL 32
AR 09636897231220073
DI 10.1177/09636897231220073
PG 23
WC Cell & Tissue Engineering; Medicine, Research & Experimental;
   Transplantation
WE Science Citation Index Expanded (SCI-EXPANDED)
SC Cell Biology; Research & Experimental Medicine; Transplantation
GA CZ4R4
UT WOS:001129044600001
PM 38135917
OA gold, Green Published
DA 2025-03-13
ER

PT J
AU Pisano, A
   Santolla, MF
   De Francesco, EM
   De Marco, P
   Rigiracciolo, DC
   Perri, MG
   Vivacqua, A
   Abonante, S
   Cappello, AR
   Dolce, V
   Belfiore, A
   Maggiolini, M
   Lappano, R
AF Pisano, Assunta
   Santolla, Maria Francesca
   De Francesco, Ernestina Marianna
   De Marco, Paola
   Rigiracciolo, Damiano Cosimo
   Perri, Maria Grazia
   Vivacqua, Adele
   Abonante, Sergio
   Cappello, Anna Rita
   Dolce, Vincenza
   Belfiore, Antonino
   Maggiolini, Marcello
   Lappano, Rosamaria
TI GPER, IGF-IR, and EGFR transduction signaling are involved in
   stimulatory effects of zinc in breast cancer cells and cancer-associated
   fibroblasts
SO MOLECULAR CARCINOGENESIS
LA English
DT Article
DE zinc; breast cancer cells; cancer-associated fibroblasts; EGFR; GPER;
   IGF-IR
ID COUPLED ESTROGEN-RECEPTOR; GENE-EXPRESSION CHANGES; GROWTH-FACTOR-I;
   STROMAL FIBROBLASTS; VOLCANIC AREA; CROSS-TALK; GPR30; MIGRATION;
   MEMBRANE; COPPER
AB Zinc (Zn) is an essential trace mineral that contributes to the regulation of several cellular functions; however, it may be also implicated in the progression of breast cancer through different mechanisms. It has been largely reported that the classical estrogen receptor (ER), as well as the G protein estrogen receptor (GPER, previously known as GPR30) can exert a main role in the development of breast tumors. In the present study, we demonstrate that zinc chloride (ZnCl2) involves GPER in the activation of insulin-like growth factor receptor I (IGF-IR)/epidermal growth factor receptor (EGFR)-mediated signaling, which in turn triggers downstream pathways like ERK and AKT in breast cancer cells, and main components of the tumor microenvironment namely cancer-associated fibroblasts (CAFs). Further corroborating these findings, ZnCl2 stimulates a functional crosstalk of GPER with IGF-IR and EGFR toward the transcription of diverse GPER target genes. Then, we show that GPER contributes to the stimulatory effects induced by ZnCl2 on cell-cycle progression, proliferation, and migration of breast cancer cells as well as migration of CAFs. Together, our data provide novel insights into the molecular mechanisms through which zinc may exert stimulatory effects in breast cancer cells and CAFs toward tumor progression. (c) 2016 Wiley Periodicals, Inc.
C1 [Pisano, Assunta; Santolla, Maria Francesca; De Francesco, Ernestina Marianna; De Marco, Paola; Rigiracciolo, Damiano Cosimo; Perri, Maria Grazia; Vivacqua, Adele; Cappello, Anna Rita; Dolce, Vincenza; Maggiolini, Marcello; Lappano, Rosamaria] Univ Calabria, Dept Pharm Hlth & Nutr Sci, Arcavacata Di Rende, Italy.
   [Abonante, Sergio] Reg Hosp, Breast Canc Unit, Cosanza, Italy.
   [Belfiore, Antonino] Magna Graecia Univ Catanzaro, Dept Hlth, Div Endocrinol, Catanzaro, Italy.
C3 University of Calabria; Magna Graecia University of Catanzaro
RP Maggiolini, M (corresponding author), Univ Calabria, Dept Pharm Hlth & Nutr Sci, Arcavacata Di Rende, Italy.
EM marcellomaggiolini@yahoo.it
RI Maggiolini, Marcello/Z-4729-2019; Santolla, Maria/AAH-5481-2020;
   Rigiracciolo, Damiano Cosimo/GRS-9234-2022; Cappello,
   Anna/AAE-2766-2020; Dolce, Vincenza/HLX-3233-2023; vivacqua,
   adele/I-2771-2015; De Francesco, Ernestina Marianna/LQK-4482-2024;
   BELFIORE, Antonino/B-4652-2011
OI vivacqua, adele/0000-0001-5333-8396; Lappano,
   Rosamaria/0000-0002-9374-9701; Rigiracciolo, Damiano
   Cosimo/0000-0003-1161-6380; De Francesco, Ernestina
   Marianna/0000-0002-2810-6128; Santolla, Maria
   Francesca/0000-0002-4838-5953; BELFIORE, Antonino/0000-0002-6181-4193;
   cappello, anna rita/0000-0001-7824-3561
FU Associazione Italiana per la Ricerca sul Cancro [16719/2015 14066/13];
   Programma Operativo Nazionale "Ricerca e Competitivita" [PON 01_01078];
   Ministero della Salute [67/GR-2010-2319511]; International Cancer
   Research Fellowship iCARE; European Union (Marie Curie Actions)
FX Grant sponsor: Associazione Italiana per la Ricerca sul Cancro; Grant
   number: 16719/2015 14066/13; Grant sponsor: Programma Operativo
   Nazionale "Ricerca e Competitivita 2007-2013"; Grant number: PON
   01_01078; Grant sponsor: Ministero della Salute; Grant number:
   67/GR-2010-2319511; Grant sponsor: International Cancer Research
   Fellowship iCARE; Grant sponsor: European Union (Marie Curie Actions)
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NR 62
TC 46
Z9 49
U1 1
U2 22
PU WILEY
PI HOBOKEN
PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA
SN 0899-1987
EI 1098-2744
J9 MOL CARCINOGEN
JI Mol. Carcinog.
PD FEB
PY 2017
VL 56
IS 2
BP 580
EP 593
DI 10.1002/mc.22518
PG 14
WC Biochemistry & Molecular Biology; Oncology
WE Science Citation Index Expanded (SCI-EXPANDED)
SC Biochemistry & Molecular Biology; Oncology
GA EI5GH
UT WOS:000392521800023
PM 27341075
DA 2025-03-13
ER

PT J
AU Jones, KM
   Karanam, B
   Jones-Triche, J
   Sandey, M
   Henderson, HJ
   Samant, RS
   Temesgen, S
   Yates, C
   Bedi, D
AF Jones, Kelvin M.
   Karanam, Balasubramanyam
   Jones-Triche, Jacqueline
   Sandey, Maninder
   Henderson, Henry J.
   Samant, Rajeev S.
   Temesgen, Samuel
   Yates, Clayton
   Bedi, Deepa
TI Phage Ligands for Identification o Mesenchymal-Like Breast Cancer Cells
   and Cancer-Associated Fibroblasts
SO FRONTIERS IN ONCOLOGY
LA English
DT Article
DE Phage display; breast cancer; fibroblasts; EMT; cancer-associated
   fibroblasts
ID TUMOR MICROENVIRONMENT; PROSTATE CARCINOMA; TRANSITION; EXPRESSION;
   PROGRESSION; ACTIVATION; SUPPRESSOR; SELECTION; PROTEINS; BINDING
AB Epithelial to mesenchymal transition (EMT) is believed to be crucial for primary tumors to escape their original residence and invade and metastasize. To properly define EMT, there is a need for ligands that can identify this phenomenon in tumor tissue and invivo. A phage-display selection screening was performed to select novel binding phage peptides for identification of EMT in breast cancer. Epithelial breast cancer cell line, MCF-7 was transformed to mesenchymal phenotype by TGF-beta treatment and was used for selection. Breast fibroblasts were used for subtractive depletion and breast cancer metastatic cell lines MDA-MB-231, T47D-shNMl were used for specificity assay. The binding peptides were identified, and their binding capacities were confirmed by phage capture assay, phage-based ELISA, immunofluorescence microscopy. The phage peptide bearing the 7-amino acid sequence, LGLRGSL, demonstrated selective binding to EMT phenotypic cells (MCF-7/TGF-beta and MDA-MB-231) as compared to epithelial subtype, MCF-7, T47D and breast fibroblasts (Hs578T). The selected phage was also able to identify metastatic breast cancer tumor in breast cancer tissue microarray (TMA). These studies suggest that the selected phage peptide LGLRGSL identified by phage-display library, showed significant ability to bind to mesenchymal-like breast cancer cells/ tissues and can serve as a novel probe/ligand for metastatic breast cancer diagnostic and imaging.
C1 [Jones, Kelvin M.; Henderson, Henry J.; Bedi, Deepa] Tuskegee Univ, Dept Biomed Sci, Coll Vet Med, Tuskegee, AL 36088 USA.
   [Karanam, Balasubramanyam; Yates, Clayton] Tuskegee Univ, Dept Biol, Ctr Canc Res, Tuskegee, AL 36088 USA.
   [Jones-Triche, Jacqueline] Troy Univ, Dept Biol & Environm Sci, Troy, NY USA.
   [Sandey, Maninder] Auburn Univ, Dept Pathobiol, Auburn, AL 36849 USA.
   [Samant, Rajeev S.] Univ Alabama Birmingham, Dept Pathobiol, Birmingham, AL USA.
   [Temesgen, Samuel] Tuskegee Univ, Coll Vet Med, Dept Pathobiol, Tuskegee, AL 36088 USA.
C3 Tuskegee University; Tuskegee University; Auburn University System;
   Auburn University; University of Alabama System; University of Alabama
   Birmingham; Tuskegee University
RP Bedi, D (corresponding author), Tuskegee Univ, Dept Biomed Sci, Coll Vet Med, Tuskegee, AL 36088 USA.
EM dbedi@tuskegee.edu
RI Yates, Clayton/JZC-8035-2024
OI Henderson, Henry/0000-0003-4218-623X; Jones,
   Jacqueline/0009-0008-8394-2605
FU NIH/NCI/NIGMS [SC2CA211028-03]; NIH/RCMI [U54-MD007585-26]; NIH/NCI [U54
   CA118623]; NIH/NCI
FX This work was supported by SC2CA211028-03 (DB) (NIH/NCI/NIGMS) and
   U54-MD007585-26 (NIH/RCMI) [CY], U54 CA118623 (NIH/NCI) [CY], (NIH/NCI).
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NR 49
TC 3
Z9 4
U1 0
U2 10
PU FRONTIERS MEDIA SA
PI LAUSANNE
PA AVENUE DU TRIBUNAL FEDERAL 34, LAUSANNE, CH-1015, SWITZERLAND
SN 2234-943X
J9 FRONT ONCOL
JI Front. Oncol.
PD DEC 17
PY 2018
VL 8
AR 625
DI 10.3389/fonc.2018.00625
PG 11
WC Oncology
WE Science Citation Index Expanded (SCI-EXPANDED)
SC Oncology
GA HE5DT
UT WOS:000453393700002
PM 30619759
OA gold, Green Published
DA 2025-03-13
ER

PT J
AU Sjöberg, E
   Augsten, M
   Bergh, J
   Jirström, K
   Östman, A
AF Sjoberg, Elin
   Augsten, Martin
   Bergh, Jonas
   Jirstrom, Karin
   Ostman, Arne
TI Expression of the chemokine CXCL14 in the tumour stroma is an
   independent marker of survival in breast cancer
SO BRITISH JOURNAL OF CANCER
LA English
DT Article
DE CXCL14; prognosis; tumour stroma; tumour microenvironment; tumour stroma
   secretome; breast cancer; chemokines
ID COLORECTAL-CARCINOMA; RECEPTOR EXPRESSION; DENDRITIC CELLS;
   GROWTH-FACTOR; LUNG-CANCER; FIBROBLASTS; ANGIOGENESIS; TISSUE; BETA;
   BRAK
AB Background: Expression of the chemokine CXCL14 has previously been shown to be elevated in the tumour stroma of, for example, prostate and breast cancer. Cancer-associated fibroblast-derived CXCL14 enhances tumour growth in mouse models of prostate and breast cancer. However, the prognostic significance of compartment-specific expression of CXCL14 has not been studied.
   Methods: CXCL14 mRNA expression was analysed in a breast cancer tissue microarray (TMA) of formalin-fixed, paraffin-embedded tumours by the RNAscope 2.0 Assay. Epithelial and stromal expression was analysed separately and correlated with clinicopathological characteristics and survival.
   Results: CXCL14 was variably and independently expressed in malignant and stromal cells of breast cancer. Total and stromal expression of CXCL14 did not associate with clinicopathological parameters. Epithelial CXCL14 expression was significantly associated with oestrogen receptor alpha (ER alpha)-positive tumours and lower proliferation status. Total CXCL14 expression correlated significantly with shorter breast cancer-specific and recurrence-free survival. High stromal, but not epithelial, CXCL14 expression was significantly associated with shorter survival in univariable and multivariable analyses. Moreover, the correlation between stromal CXCL14 expression and survival was more prominent in ER negative, triple negative and basal-like breast cancers.
   Conclusions: The identification of prognostic significance of stromal CXCL14 in breast cancer demonstrates novel clinical relevance of a stroma-derived secreted factor and illustrates the importance of tumour compartment-specific analyses. On the basis of the prognostic signals from difficult-to-treat subgroups, CXCL14 should also be considered as a candidate drug target.
C1 [Sjoberg, Elin; Ostman, Arne] Karolinska Inst, CCK, Dept Oncol Pathol, S-17176 Stockholm, Sweden.
   [Augsten, Martin] German Canc Res Ctr, Div Vasc Oncol & Metastasis, D-69120 Heidelberg, Germany.
   [Bergh, Jonas] Karolinska Univ Hosp, Dept Oncol Pathol, CCK, Karolinska Inst, S-17176 Stockholm, Sweden.
   [Bergh, Jonas] Karolinska Univ Hosp, Radiumhemmet Karolinska Oncol, S-17176 Stockholm, Sweden.
   [Jirstrom, Karin] Lund Univ, Dept Clin Sci, Div Oncol & Pathol, S-22185 Lund, Sweden.
C3 Karolinska Institutet; Helmholtz Association; German Cancer Research
   Center (DKFZ); Karolinska Institutet; Karolinska University Hospital;
   Karolinska Institutet; Karolinska University Hospital; Lund University
RP Östman, A (corresponding author), Karolinska Inst, CCK, Dept Oncol Pathol, S-17176 Stockholm, Sweden.
EM arne.ostman@ki.se
RI Sjöberg, Elin/AFQ-2245-2022
OI Jirstrom, Karin/0000-0003-2257-5000; Bergh, Jonas/0000-0001-5526-1847
FU Swedish Research Council (STARGET network); Breast Cancer Theme Center
   (BRECT) at Karolinska Institutet; Swedish Cancer Society; research funds
   at Radiumhemmet; Stockholm County Council (ALF); Knut and Alice
   Wallenberg grant; KI-AstraZeneca collaboration; Swedish Breast Cancer
   Association; Swedish Research Council; Gunnar Nilsson Cancer Foundation;
   Kamprad Family Foundation; Mrs Berta Kamprad Foundation; Swedish
   Government Grant for Clinical Research; Lund University Faculty of
   Medicine
FX Members of the AO group are acknowledged for support and constructive
   criticism throughout the study, and Inger Bodin at the Department of
   Oncology-Pathology, Karolinska Institutet, for technical assistance. The
   AO and JB groups are supported from grants from the Swedish Research
   Council (STARGET network), the Breast Cancer Theme Center (BRECT) at
   Karolinska Institutet, Swedish Cancer Society, the research funds at
   Radiumhemmet and Stockholm County Council (ALF). The JB group is also
   supported by Knut and Alice Wallenberg grant, the KI-AstraZeneca
   collaboration, and the Swedish Breast Cancer Association. KJ receives
   support from the Swedish Research Council, the Swedish Cancer Society,
   the Gunnar Nilsson Cancer Foundation, the Kamprad Family Foundation, the
   Mrs Berta Kamprad Foundation, the Swedish Government Grant for Clinical
   Research, and Lund University Faculty of Medicine.
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NR 37
TC 55
Z9 60
U1 0
U2 13
PU NATURE PUBLISHING GROUP
PI LONDON
PA MACMILLAN BUILDING, 4 CRINAN ST, LONDON N1 9XW, ENGLAND
SN 0007-0920
EI 1532-1827
J9 BRIT J CANCER
JI Br. J. Cancer
PD MAY 10
PY 2016
VL 114
IS 10
BP 1117
EP 1124
DI 10.1038/bjc.2016.104
PG 8
WC Oncology
WE Science Citation Index Expanded (SCI-EXPANDED)
SC Oncology
GA DM6AA
UT WOS:000376430800015
PM 27115465
OA Green Published, hybrid
DA 2025-03-13
ER

PT J
AU Tan, ZY
   Kan, C
   Sun, MQ
   Yang, F
   Wong, MY
   Wang, SY
   Zheng, H
AF Tan, Zhenya
   Kan, Chen
   Sun, Minqiong
   Yang, Fan
   Wong, Mandy
   Wang, Siying
   Zheng, Hong
TI Mapping Breast Cancer Microenvironment Through Single-Cell Omics
SO FRONTIERS IN IMMUNOLOGY
LA English
DT Review
DE breast cancer; microenvironment; single-cell RNA sequencing; single-cell
   omics; heterogeneity
ID B-CELLS; STROMAL CELLS; RNA-SEQ; IMMUNOTHERAPY; HETEROGENEITY;
   INFILTRATION; METASTASIS; LANDSCAPE; SURVIVAL
AB Breast cancer development and progression rely not only on the proliferation of neoplastic cells but also on the significant heterogeneity in the surrounding tumor microenvironment. Its unique microenvironment, including tumor-infiltrating lymphocytes, complex myeloid cells, lipid-associated macrophages, cancer-associated fibroblasts (CAFs), and other molecules that promote the growth and migration of tumor cells, has been shown to play a crucial role in the occurrence, growth, and metastasis of breast cancer. However, a detailed understanding of the complex microenvironment in breast cancer remains largely unknown. The unique pattern of breast cancer microenvironment cells has been poorly studied, and neither has the supportive role of these cells in pathogenesis been assessed. Single-cell multiomics biotechnology, especially single-cell RNA sequencing (scRNA-seq) reveals single-cell expression levels at much higher resolution, finely dissecting the molecular characteristics of tumor microenvironment. Here, we review the recent literature on breast cancer microenvironment, focusing on scRNA-seq studies and analyzing heterogeneity and spatial location of different cells, including T and B cells, macrophages/monocytes, neutrophils, and stromal cells. This review aims to provide a more comprehensive perception of breast cancer microenvironment and annotation for their clinical classification, diagnosis, and treatment. Furthermore, we discuss the impact of novel single-cell omics technologies, such as abundant omics exploration strategies, multiomics conjoint analysis mode, and deep learning network architecture, on the future research of breast cancer immune microenvironment.
RI Tan, Zhenya/IUN-9898-2023
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NR 84
TC 22
Z9 23
U1 4
U2 72
PU FRONTIERS MEDIA SA
PI LAUSANNE
PA AVENUE DU TRIBUNAL FEDERAL 34, LAUSANNE, CH-1015, SWITZERLAND
SN 1664-3224
J9 FRONT IMMUNOL
JI Front. Immunol.
PD APR 20
PY 2022
VL 13
AR 868813
DI 10.3389/fimmu.2022.868813
PG 10
WC Immunology
WE Science Citation Index Expanded (SCI-EXPANDED)
SC Immunology
GA 2B9QJ
UT WOS:000810515400001
PM 35514975
OA gold, Green Published
DA 2025-03-13
ER

PT J
AU Rogenes, H
   Finne, K
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   Milosevic, V
AF Rogenes, Hanna
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   Ostman, Arne
   Milosevic, Vladan
TI Development of 42 marker panel for in-depth study of cancer associated
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SO FRONTIERS IN IMMUNOLOGY
LA English
DT Article
DE imaging mass cytometry; tumor microenvironment; cancer associated
   fibroblasts; microniches; breast cancer
ID ACTIVATED FIBROBLASTS; POOR-PROGNOSIS; EXPRESSION; GENERATION; BETA; EMT
AB Imaging Mass Cytometry (IMC) is a novel, and formidable high multiplexing imaging method emerging as a promising tool for in-depth studying of tissue architecture and intercellular communications. Several studies have reported various IMC antibody panels mainly focused on studying the immunological landscape of the tumor microenvironment (TME). With this paper, we wanted to address cancer associated fibroblasts (CAFs), a component of the TME very often underrepresented and not emphasized enough in present IMC studies. Therefore, we focused on the development of a comprehensive IMC panel that can be used for a thorough description of the CAF composition of breast cancer TME and for an in-depth study of different CAF niches in relation to both immune and breast cancer cell communication. We established and validated a 42 marker panel using a variety of control tissues and rigorous quantification methods. The final panel contained 6 CAF-associated markers (aSMA, FAP, PDGFRa, PDGFRb, YAP1, pSMAD2). Breast cancer tissues (4 cases of luminal, 5 cases of triple negative breast cancer) and a modified CELESTA pipeline were used to demonstrate the utility of our IMC panel for detailed profiling of different CAF, immune and cancer cell phenotypes.
C1 [Rogenes, Hanna; Finne, Kenneth; Winge, Ingeborg; Akslen, Lars A.; Ostman, Arne; Milosevic, Vladan] Univ Bergen, Ctr Canc Biomarkers CCBIO, Dept Clin Med, Bergen, Norway.
   [Akslen, Lars A.] Haukeland Hosp, Dept Pathol, Bergen, Norway.
   [Ostman, Arne] Karolinska Inst, Dept Oncol & Pathol, Solna, Sweden.
C3 University of Bergen; University of Bergen; Haukeland University
   Hospital; Karolinska Institutet
RP Milosevic, V (corresponding author), Univ Bergen, Ctr Canc Biomarkers CCBIO, Dept Clin Med, Bergen, Norway.
EM v.milosevic@uib.no
OI Milosevic, Vladan/0000-0001-6991-6795; Finne,
   Kenneth/0000-0001-6251-5817
FU Norwegian Cancer Society (Kreftforeningen)
FX The author(s) declare financial support was received for the research,
   authorship, and/or publication of this article. This work was supported
   by the by the Norwegian Cancer Society (Kreftforeningen).
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NR 70
TC 3
Z9 3
U1 8
U2 10
PU FRONTIERS MEDIA SA
PI LAUSANNE
PA AVENUE DU TRIBUNAL FEDERAL 34, LAUSANNE, CH-1015, SWITZERLAND
SN 1664-3224
J9 FRONT IMMUNOL
JI Front. Immunol.
PD APR 22
PY 2024
VL 15
AR 1325191
DI 10.3389/fimmu.2024.1325191
PG 15
WC Immunology
WE Science Citation Index Expanded (SCI-EXPANDED)
SC Immunology
GA WY7D7
UT WOS:001258490400001
PM 38711512
OA gold, Green Published
DA 2025-03-13
ER

PT J
AU Gu, XY
   Gao, YZ
   Wang, P
   Wang, LX
   Peng, HB
   He, YZ
   Liu, Y
   Feng, NAP
AF Gu, Xiaoyan
   Gao, Yunzhen
   Wang, Ping
   Wang, Lixin
   Peng, Haibao
   He, Yuanzhi
   Liu, Ying
   Feng, Nianping
TI Nano-delivery systems focused on tumor microenvironment regulation and
   biomimetic strategies for treatment of breast cancer metastasis
SO JOURNAL OF CONTROLLED RELEASE
LA English
DT Review
DE Breast cancer metastasis; Tumor microenvironment; Nano-delivery system;
   Biomimetic nanoparticle; Combinatorial therapy
ID MEMBRANE-COATED NANOPARTICLES; ANTI-ANGIOGENESIS THERAPY; GENE
   CO-DELIVERY; LUNG METASTASIS; DRUG-RELEASE; MULTIFUNCTIONAL
   NANOPARTICLES; SILICA NANOPARTICLES; MACROPHAGE-MEMBRANE; TARGETED
   THERAPY; CELLS
AB Breast cancer metastasis and recurrence accounts for vast majority of breast cancer-induced mortality. Tumor microenvironment (TME) plays an important role at each step of metastasis, evasion of immunosurveillance, and therapeutic resistance. Consequently, TME-targeting alternatives to traditional therapies focused on breast cancer cells are gaining increasing attention. These new therapies involve the use of tumor cells, and key TME components or secreted bioactive molecules as therapeutic targets, alone or in combination. Recently, TMErelated nanoparticles have been developed to deliver various agents, such as bioactive ingredients extracted from natural sources or chemotherapeutic agents, genes, proteins, small interfering RNAs, and vaccines; they have shown great therapeutic potential against breast cancer metastasis. Among various types of nanoparticles, biomimetic nanovesicles are a promising means of addressing the limitations of conventional nanocarriers. This review highlights various nanoparticles related to or mediated by TME according to the key TME components responsible for metastasis. Furthermore, TME-related biomimetic nanoparticles against breast cancer metastasis have garnered attention owing to their promising efficiency, especially in payload delivery and therapeutic action. Here, we summarize recent representative studies on nanoparticles related to cancer-associated fibroblasts, extracellular matrix, endothelial cells, angiogenesis, and immune cells, as well as advanced biomimetic nanoparticles. Future challenges and opportunities in the field are also discussed.
C1 [Gu, Xiaoyan; Gao, Yunzhen; Wang, Ping; Peng, Haibao; He, Yuanzhi; Liu, Ying; Feng, Nianping] Shanghai Univ Tradit Chinese Med, Sch Pharm, Shanghai 201203, Peoples R China.
   [Wang, Lixin] Shanghai Univ Tradit Chinese Med, Sch Basic Med Sci, Shanghai 201203, Peoples R China.
C3 Shanghai University of Traditional Chinese Medicine; Shanghai University
   of Traditional Chinese Medicine
RP Liu, Y; Feng, NAP (corresponding author), Shanghai Univ Tradit Chinese Med, Sch Pharm, Dept Pharmaceut Sci, 1200 Cailun Rd,Zhangjiang Hitech Pk, Shanghai 201203, Peoples R China.
EM debbyly@shutcm.edu.cn; npfeng@shutcm.edu.cn
RI Feng, Nianping/ABG-5415-2021; Wu, Xiaojun/JQI-5643-2023
OI Gao, Yunzhen/0000-0001-8578-0787; Feng, Nianping/0000-0002-5303-2941
FU National Natural Science Foundation of China [81773913, 81303232,
   82074279]; Natural Science Foundation of Shanghai [20ZR1458300]
FX This work was funded by the National Natural Science Foundation of China
   (No. 81773913, No. 81303232, No. 82074279) and the Natural Science
   Foundation of Shanghai [20ZR1458300].
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NR 143
TC 50
Z9 53
U1 5
U2 149
PU ELSEVIER
PI AMSTERDAM
PA RADARWEG 29, 1043 NX AMSTERDAM, NETHERLANDS
SN 0168-3659
EI 1873-4995
J9 J CONTROL RELEASE
JI J. Control. Release
PD MAY 10
PY 2021
VL 333
BP 374
EP 390
DI 10.1016/j.jconrel.2021.03.039
EA APR 2021
PG 17
WC Chemistry, Multidisciplinary; Pharmacology & Pharmacy
WE Science Citation Index Expanded (SCI-EXPANDED)
SC Chemistry; Pharmacology & Pharmacy
GA SD8LP
UT WOS:000651627800005
PM 33798666
DA 2025-03-13
ER

PT J
AU Amornsupak, K
   Thongchot, S
   Thinyakul, C
   Box, C
   Hedayat, S
   Thuwajit, P
   Eccles, SA
   Thuwajit, C
AF Amornsupak, Kamolporn
   Thongchot, Suyanee
   Thinyakul, Chanida
   Box, Carol
   Hedayat, Somaieh
   Thuwajit, Peti
   Eccles, Suzanne A.
   Thuwajit, Chanitra
TI HMGB1 mediates invasion and PD-L1 expression through RAGE-PI3K/AKT
   signaling pathway in MDA-MB-231 breast cancer cells
SO BMC CANCER
LA English
DT Article
DE Breast cancer; HMGB1; RAGE; PI3K-AKT; Migration; Invasion; PD-L1
ID CYCLE ARREST; MIGRATION; RAGE; FIBROBLASTS; ACTIVATION; ERK1/2; LINE
AB Background High-mobility group box 1 (HMGB1) is increased in breast cancer cells as the result of exposure to the secreted substances from cancer-associated fibroblasts and plays a crucial role in cancer progression and drug resistance. Its effect, however, on the expression of programmed death ligand 1 (PD-L1) in breast cancer cells has not been investigated. This study aimed to investigate the mechanism of HMGB1 through receptors for advanced glycation end products (RAGE) on cell migration/invasion and PD-L1 expression in breast cancer cells. Methods A 3-dimensional (3-D) migration and invasion assay and Western blotting analysis to evaluate the function and the mechanism under recombinant HMGB1 (rHMGB1) treatment with knockdown of RAGE using shRAGE and PI3K/AKT inhibitors was performed. Results The results revealed that rHMGB1 induced MDA-MB-231 cell migration and invasion. The knockdown of RAGE using shRAGE and PI3K/AKT inhibitors attenuated 3-D migration and invasion in response to rHMGB1 compared to mock cells. PD-L1 up-regulation was observed in both parental MDA-MB-231 (P) and MDA-MB-231 metastasis to bone marrow (BM) cells treated with rHMGB1, and these effects were alleviated in RAGE-knock down (KD) breast cancer cells as well as in PI3K/AKT inhibitor-treated cells. Conclusions Collectively, these findings indicate that HMGB1-RAGE through PI3K/AKT signaling promotes not only breast cancer cell invasion but also PD-L1 expression which leads to the destruction of the effector T cells. The attenuating HMGB1-RAGE-PI3K/AKT pathway may help to attenuate breast cancer cell aggressive phenotypes.
C1 [Amornsupak, Kamolporn] Chulalongkorn Univ, Fac Allied Hlth Sci, Dept Transfus Med & Clin Microbiol, Bangkok 10330, Thailand.
   [Amornsupak, Kamolporn] Chulalongkorn Univ, Fac Allied Hlth Sci, Immunomodulat Nat Prod Res Grp, Bangkok 10330, Thailand.
   [Thongchot, Suyanee; Thinyakul, Chanida; Thuwajit, Peti; Thuwajit, Chanitra] Mahidol Univ, Siriraj Hosp, Dept Immunol, Fac Med, Bangkok 10700, Thailand.
   [Thongchot, Suyanee] Mahidol Univ, Siriraj Hosp, Siriraj Ctr Res Excellence Canc Immunotherapy, Res Dept,Fac Med, Bangkok 10700, Thailand.
   [Box, Carol] Inst Canc Res, Div Radiotherapy & Imaging, Ctr Canc Imaging, London SW7 3RP, England.
   [Box, Carol; Hedayat, Somaieh; Eccles, Suzanne A.] Inst Canc Res, Canc Therapeut Unit, Canc Res UK, London SW7 3RP, England.
C3 Chulalongkorn University; Chulalongkorn University; Mahidol University;
   Mahidol University; Royal Marsden NHS Foundation Trust; University of
   London; Institute of Cancer Research - UK; University of London;
   Institute of Cancer Research - UK; Cancer Research UK; Royal Marsden NHS
   Foundation Trust
RP Thuwajit, C (corresponding author), Mahidol Univ, Siriraj Hosp, Dept Immunol, Fac Med, Bangkok 10700, Thailand.
EM cthuwajit@yahoo.com
RI Thuwajit, Peti/AAD-1014-2021; Thuwajit, Chanitra/AAT-7933-2021
OI THINYAKUL, CHANIDA/0000-0002-2927-0595
FU National Research Council of Thailand [RSA6280091]; Oracle Cancer Trust
FX CThuwajit has been supported by the Mid-career Research Grant
   (RSA6280091), National Research Council of Thailand. CB was funded by
   the Oracle Cancer Trust.
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NR 33
TC 30
Z9 31
U1 3
U2 15
PU BMC
PI LONDON
PA CAMPUS, 4 CRINAN ST, LONDON N1 9XW, ENGLAND
EI 1471-2407
J9 BMC CANCER
JI BMC Cancer
PD MAY 24
PY 2022
VL 22
IS 1
AR 578
DI 10.1186/s12885-022-09675-1
PG 13
WC Oncology
WE Science Citation Index Expanded (SCI-EXPANDED)
SC Oncology
GA 1O2MX
UT WOS:000801174300001
PM 35610613
OA gold, Green Published
DA 2025-03-13
ER

PT J
AU Catalano, S
   Panza, S
   Augimeri, G
   Giordano, C
   Malivindi, R
   Gelsomino, L
   Marsico, S
   Giordano, F
   Gyorffy, B
   Bonofiglio, D
   Andò, S
   Barone, I
AF Catalano, Stefania
   Panza, Salvatore
   Augimeri, Giuseppina
   Giordano, Cinzia
   Malivindi, Rocco
   Gelsomino, Luca
   Marsico, Stefania
   Giordano, Francesca
   Gyorffy, Balazs
   Bonofiglio, Daniela
   Ando, Sebastiano
   Barone, Ines
TI Phosphodiesterase 5 (PDE5) Is Highly Expressed in Cancer-Associated
   Fibroblasts and Enhances Breast Tumor Progression
SO CANCERS
LA English
DT Article
DE breast cancer; PDE5; tumor microenvironment; targeted therapy; CXCL16
ID DEPENDENT PROTEIN-KINASE; STROMAL FIBROBLASTS; CYCLIC-GMP; INDUCED
   APOPTOSIS; PROSTATE-CANCER; STRESS FIBERS; GROWTH; METASTASIS;
   ACTIVATION; INHIBITORS
AB The overexpression of phosphodiesterase (PDE) 5 is frequently found in various human cancers, such as those of the breast. However, PDE5's role in the tumor microenvironment is still unknown. As PDE5 represents a high-value therapeutic target, we investigated whether the expression and function of PDE5 in breast cancer-associated fibroblasts (CAFs) may be clinically relevant to malignant progression. PDE5 expression was increased in human breast cancer stroma compared with normal stroma and was correlated to a shorter overall survival. Treatment of CAFs, isolated from breast tumor biopsies, with selective PDE5 inhibitors inhibited their proliferation, motility, and invasiveness, and negatively controlled tumor-stroma interactions in both 'in vitro' and 'in vivo' models. PDE5 stable overexpression transformed immortalized mouse embryonic fibroblasts (MEFs) towards an activated fibroblast phenotype, impacting their intrinsic characteristics and paracrine effects on breast cancer cell growth and migration through an enhanced production of the C-X-C motif chemokine 16 (CXCL16). On the other hand, CAF exposure to PDE5 inhibitors was associated with reduced CXCL16 expression and secretion. Importantly, CXCL16 levels in breast cancer stroma showed a strong correlation with PDE5 levels and poor patient outcomes. In conclusion, PDE5 is overexpressed in breast cancer stroma, enhances the tumor-stimulatory activities of fibroblasts, and impacts clinical outcomes; thus, we propose this enzyme as an attractive candidate for prognosis and a potential target for treatments in breast cancer patients.
C1 [Catalano, Stefania; Panza, Salvatore; Augimeri, Giuseppina; Giordano, Cinzia; Malivindi, Rocco; Gelsomino, Luca; Marsico, Stefania; Giordano, Francesca; Bonofiglio, Daniela; Ando, Sebastiano; Barone, Ines] Univ Calabria, Dept Pharm Hlth & Nutr Sci, I-87036 Arcavacata Di Rende, CS, Italy.
   [Giordano, Cinzia; Ando, Sebastiano] Univ Calabria, Ctr Sanitario, I-87036 Arcavacata Di Rende, CS, Italy.
   [Gyorffy, Balazs] Semmelweis Univ, MTA TTK Lendulet Canc Biomarker Res Grp, Dept Pediat 2, H-1094 Budapest, Hungary.
C3 University of Calabria; University of Calabria; Semmelweis University;
   HUN-REN; HUN-REN Research Centre for Natural Sciences
RP Andò, S; Barone, I (corresponding author), Univ Calabria, Dept Pharm Hlth & Nutr Sci, I-87036 Arcavacata Di Rende, CS, Italy.; Andò, S (corresponding author), Univ Calabria, Ctr Sanitario, I-87036 Arcavacata Di Rende, CS, Italy.
EM stefcatalano@libero.it; sasapanza@libero.it; giusy.augimeri@gmail.com;
   cinzia.giordano@unical.it; rocco.malivindi@unical.it; lugelso@gmail.com;
   stefania.marsico@unical.it; francesca.giordano@unical.it;
   zsalab2@yahoo.com; daniela.bonofiglio@unical.it;
   sebastiano.ando@unical.it; ines.barone@unical.it
RI Gyorffy, Balazs/AAA-9135-2021; MARSICO, Stefania/J-9938-2019;
   Bonofiglio, Daniela/AAV-8371-2020; Giordano, Francesca/E-4039-2017;
   Malivindi, Rocco/ABB-8562-2021
OI MARSICO, Stefania/0000-0003-1598-0526; MALIVINDI,
   Rocco/0000-0002-8313-2492; GIORDANO, Cinzia/0000-0003-4969-0607; ,
   giuseppina/0000-0003-4759-5147; BARONE, Ines/0000-0002-9769-1615;
   CATALANO, Stefania/0000-0002-6352-9628; Gelsomino,
   Luca/0000-0003-3076-3482; BONOFIGLIO, Daniela/0000-0002-4142-0496;
   Gyorffy, Balazs/0000-0002-5772-3766
FU My First AIRC Grant (MFAG) [16899]; AIRC Investigator Grant [18602,
   21414]; National Research, Development and Innovation Office (Hungary)
   [NVKP_16-1-2016-0037, 2018-1.3.1-VKE-2018-00032]
FX This research was funded by My First AIRC Grant (MFAG) #16899 to I.
   Barone, by AIRC Investigator Grant (IG) #18602 to S. Ando and #21414 to
   S. Catalano; NVKP_16-1-2016-0037 and 2018-1.3.1-VKE-2018-00032 grants of
   the National Research, Development and Innovation Office (Hungary) to
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TC 29
Z9 31
U1 3
U2 8
PU MDPI
PI BASEL
PA ST ALBAN-ANLAGE 66, CH-4052 BASEL, SWITZERLAND
EI 2072-6694
J9 CANCERS
JI Cancers
PD NOV
PY 2019
VL 11
IS 11
AR 1740
DI 10.3390/cancers11111740
PG 21
WC Oncology
WE Science Citation Index Expanded (SCI-EXPANDED)
SC Oncology
GA JV3UB
UT WOS:000502290100122
PM 31698786
OA Green Published, gold
DA 2025-03-13
ER

PT J
AU Sun, XQ
   Qu, Q
   Lao, YM
   Zhang, M
   Yin, XL
   Zhu, HQ
   Wang, Y
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AF Sun, Xueqing
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   Yang, Jie
   Yi, Jing
   Hao, Mingang
TI Tumor suppressor HIC1 is synergistically compromised by
   cancer-associated fibroblasts and tumor cells through the IL-6/pSTAT3
   axis in breast cancer
SO BMC CANCER
LA English
DT Article
DE Breast cancer; CAF; IL-6; STAT3; HIC1
ID STROMAL FIBROBLASTS; GENE; METHYLATION; PROGRESSION; METASTASIS;
   STATISTICS; CARCINOMA; GROWTH; IL-6
AB Background: Interleukin-6 (IL-6) is commonly highly secreted in the breast cancer (BrCA) microenvironment and implicated in disease development. In this study, we aimed to determine the role of the IL-6/pSTAT3/HIC1 axis in the breast cancer microenvironment, including in cancer-associated fibroblasts (CAFs) and breast cancer cells.
   Methods: Stromal fibroblasts from the breast cancer tissue were isolated, and the supernatants of the fibroblasts were analyzed. Recombinant human IL-6 (rhIL-6) was applied to simulate the effect of CAF-derived IL-6 to study the mechanism of HIC1 (tumor suppressor hypermethylated in cancer 1) downregulation. IL-6 was knocked down in the high IL-6-expressing BrCA cell line MDA-MB-231, which enabled the investigation of the IL-6/pSTAT3/HIC1 axis in the autocrine pathway.
   Results: Increased IL-6 was found in the supernatant of isolated CAFs, which suppressed HIC1 expression in cancer cells and promoted BrCA cell proliferation. After stimulating the BrCA cell line SK-BR-3 (where IL-6R is highly expressed) with rhIL-6, signal transducers and activators of transcription 3 (STAT3) was found to be phosphorylated and HIC1 decreased, and a STAT3 inhibitor completely rescued HIC1 expression. Moreover, HIC1 was restored upon knocking down IL-6 expression in MDA-MB-231 cells, accompanied by a decrease in STAT3 activity.
   Conclusions: These findings indicate that IL-6 downregulates the tumor suppressor HIC1 and promotes BrCA development in the tumor microenvironment through paracrine or autocrine signaling.
C1 [Sun, Xueqing; Lao, Yimin; Zhu, Huiqin; Wang, Ying; Yang, Jie; Yi, Jing; Hao, Mingang] Shanghai Jiao Tong Univ, Sch Med, Shanghai Key Lab Tumor Microenvironm & Inflammat, Dept Biochem & Mol Cell Biol, Shanghai 200025, Peoples R China.
   [Qu, Qing] Shanghai Jiao Tong Univ, Sch Med, Ruijin Hosp, Dept Oncol, Shanghai 200025, Peoples R China.
   [Zhang, Mi] Chongqing Med Univ, Inst Life Sci, Chongqing 400016, Peoples R China.
   [Yin, Xiaoling] Shanghai Jiao Tong Univ, Sch Med, Shanghai Peoples Hosp 9, Dept Otolaryngol Head & Neck Surg, Shanghai 200011, Peoples R China.
   [Hao, Mingang] Univ Cincinnati, Coll Med, Dept Canc Biol, Cincinnati, OH 45267 USA.
C3 Shanghai Jiao Tong University; Shanghai Jiao Tong University; Chongqing
   Medical University; Shanghai Jiao Tong University; University System of
   Ohio; University of Cincinnati
RP Sun, XQ; Hao, MG (corresponding author), Shanghai Jiao Tong Univ, Sch Med, Shanghai Key Lab Tumor Microenvironm & Inflammat, Dept Biochem & Mol Cell Biol, Shanghai 200025, Peoples R China.; Hao, MG (corresponding author), Univ Cincinnati, Coll Med, Dept Canc Biol, Cincinnati, OH 45267 USA.
EM sunxueqing@msn.com; rogerbao2001@hotmail.com
RI Yang, Jie/JCD-9867-2023; Hao, Mingang/AAL-7254-2020
OI Hao, Mingang/0000-0001-6456-1710
FU National Natural Science Foundation of China [31771522]; Natural Science
   Foundation of Shanghai [16ZR1418400]
FX This study was supported by the National Natural Science Foundation of
   China (No. 81402282 and 81602308) in sample collection, most data
   analysis and writing the manuscript. The study was also supported by the
   National Natural Science Foundation of China (No. 31771522) and the
   Natural Science Foundation of Shanghai (No.16ZR1418400) in partial data
   analysis.
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NR 29
TC 21
Z9 24
U1 2
U2 12
PU BMC
PI LONDON
PA CAMPUS, 4 CRINAN ST, LONDON N1 9XW, ENGLAND
EI 1471-2407
J9 BMC CANCER
JI BMC Cancer
PD DEC 3
PY 2019
VL 19
IS 1
AR 1180
DI 10.1186/s12885-019-6333-6
PG 11
WC Oncology
WE Science Citation Index Expanded (SCI-EXPANDED)
SC Oncology
GA KI6GD
UT WOS:000511446900010
PM 31795965
OA Green Published, gold
DA 2025-03-13
ER

PT J
AU Wen, SY
   Hou, YX
   Fu, LX
   Xi, L
   Yang, D
   Zhao, MJ
   Qin, YL
   Sun, KX
   Teng, Y
   Liu, MR
AF Wen, Siyang
   Hou, Yixuan
   Fu, Lixin
   Xi, Lei
   Yang, Dan
   Zhao, Maojia
   Qin, Yilu
   Sun, Kexin
   Teng, Yong
   Liu, Manran
TI Cancer-associated fibroblast (CAF)-derived IL32 promotes breast cancer
   cell invasion and metastasis via integrin β3-p38 MAPK signalling
SO CANCER LETTERS
LA English
DT Article
DE CAF; IL32; Integrin beta 3; p38 MAPK; Tumour invasion
ID EPITHELIAL-MESENCHYMAL TRANSITION; NF-KAPPA-B; ESTROGEN-RECEPTOR;
   EXPRESSION; IL-32; GROWTH; MICROENVIRONMENT; INACTIVATION;
   INTERLEUKIN-32; INFLAMMATION
AB Metastasis is the leading cause of breast cancer-related deaths. Cancer-associated fibroblasts (CAFs), the predominant stromal cell type in the breast tumour microenvironment, may contribute to cancer progression through interaction with tumour cells. Nonetheless, little is known about the details of the underlying mechanism. Here we found that interaction of interleukin 32 (IL32) with integrin beta 3 (encoded by ITGB3; a member of the integrin family) mediating the cross-talk between CAFs and breast cancer cells plays a crucial role in CAF-induced breast tumour invasiveness. IL32, an 'RGD' motif-containing cytokine, was found to be abundantly expressed in CAFs. Integrin beta 3 turned out to be up-regulated in breast cancer cells during epithelial-mesenchymal transition (EMT). CAF-derived IL32 specifically bound to integrin beta 3 through the RGD motif, thus activating intracellular downstream p38 MAPK signalling in breast cancer cells. This signalling increased the expression of EMT markers (fibronectin, N-cadherin, and vimentin) and promoted tumour cell invasion. Counteracting IL32 activity, a knockdown of IL32 or integrin beta 3 led to specific inactivation of p38 MAPK signalling in tumour cells. Blockage of the p38 MAPK pathway also diminished IL32-induced expression of EMT markers and breast cancer cell invasion and metastasis. Thus, our data indicate that CAF-secreted IL32 promotes breast cancer cell invasion and metastasis via integrin beta 3-p38 MAPK signalling.
C1 [Wen, Siyang; Hou, Yixuan; Fu, Lixin; Xi, Lei; Yang, Dan; Zhao, Maojia; Qin, Yilu; Sun, Kexin; Liu, Manran] Chongqing Med Univ, Chinese Minist Educ, Key Lab Lab Med Diagnost, 1 Yi Xue Yuan Rd, Chongqing 400016, Peoples R China.
   [Hou, Yixuan] Chongqing Med Univ, Expt Teaching Ctr Basic Med Sci, Chongqing 400016, Peoples R China.
   [Teng, Yong] Augusta Univ, Georgia Canc Ctr, Dent Coll Georgia, Dept Oral Biol, Augusta, GA USA.
C3 Chongqing Medical University; Chongqing Medical University; University
   System of Georgia; Augusta University
RP Liu, MR (corresponding author), Chongqing Med Univ, Chinese Minist Educ, Key Lab Lab Med Diagnost, 1 Yi Xue Yuan Rd, Chongqing 400016, Peoples R China.
EM mliu-hncq@hotmail.com
RI fu, lixin/AAD-4107-2022; Teng, Yong/AAK-4160-2020
OI Wen, Siyang/0000-0002-8917-8379; Teng, Yong/0000-0002-1856-7289
FU National Natural Science Foundation of China [NSFC 81472476, NSFC
   31171336, NSFC 31671481]; Doctoral Fund of Ministry of Education of
   China [20125503110001]; Scientific Research Foundation for the Returned
   Overseas Chinese Scholars, Ministry of Education, China [[2011]508]
FX This work was supported in part by the National Natural Science
   Foundation of China (NSFC 81472476, NSFC 31171336, NSFC 31671481); the
   Doctoral Fund of Ministry of Education of China (20125503110001); and
   the Scientific Research Foundation for the Returned Overseas Chinese
   Scholars, Ministry of Education, China ([2011]508).
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NR 54
TC 228
Z9 242
U1 9
U2 114
PU ELSEVIER IRELAND LTD
PI CLARE
PA ELSEVIER HOUSE, BROOKVALE PLAZA, EAST PARK SHANNON, CO, CLARE, 00000,
   IRELAND
SN 0304-3835
EI 1872-7980
J9 CANCER LETT
JI Cancer Lett.
PD FEB 1
PY 2019
VL 442
BP 320
EP 332
DI 10.1016/j.canlet.2018.10.015
PG 13
WC Oncology
WE Science Citation Index Expanded (SCI-EXPANDED)
SC Oncology
GA HI3ME
UT WOS:000456353500031
PM 30391782
OA hybrid
HC Y
HP N
DA 2025-03-13
ER

PT J
AU Smeland, HYH
   Askeland, C
   Wik, E
   Knutsvik, G
   Molven, A
   Edelmann, RJ
   Reed, RK
   Warren, DJ
   Gullberg, D
   Stuhr, L
   Akslen, LA
AF Smeland, Hilde Ytre-Hauge
   Askeland, Cecilie
   Wik, Elisabeth
   Knutsvik, Goril
   Molven, Anders
   Edelmann, Reidunn J.
   Reed, Rolf K.
   Warren, David J.
   Gullberg, Donald
   Stuhr, Linda
   Akslen, Lars A.
TI Integrin α11β1 is expressed in breast cancer stroma and associates with
   aggressive tumor phenotypes
SO JOURNAL OF PATHOLOGY CLINICAL RESEARCH
LA English
DT Article
DE integrin alpha 11 beta 1; monoclonal antibody; breast cancer; cancer
   associated fibroblasts; myoepithelial cells; clinico-pathologic features
ID PROGNOSTIC-SIGNIFICANCE; FIBROBLASTS; MYOFIBROBLASTS; PROGRESSION;
   CARCINOMA; FIBROSIS; RECEPTOR; TISSUE; CELLS; BETA
AB Cancer-associated fibroblasts are essential modifiers of the tumor microenvironment. The collagen-binding integrin alpha 11 beta 1 has been proposed to be upregulated in a pro-tumorigenic subtype of cancer-associated fibroblasts. Here, we analyzed the expression and clinical relevance of integrin alpha 11 beta 1 in a large breast cancer series using a novel antibody against the human integrin alpha 11 chain. Several novel monoclonal antibodies against the integrin alpha 11 subunit were tested for use on formalin-fixed paraffin-embedded tissues, and Ab 210F4B6A4 was eventually selected to investigate the immunohistochemical expression in 392 breast cancers using whole sections. mRNA data from METABRIC and co-expression patterns of integrin alpha 11 in relation to alpha SMA and cytokeratin-14 were also investigated. Integrin alpha 11 was expressed to varying degrees in spindle-shaped cells in the stroma of 99% of invasive breast carcinomas. Integrin alpha 11 co-localized with alpha SMA in stromal cells, and with alpha SMA and cytokeratin-14 in breast myoepithelium. High stromal integrin alpha 11 expression (66% of cases) was associated with aggressive breast cancer features such as high histologic grade, increased tumor cell proliferation, ER negativity, HER2 positivity, and triple-negative phenotype, but was not associated with breast cancer specific survival at protein or mRNA levels. In conclusion, high stromal integrin alpha 11 expression was associated with aggressive breast cancer phenotypes.
C1 [Smeland, Hilde Ytre-Hauge; Askeland, Cecilie; Wik, Elisabeth; Knutsvik, Goril; Edelmann, Reidunn J.; Akslen, Lars A.] Univ Bergen, Dept Clin Med, Ctr Canc Biomarkers CCBIO, Bergen, Norway.
   [Smeland, Hilde Ytre-Hauge; Reed, Rolf K.; Gullberg, Donald; Stuhr, Linda] Univ Bergen, Dept Biomed, Ctr Canc Biomarkers CCBIO, Bergen, Norway.
   [Askeland, Cecilie; Wik, Elisabeth; Knutsvik, Goril; Molven, Anders; Akslen, Lars A.] Haukeland Hosp, Dept Pathol, Bergen, Norway.
   [Molven, Anders] Univ Bergen, Dept Clin Med, Gade Lab Pathol, Bergen, Norway.
   [Warren, David J.] Oslo Univ Hosp, Dept Med Biochem, Oslo, Norway.
C3 University of Bergen; University of Bergen; University of Bergen;
   Haukeland University Hospital; University of Bergen; University of Oslo
RP Akslen, LA (corresponding author), Univ Bergen, Haukeland Univ Hosp, Dept Clin Med, Ctr Canc Biomarkers CCBIO,Sect Pathol, N-5021 Bergen, Norway.
EM lars.akslen@uib.no
RI Wik, E./AAA-9105-2020; Akslen, Lars/C-1202-2017; Gullberg,
   Donald/H-2495-2016; Reed, Rolf K./B-9422-2017
OI Smeland, Hilde Ytre-Hauge/0000-0001-5607-6416; Reed, Rolf
   K./0000-0002-2633-6595
FU Research Council of Norway through its Centres of Excellence funding
   scheme [223250]; Meltzer Fund Research Grant
FX The authors would like to thank Ning Lu (RT-qPCR, western blotting and
   immunofluorescence staining), Gerd Lillian Hallseth
   (immunohistochemistry) and Bendik Nordanger (histochemical work) for
   excellent technical assistance. This work was supported by the Research
   Council of Norway through its Centres of Excellence funding scheme,
   project number 223250, and by a Meltzer Fund Research Grant.
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PU WILEY
PI HOBOKEN
PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA
EI 2056-4538
J9 J PATHOL CLIN RES
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PD JAN
PY 2020
VL 6
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BP 69
EP 82
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EA DEC 2019
PG 14
WC Pathology
WE Science Citation Index Expanded (SCI-EXPANDED)
SC Pathology
GA KD1PQ
UT WOS:000500239700001
PM 31605508
OA Green Accepted, Green Published
DA 2025-03-13
ER

PT J
AU Zhang, SM
   Huang, XJ
   Zhu, WB
   Liu, YM
   Qiu, N
   Cai, ZY
   Xu, T
   Wu, Y
   Fan, YL
   Qiu, DQ
   Zhu, JQ
   Li, HS
AF Zhang, Siming
   Huang, Xiaojia
   Zhu, Wenbiao
   Liu, Yumei
   Qiu, Ni
   Cai, Zheyou
   Xu, Tai
   Wu, Yuan
   Fan, Yuanlin
   Qiu, Dongqin
   Zhu, Junqiang
   Li, Hongsheng
TI Single-Cell Analysis Reveals Adipose Cancer-Associated Fibroblasts
   Linked to Trastuzumab Resistance in Human Epidermal Growth Factor
   Receptor 2-Positive Breast Cancer
SO SCIENCE OF ADVANCED MATERIALS
LA English
DT Article
DE Drug Resistance; Cancer-Associated Fibroblasts; Single-Cell Analysis
ID INSULIN; IGF-1
AB Trastuzumab, a first-line targeted agent for HER-2-positive breast cancer, often faces challenges due to resis-tance. The IGF-1R/IRS-1/AKT pathway hyperactivation has been linked to this resistance, but the primary culprit, whether epithelial cells or cancer-associated fibroblasts (CAFs), remains uncertain. To investigate, we employed seRNA-seq to differentiate CAFs and epithelial cells in trastuzumab-sensitive and resistant breast cancer samples. iTALK analysis revealed potentialintractions between CAFs and epithelial cells through IP: 203.8.109.10 On: Tue, 31 Oct 2023 09:28:53 IGF-1. We then analyzed 43 HER-2-positve breast cancer samples treated with trastuzumab, confirming higher Copyright: American Scientific Publishers Delivered by Ingenta expression of IGF-1R/IRS-1/AKT pathway proteins using immunohistochemistry. Notably, we identified five CAFs subtypes with varying proportions in both trastuzumab-sensitive and resistant samples. Further analysis revealed elevated IGF-1 levels in CAFs of trastuzumab-resistant tissues, particularly in adipose CAFs. Immuno-histochemistry staining corroborated overexpression of COL11A1 (an adipose CAF marker) and increased IGF-1R and Tyr-phosphorylated IRS-1 in HER-2-positive breast cancer, associated with poor trastuzumab response. Our findings suggest that CAFs, particularly adipose CAFs, may induce trastuzumab resistance in HER2-positive breast cancer epithelial cells through IGF-1-mediated activation of the IGF-1R/IRS-1/AKT pathway.
C1 [Zhang, Siming; Xu, Tai; Wu, Yuan; Fan, Yuanlin; Qiu, Dongqin; Zhu, Junqiang] Meizhou Peoples Hosp, Dept Breast Surg, Meizhou 514000, Peoples R China.
   [Huang, Xiaojia; Qiu, Ni; Cai, Zheyou; Li, Hongsheng] Guangzhou Med Univ, Affiliated Canc Hosp & Inst, Dept Breast Oncol Surg, Guangzhou 510095, Peoples R China.
   [Zhu, Wenbiao] Meizhou Peoples Hosp, Dept Pathol, Meizhou 514000, Peoples R China.
   [Liu, Yumei] Jiaying Univ, Dept Pharmacol, Meizhou 514000, Peoples R China.
C3 Guangzhou Medical University; Jiaying University
RP Li, HS (corresponding author), Guangzhou Med Univ, Affiliated Canc Hosp & Inst, Dept Breast Oncol Surg, Guangzhou 510095, Peoples R China.
EM lihongsheng@gzhmu.edu.cn
RI Huang, Xiaojia/GVS-0843-2022; Li, Hongsheng/AES-5328-2022
FU Meizhou Science and Technology Bureau [2011141720 50542]; National
   Natural Science Foundation of China [82072899, 82002778]; Clinical Key
   Specialty Construction Project of Guangzhou Medical University [202005];
   Natural Science Foundation of Guangdong Province [2023A1515010203];
   Guangzhou Science and Technology [202102010042]
FX Acknowledgments: This study was supported by the Meizhou Science and
   Technology Bureau (2011141720 50542) , the National Natural Science
   Foundation of China (82072899, 82002778) , the Clinical Key Specialty
   Construction Project of Guangzhou Medical University (202005) , the
   Natural Science Foundation of Guangdong Province (2023A1515010203) , and
   Guangzhou Science and Technology (202102010042) . The funders had no
   role in the study design, data collection or analysis, decision to
   publish, or manuscript preparation.
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NR 30
TC 0
Z9 0
U1 2
U2 7
PU AMER SCIENTIFIC PUBLISHERS
PI VALENCIA
PA 26650 THE OLD RD, STE 208, VALENCIA, CA 91381-0751 USA
SN 1947-2935
EI 1947-2943
J9 SCI ADV MATER
JI Sci. Adv. Mater.
PD OCT
PY 2023
VL 15
IS 10
BP 1385
EP 1393
DI 10.1166/sam.2023.4536
PG 9
WC Nanoscience & Nanotechnology; Materials Science, Multidisciplinary;
   Physics, Applied
WE Science Citation Index Expanded (SCI-EXPANDED)
SC Science & Technology - Other Topics; Materials Science; Physics
GA X3KN3
UT WOS:001097476600002
DA 2025-03-13
ER

PT J
AU Lv, MH
AF Lv, Minghe
TI MYL5 as a Novel Prognostic Marker is Associated with Immune Infiltrating
   in Breast Cancer: A Preliminary Study
SO BREAST JOURNAL
LA English
DT Article
ID LIGHT-CHAIN KINASE; TUMOR PROGRESSION; MYOSIN; INHIBITORS; ADHESION;
   INVASION
AB Background. Myosin light chain plays a vital regulatory function in a large-scale cellular physiological procedure, however, the role of myosin light chain 5 (MYL5) in breast cancer has not been reported. In this study, we aimed to elucidate the effects of MYL5 on clinical prognosis and immune cell infiltration, and further explore the potential mechanism in breast cancer patients. Methods. In this study, we first explored the expression pattern and prognostic value of MYL5 in breast cancer across multiple databases, including Oncomine, TCGA, GTEx, GEPIA2, PrognoScan, and Kaplan-Meier Plotter. The correlations of MYL5 expression with immune cell infiltration and associational gene markers in breast cancer were analyzed by using the TIMER, TIMER2.0, and TISIDB databases. The enrichment and prognosis analysis of MYL5-related genes were implemented by using LinkOmics datasets. Results. We found that there was a low expression of MYL5 in breast cancer than in corresponding normal tissue by analyzing the data from Oncomine and TCGA datasets. Furthermore, research showed the prognosis of the MYL5 high-expression group was better than the low-expression group in breast cancer patients. Furthermore, MYL5 expression is markedly related to the tumor-infiltrating immune cells (TIICs), including cancer-associated fibroblast, B cell, CD8(+) T cell, CD4(+) T cell, macrophage, neutrophil, and dendritic cell, and related to immune molecules as well as the associated gene markers of TIICs. Conclusion. MYL5 can serve as a prognostic signature in breast cancer and is associated with immune infiltration. This study first offers a relatively comprehensive understanding of the oncogenic roles of MYL5 for breast cancer.
C1 [Lv, Minghe] Fudan Univ, Shanghai Canc Ctr, Dept Radiat Oncol, Shanghai, Peoples R China.
   [Lv, Minghe] Fudan Univ, Shanghai Med Coll, Dept Oncol, Shanghai, Peoples R China.
   [Lv, Minghe] Shanghai Clin Res Ctr Radiotherapy Oncol, Shanghai Key Lab Radiat Oncol, Shanghai 200032, Peoples R China.
C3 Fudan University; Fudan University
RP Lv, MH (corresponding author), Fudan Univ, Shanghai Canc Ctr, Dept Radiat Oncol, Shanghai, Peoples R China.; Lv, MH (corresponding author), Fudan Univ, Shanghai Med Coll, Dept Oncol, Shanghai, Peoples R China.; Lv, MH (corresponding author), Shanghai Clin Res Ctr Radiotherapy Oncol, Shanghai Key Lab Radiat Oncol, Shanghai 200032, Peoples R China.
EM 17211270006@fudan.edu.cn
OI Lv, Minghe/0000-0001-9342-773X
CR Bond LM, 2013, FUTURE MED CHEM, V5, P41, DOI 10.4155/fmc.12.185
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NR 34
TC 2
Z9 2
U1 0
U2 0
PU WILEY
PI HOBOKEN
PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA
SN 1075-122X
EI 1524-4741
J9 BREAST J
JI Breast J.
PD FEB 17
PY 2023
VL 2023
AR 9508632
DI 10.1155/2023/9508632
PG 21
WC Oncology; Obstetrics & Gynecology
WE Science Citation Index Expanded (SCI-EXPANDED)
SC Oncology; Obstetrics & Gynecology
GA 9I6KZ
UT WOS:000939618200001
PM 36846347
OA Green Published, gold
DA 2025-03-13
ER

PT J
AU Tyan, SW
   Kuo, WH
   Huang, CK
   Pan, CC
   Shew, JY
   Chang, KJ
   Lee, EYHP
   Lee, WH
AF Tyan, Shiaw-Wei
   Kuo, Wen-Hung
   Huang, Chun-Kai
   Pan, Chi-Chun
   Shew, Jin-Yuh
   Chang, King-Jen
   Lee, Eva Y. -H. P.
   Lee, Wen-Hwa
TI Breast Cancer Cells Induce Cancer-Associated Fibroblasts to Secrete
   Hepatocyte Growth Factor to Enhance Breast Tumorigenesis
SO PLOS ONE
LA English
DT Article
ID TUMOR-STROMAL INTERACTIONS; MICROENVIRONMENT; HETEROGENEITY; METASTASIS;
   CARCINOMAS; BETA; MET
AB It has been well documented that microenvironment consisting of stroma affects breast cancer progression. However, the mechanisms by which cancer cells and fibroblasts, the major cell type in stroma, interact with each other during tumor development remains to be elucidated. Here, we show that the human cancer-associated fibroblasts (CAFs) had higher activity in enhancing breast tumorigenecity compared to the normal tissue-associated fibroblasts (NAFs) isolated from the same patients. The expression level of hepatocyte growth factor (HGF) in these fibroblasts was positively correlated with their ability to enhance breast tumorigenesis in mice. Deprivation of HGF using a neutralizing antibody reduced CAF-mediated colony formation of human breast cancer cells, indicating that CAFs enhanced cancer cell colony formation mainly through HGF secretion. Co-culture with human breast cancer MDA-MB-468 cells in a transwell system enhanced NAFs to secret HGF as well as promote tumorigenecity. The newly gained ability of these "educated'' NAFs became irreversible after continuing this process till fourth passage. These results suggested that breast cancer cells could alter the nature of its surrounding fibroblasts to secrete HGF to support its own progression through paracrine signaling.
C1 [Tyan, Shiaw-Wei; Huang, Chun-Kai; Pan, Chi-Chun; Shew, Jin-Yuh; Lee, Eva Y. -H. P.; Lee, Wen-Hwa] Acad Sinica, Genom Res Ctr, Taipei 115, Taiwan.
   [Kuo, Wen-Hung; Chang, King-Jen] Natl Taiwan Univ Hosp, Dept Surg, Taipei 100, Taiwan.
   [Lee, Eva Y. -H. P.] Univ Calif Irvine, Dept Dev & Cell Biol, Irvine, CA 92717 USA.
   [Lee, Eva Y. -H. P.; Lee, Wen-Hwa] Univ Calif Irvine, Dept Biol Chem, Irvine, CA 92717 USA.
C3 Academia Sinica - Taiwan; National Taiwan University; National Taiwan
   University Hospital; University of California System; University of
   California Irvine; University of California System; University of
   California Irvine
RP Tyan, SW (corresponding author), Acad Sinica, Genom Res Ctr, Taipei 115, Taiwan.
EM kingjen@ntu.edu.tw; elee@uci.edu; whlee@uci.edu
RI Lee, Wen-Hwa/C-2519-2014; Kim, Nam Hoon/HNS-5794-2023
OI Chang, King jen/0000-0001-9811-3422; KUO, WEN-HUNG/0000-0002-9881-4605
FU Academia Sinica [2371, 4012]; biotech company; GeneTex
FX This work was supported by Academia Sinica Peak Project (grant number
   2371, 4012, http://www.sinica.edu.tw). The funders had no role in study
   design, data collection and analysis, decision to publish, or
   preparation of the manuscript.Based on University of California Irvine
   policy, WHL and EL declare that they have financial interests of a
   biotech company, GeneTex, which distributes research reagents globally
   and owns stock from Schering-Plough, a publicly traded pharmaceutical
   company, like any stockholder. WHL is on the board of directors, and EL
   is a consultant. GeneTex did not support this work in any way. These
   data and material will be distributed freely following the policies of
   PLoS ONE. It is the authors' recognition that these financial interests
   could not generate any bias toward this work, and do not alter their
   adherence to all the PLoS ONE policies on sharing data and materials.
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NR 24
TC 138
Z9 171
U1 1
U2 10
PU PUBLIC LIBRARY SCIENCE
PI SAN FRANCISCO
PA 1160 BATTERY STREET, STE 100, SAN FRANCISCO, CA 94111 USA
SN 1932-6203
J9 PLOS ONE
JI PLoS One
PD JAN 13
PY 2011
VL 6
IS 1
AR e15313
DI 10.1371/journal.pone.0015313
PG 9
WC Multidisciplinary Sciences
WE Science Citation Index Expanded (SCI-EXPANDED)
SC Science & Technology - Other Topics
GA 710ME
UT WOS:000286515000004
PM 21249190
OA Green Published, gold
DA 2025-03-13
ER

PT J
AU Knower, KC
   To, SQ
   Takagi, K
   Miki, Y
   Sasano, H
   Simpson, ER
   Clyne, CD
AF Knower, Kevin C.
   To, Sarah Q.
   Takagi, Kiyoshi
   Miki, Yasuhiro
   Sasano, Hironobu
   Simpson, Evan R.
   Clyne, Colin D.
TI Melatonin suppresses aromatase expression and activity in breast cancer
   associated fibroblasts
SO BREAST CANCER RESEARCH AND TREATMENT
LA English
DT Article
DE Melatonin; Aromatase; Postmenopause; Breast cancer; Epigenetic;
   Prostaglandin E-2
ID ADIPOSE STROMAL CELLS; RECEPTOR; GROWTH; BIOSYNTHESIS; MECHANISMS;
   TUMOR; ALPHA; LIGHT; AMP
AB The main biological active substance secreted by the pineal gland, melatonin (MLT), counteracts the effects of estrogens in breast cancer via exerting a number of its own oncostatic properties. Recent studies of postmenopausal women have identified that the major metabolite of MLT is statistically significantly associated with a lower risk of developing breast cancer. While MLT production decreases with age, breast cancer risk, however, increases with age and obesity. We hypothesize that MLT inhibits estrogen production in breast adipose fibroblasts (BAFs), the main local source of estrogen in breast tumors of postmenopausal women, by inhibiting transcription of the CYP19A1 gene that encodes the key enzyme aromatase. Normal BAFs were cultured from women undergoing breast reduction surgery, while breast cancer-associated fibroblasts (CAFs) were isolated from three women with estrogen receptor (ER) positive invasive ductal carcinomas. MTNR1A and MTNR1B receptor expression and CYP19A1 mRNA expression following MLT treatments were determined by qRT-PCR. BAFs express the G-protein coupled MLT receptors MTNR1A and MTNR1B with elevated levels of MTNR1A found in CAFs. Treatment of BAFs and CAFs with MLT resulted in significant suppression of CYP19A1 transcription and aromatase activity at pharmacological, physiological and sub-physiological concentrations. MLT suppression occurred through promoter-specific PI.4-, PI.3- and PII-derived CYP19A1 mRNA. Stimulation of CYP19A1 PII-mRNA and aromatase activity by prostaglandin E-2 (PGE(2)) were significantly attenuated by physiological doses of MLT. Lower levels of MLT in aging women may increase the risk of progressing ER-positive breast cancer through a decreased ability to suppress CYP19A1 expression and subsequent local estrogen production in BAFs/CAFs.
C1 [Knower, Kevin C.; To, Sarah Q.; Clyne, Colin D.] Prince Henrys Inst Med Res, Canc Drug Discovery Lab, Clayton, Vic 3168, Australia.
   [Takagi, Kiyoshi; Miki, Yasuhiro; Sasano, Hironobu] Tohoku Univ, Dept Pathol, Grad Sch Med, Sendai, Miyagi 980, Japan.
   [Simpson, Evan R.] Prince Henrys Inst, Metab & Canc Lab, Clayton, Vic, Australia.
   [Simpson, Evan R.; Clyne, Colin D.] Monash Univ, Dept Biochem & Mol Biol, Clayton, Vic, Australia.
C3 Prince Henry's Institute of Medical Research; Tohoku University; Prince
   Henry's Institute of Medical Research; Monash University
RP Knower, KC (corresponding author), Prince Henrys Inst Med Res, Canc Drug Discovery Lab, POB 5152, Clayton, Vic 3168, Australia.
EM kevin.knower@princehenrys.org
RI Takagi, Kiyoshi/ABJ-3265-2022; Miki, Yasuhiro/AFQ-3410-2022; Knower,
   Kevin/C-2869-2014
OI To, Sarah Quynh Giao/0000-0002-7198-484X
FU U.S. Department of Defense [W81XWH-08-BCRP-POSTDOC]; National Health and
   Medical Research Council of Australia [338518, 550900]; Victoria Breast
   Cancer Research Consortium Inc.; Victorian Government
FX KCK was supported by a U.S. Department of Defense Post-doctoral Training
   Award (W81XWH-08-BCRP-POSTDOC). This work was supported by the National
   Health and Medical Research Council of Australia through fellowships to
   CDC (#338518) and ERS (#550900); the Victoria Breast Cancer Research
   Consortium Inc.; and the Victorian Government's Operational
   Infrastructure Support Program. PHI Data Audit #11-17.
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NR 30
TC 37
Z9 39
U1 1
U2 7
PU SPRINGER
PI NEW YORK
PA ONE NEW YORK PLAZA, SUITE 4600, NEW YORK, NY, UNITED STATES
SN 0167-6806
EI 1573-7217
J9 BREAST CANCER RES TR
JI Breast Cancer Res. Treat.
PD APR
PY 2012
VL 132
IS 2
BP 765
EP 771
DI 10.1007/s10549-012-1953-4
PG 7
WC Oncology
WE Science Citation Index Expanded (SCI-EXPANDED)
SC Oncology
GA 909ER
UT WOS:000301545900041
PM 22237979
DA 2025-03-13
ER

PT J
AU Chen, LY
   Zeng, X
   Kleibeuker, E
   Buffa, F
   Barberis, A
   Leek, RD
   Roxanis, I
   Zhang, W
   Worth, A
   Beech, JS
   Harris, AL
   Cai, SJ
AF Chen, Liye
   Zeng, Xin
   Kleibeuker, Esther
   Buffa, Francesca
   Barberis, Alessandro
   Leek, Russell D.
   Roxanis, Ioannis
   Zhang, Wei
   Worth, Andrew
   Beech, John S.
   Harris, Adrian L.
   Cai, Shijie
TI Paracrine effect of GTP cyclohydrolase and angiopoietin-1 interaction in
   stromal fibroblasts on tumor Tie2 activation and breast cancer growth
SO ONCOTARGET
LA English
DT Article
DE cancer-associated fibroblasts; RTK Tie2; angiopoietin; GTP
   cyclohydrolase; breast cancer
ID RECEPTOR TYROSINE KINASE; ENDOTHELIAL-CELLS; EXPRESSION; ANGIOGENESIS;
   PROGRESSION; MATRIX; TETRAHYDROBIOPTERIN; OVEREXPRESSION;
   MYOFIBROBLASTS; METASTASIS
AB Cancer-associated fibroblasts (CAFs) play a key role in promoting tumor growth, acting through complex paracrine regulation. GTP cyclohydrolase (GTPCH) expression for tetrahydrobiopterin synthesis in tumor stroma is implicated in angiogenesis and tumor development. However, the clinical significance of GTPCH expression in breast cancer is still elusive and how GTPCH regulates stromal fibroblast and tumor cell communication remains unknown. We found that GTPCH was upregulated in breast CAFs and epithelia, and high GTPCH RNA was significantly correlated with larger high grade tumors and worse prognosis. In cocultures, GTPCH expressing fibroblasts stimulated breast cancer cell proliferation and motility, cancer cell Tie2 phosphorylation and consequent downstream pathway activation. GTPCH interacted with Ang-1 in stromal fibroblasts and enhanced Ang-1 expression and function, which in turn phosphorylated tumor Tie2 and induced cell proliferation. In coimplantation xenografts, GTPCH in fibroblasts enhanced tumor growth, upregulating Ang-1 and alpha-smooth muscle actin mainly in fibroblast-like cells. GTPCH inhibition resulted in the attenuation of tumor growth and angiogenesis. GTPCH/Ang-1 interaction in stromal fibroblasts and activation of Tie2 on breast tumor cells could play an important role in supporting breast cancer growth. GTPCH may be an important mechanism of paracrine tumor growth and hence a target for therapy in breast cancer.
C1 [Chen, Liye; Zeng, Xin; Kleibeuker, Esther; Buffa, Francesca; Barberis, Alessandro; Leek, Russell D.; Harris, Adrian L.; Cai, Shijie] Univ Oxford, Weatherall Inst Mol Med, Mol Oncol Labs, Dept Oncol,John Radcliffe Hosp, Oxford OX3 9DS, England.
   [Roxanis, Ioannis] Oxford Univ Hosp, Dept Cellular Pathol, Oxford OX3 9DU, England.
   [Roxanis, Ioannis] John Radcliffe Hosp, NIHR Biomed Res Ctr, Oxford OX3 9DU, England.
   [Zhang, Wei] John Radcliffe Hosp, Nuffield Dept Obstet & Gynaecol, Oxford OX3 9DU, England.
   [Worth, Andrew] Univ Oxford, Jenner Inst, Nuffield Dept Med, Oxford OX3 7DQ, England.
   [Beech, John S.] Univ Oxford, Gray Inst Radiat Oncol & Biol, Dept Oncol, Oxford OX3 7DQ, England.
   [Zeng, Xin] Xiamen Univ, Affiliated Hosp 1, Xiamen Inst Diabet Res, Xiamen, Peoples R China.
C3 University of Oxford; University of Oxford; University of Oxford;
   University of Oxford; Jenner Institute; University of Oxford; Xiamen
   University
RP Cai, SJ (corresponding author), Univ Oxford, Weatherall Inst Mol Med, Mol Oncol Labs, Dept Oncol,John Radcliffe Hosp, Oxford OX3 9DS, England.
EM sjcai0333@gmail.com
RI Cai, Shijie/JHN-1228-2023; Barberis, Alessandro/HGB-2377-2022; Chen,
   Li-Ye/AAE-3399-2019; Buffa, Francesca/D-2574-2013; Harris,
   Adrian/ABA-3343-2020
OI Leek, Russell/0000-0002-8038-8660; Harris, Adrian/0000-0003-1376-8409
FU Oxford University Challenge Seed Fund; Bayer HealthCare 'From Targets to
   Novel Drugs'; p-Medicine; Breast Cancer Research Foundation; Cancer
   Research UK; EURECA; Xiamen Science & Technology Planning Project Grant,
   China [3502Z20113023]
FX This work was supported by grants from the Oxford University Challenge
   Seed Fund, Bayer HealthCare 'From Targets to Novel Drugs', p-Medicine,
   Breast Cancer Research Foundation, Cancer Research UK and EURECA and
   Xiamen Science & Technology Planning Project Grant, China
   (3502Z20113023).
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NR 42
TC 19
Z9 20
U1 0
U2 3
PU IMPACT JOURNALS LLC
PI ORCHARD PARK
PA 6666 E QUAKER ST, STE 1, ORCHARD PARK, NY 14127 USA
EI 1949-2553
J9 ONCOTARGET
JI Oncotarget
PD FEB 23
PY 2016
VL 7
IS 8
BP 9354
EP 9368
DI 10.18632/oncotarget.6981
PG 15
WC Oncology; Cell Biology
WE Science Citation Index Expanded (SCI-EXPANDED)
SC Oncology; Cell Biology
GA DL4OW
UT WOS:000375618100068
PM 26814432
OA Green Published, gold, Green Submitted
DA 2025-03-13
ER

PT J
AU Shani, O
   Vorobyov, T
   Monteran, L
   Lavie, D
   Cohen, N
   Raz, Y
   Tsarfaty, G
   Avivi, C
   Barshack, I
   Erez, N
AF Shani, Ophir
   Vorobyov, Tatiana
   Monteran, Lea
   Lavie, Dor
   Cohen, Noam
   Raz, Yael
   Tsarfaty, Galia
   Avivi, Camila
   Barshack, Iris
   Erez, Neta
TI Fibroblast-Derived IL33 Facilitates Breast Cancer Metastasis by
   Modifying the Immune Microenvironment and Driving Type 2 Immunity
SO CANCER RESEARCH
LA English
DT Article
ID T-CELLS; PULMONARY METASTASIS; IL-33; INFLAMMATION; CYTOKINE; PROMOTES;
   INTERLEUKIN-33; NEUTROPHILS; HEALTH; GROWTH
AB Lungs are one of the main sites of breast cancer metastasis. The metastatic microenvironment is essential to facilitate growth of disseminated tumor cells. Cancer-associated fibroblasts (CAF) are prominent players in the microenvironment of breast cancer. However, their role in the formation of a permissive metastatic niche is unresolved. Here we show that IL33 is upregulated in metastases-associated fibroblasts in mouse models of spontaneous breast cancer metastasis and in patients with breast cancer with lung metastasis. Upregulation of IL33 instigated type 2 inflammation in the metastatic microenvironment and mediated recruitment of eosinophils, neutrophils, and inflammatory monocytes to lung metastases. Importantly, targeting of IL33 in vivo resulted in inhibition of lung metastasis and significant attenuation of immune cell recruitment and type 2 immunity. These findings demonstrate a key function of IL33 in facilitating lung metastatic relapse by modulating the immune microenvironment. Our study shows a novel interaction axis between CAF and immune cells and reveals the central role of CAF in establishing a hospitable inflammatory niche in lung metastasis.
   Significance: This study elucidates a novel role for fibroblast-derived IL33 in facilitating breast cancer lung metastasis by modifying the immune microenvironment at the metastatic niche toward type 2 inflammation.
C1 [Shani, Ophir; Vorobyov, Tatiana; Monteran, Lea; Lavie, Dor; Cohen, Noam; Raz, Yael; Erez, Neta] Tel Aviv Univ, Sackler Fac Med, Dept Pathol, Tel Aviv, Israel.
   [Tsarfaty, Galia] Tel Aviv Univ, Sackler Fac Med, Chaim Sheba Med Ctr, Dept Diagnost Imaging, Tel Aviv, Israel.
   [Avivi, Camila; Barshack, Iris] Sheba Med Ctr, Dept Pathol, Tel Hashomer, Israel.
   [Avivi, Camila; Barshack, Iris] Tel Aviv Univ, Sackler Fac Med, IL-69978 Tel Aviv, TA, Israel.
C3 Tel Aviv University; Sackler Faculty of Medicine; Chaim Sheba Medical
   Center; Tel Aviv University; Sackler Faculty of Medicine; Chaim Sheba
   Medical Center; Tel Aviv University; Sackler Faculty of Medicine
RP Erez, N (corresponding author), Tel Aviv Univ, Sackler Fac Med, IL-69978 Tel Aviv, TA, Israel.
EM netaerez@tauex.tau.ac.il
RI Erez, Neta/G-8584-2012
OI Cohen, Noam/0009-0003-7047-8843; Monteran, Lea/0000-0002-7633-2090;
   Erez, Neta/0000-0001-6506-9074; Barshack, Iris/0000-0001-8216-8963
FU European Research Council (ERC) under the European Union [637069
   MetCAF]; Israel Science Foundation [1060/18]; Emerson Collective; Israel
   Cancer Research Fund (ICRF Project Grant)
FX This research was supported by grants to N. Erez from the European
   Research Council (ERC) under the European Union's Horizon 2020 Research
   and Innovation Programme (grant agreement No. 637069 MetCAF), from the
   Israel Science Foundation (#1060/18), the Emerson Collective, and the
   Israel Cancer Research Fund (ICRF Project Grant). The authors would like
   to thank Sharon Grisaru for her assistance with staining of eosinophils
   and Ariel Munitz for critical reading and useful discussion of the
   manuscript.
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NR 50
TC 97
Z9 103
U1 3
U2 42
PU AMER ASSOC CANCER RESEARCH
PI PHILADELPHIA
PA 615 CHESTNUT ST, 17TH FLOOR, PHILADELPHIA, PA 19106-4404 USA
SN 0008-5472
EI 1538-7445
J9 CANCER RES
JI Cancer Res.
PD DEC 1
PY 2020
VL 80
IS 23
BP 5317
EP 5329
DI 10.1158/0008-5472.CAN-20-2116
PG 13
WC Oncology
WE Science Citation Index Expanded (SCI-EXPANDED)
SC Oncology
GA PC0WE
UT WOS:000596730000016
PM 33023944
OA Green Accepted, Green Submitted, Bronze
DA 2025-03-13
ER

PT J
AU Borzone, FR
   Giorello, MB
   Sanmartin, MC
   Yannarelli, G
   Martinez, LM
   Chasseing, NA
AF Borzone, Francisco Raul
   Belen Giorello, Maria
   Cecilia Sanmartin, Maria
   Yannarelli, Gustavo
   Marcelo Martinez, Leandro
   Alejandra Chasseing, Norma
TI Mesenchymal stem cells and cancer-associated fibroblasts as a
   therapeutic strategy for breast cancer
SO BRITISH JOURNAL OF PHARMACOLOGY
LA English
DT Review
DE breast cancer; cancer-associated fibroblasts; mesenchymal stem cells;
   therapeutic approaches
ID CARCINOMA-ASSOCIATED FIBROBLASTS; PROMOTE TUMOR-GROWTH; BONE-MARROW;
   STROMAL CELLS; ACTIVATION PROTEIN; TARGETED-DELIVERY; CONCISE GUIDE;
   DOWN-REGULATION; SIGNALING AXIS; DRUG-DELIVERY
AB Breast cancer is the most common type of cancer and the leading cause of death among women. Recent evidence suggests that mesenchymal stromal/stem cells and cancer-associated fibroblasts (CAFs) have an essential role in cancer progression, invasion and therapy resistance. Therefore, they are considered as highly promising future therapeutic targets against breast cancer. The intrinsic tumour tropism and immunomodulatory capacities of mesenchymal stromal/stem cells are of special relevance for developing mesenchymal stromal/stem cells-based anti-tumour therapies that suppress primary tumour growth and metastasis. In addition, the utilization of therapies that target the stromal components of the tumour microenvironment in combination with standard drugs is an innovative tool that could improve patients' response to therapies and their survival. In this review, we discuss the currently available information regarding the possible use of mesenchymal stromal/stem cells-derived anti-tumour therapies, as well as the utilization of therapies that target CAFs in breast cancer microenvironment. Finally, these data can serve as a guide map for future research in this field, ultimately aiding the effective transition of these results into the clinic.
C1 [Borzone, Francisco Raul; Belen Giorello, Maria; Cecilia Sanmartin, Maria; Alejandra Chasseing, Norma] Consejo Nacl Invest Cient & Tecn CONICET, Lab Inmunohematol, Inst Biol & Med Expt IBYME, Buenos Aires, DF, Argentina.
   [Cecilia Sanmartin, Maria; Yannarelli, Gustavo] Univ Favaloro CONICET, Lab Regulac Gen & Celulas Madre, Inst Med Traslac Trasplante & Bioingn & MeTTyB, Buenos Aires, DF, Argentina.
   [Marcelo Martinez, Leandro] Weill Cornell Med Coll, Dept Med, Hematol & Med Oncol 1, New York, NY USA.
C3 Consejo Nacional de Investigaciones Cientificas y Tecnicas (CONICET);
   Institute of Biology & Experimental Medicine; Cornell University; Weill
   Cornell Medicine
RP Chasseing, NA (corresponding author), Consejo Nacl Invest Cient & Tecn CONICET, Lab Inmunohematol IBYME, Inst Biol & Med Expt, Vuelta Obligado 2490, RA-1428 Buenos Aires, DF, Argentina.
EM alejachase@gmail.com
RI Yannarelli, Gustavo/J-6055-2019
OI Sanmartin, Maria Cecilia/0000-0001-5967-7284; Martinez, Leandro
   Marcelo/0000-0002-9283-5093; Borzone, Francisco
   Raul/0000-0002-3832-9923; Chasseing, Norma
   Alejandra/0000-0001-5486-2245; Giorello, Maria Belen/0000-0001-6983-8301
FU Fundacion Alberto J. Roemmers; Fundacion Williams; Fundacion Rene Baron;
   Fundacion Florencio Fiorini; Fundacion Alberto Roemmers; Fondo para la
   Investigacion Cientifica y Tecnologica; Consejo Nacional de
   Investigaciones Cientificas y Tecnicas
FX Fundacion Alberto J. Roemmers; Fundacion Williams; Fundacion Rene Baron;
   Fundacion Florencio Fiorini; Fundacion Alberto Roemmers; Fondo para la
   Investigacion Cientifica y Tecnologica; Consejo Nacional de
   Investigaciones Cientificas y Tecnicas
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NR 173
TC 11
Z9 11
U1 2
U2 13
PU WILEY
PI HOBOKEN
PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA
SN 0007-1188
EI 1476-5381
J9 BRIT J PHARMACOL
JI Br. J. Pharmacol.
PD JAN
PY 2024
VL 181
IS 2
BP 238
EP 256
DI 10.1111/bph.15861
EA MAY 2022
PG 19
WC Pharmacology & Pharmacy
WE Science Citation Index Expanded (SCI-EXPANDED)
SC Pharmacology & Pharmacy
GA DX4D7
UT WOS:000796615900001
PM 35485850
OA Bronze
DA 2025-03-13
ER

PT J
AU Xia, ZH
   Vermeulen, S
   Suwal, U
   Rappu, P
   Heino, J
   De Vuyst, F
   Dedeyne, S
   Hendrix, A
   Denys, H
   De Wever, O
AF Xia, Zihan
   Vermeulen, Stephanie
   Suwal, Ujjwal
   Rappu, Pekka
   Heino, Jyrki
   De Vuyst, Felix
   Dedeyne, Sandor
   Hendrix, An
   Denys, Hannelore
   De Wever, Olivier
TI Cancer-associated fibroblasts mediate resistance to neoadjuvant therapy
   in breast cancer
SO CLINICAL AND TRANSLATIONAL MEDICINE
LA English
DT Article
C1 [Xia, Zihan; Vermeulen, Stephanie; De Vuyst, Felix; Dedeyne, Sandor; Hendrix, An; De Wever, Olivier] Univ Ghent, Dept Human Struct & Repair, Lab Expt Canc Res, Ghent, Belgium.
   [Xia, Zihan; Vermeulen, Stephanie; De Vuyst, Felix; Dedeyne, Sandor; Hendrix, An; Denys, Hannelore; De Wever, Olivier] Canc Res Inst Ghent, Ghent, Belgium.
   [Suwal, Ujjwal; Rappu, Pekka; Heino, Jyrki] Univ Turku, Dept Life Technol, Turku, Finland.
   [Denys, Hannelore] Ghent Univ Hosp, Dept Med Oncol, Ghent, Belgium.
C3 Ghent University; Ghent University; University of Turku; Ghent
   University; Ghent University Hospital
RP De Wever, O (corresponding author), Univ Ghent, Dept Human Struct & Repair, Lab Expt Canc Res, Ghent, Belgium.
EM olivier.dewever@ugent.be
RI Hendrix, An/L-5918-2019; Siljamäki, Elina/HOA-9317-2023; Rappu,
   Pekka/LKJ-2664-2024; denys, hannelore/E-5420-2018
OI Xia, Zihan/0009-0001-1935-2183; Suwal, Ujjwal/0000-0002-9389-2911;
   Vermeulen, Stephanie/0000-0002-9655-2293
FU China Scholarship Council [202006160045]; Kom Op Tegen Kanker, Stichting
   Tegen Kanker and Concerted Research Actions of Ghent University
FX This work was supported by the China Scholarship Council (202006160045),
   Kom Op Tegen Kanker, Stichting Tegen Kanker and Concerted Research
   Actions of Ghent University.
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NR 10
TC 0
Z9 0
U1 2
U2 3
PU JOHN WILEY & SONS LTD
PI CHICHESTER
PA THE ATRIUM, SOUTHERN GATE, CHICHESTER PO19 8SQ, W SUSSEX, ENGLAND
SN 2001-1326
J9 CLIN TRANSL MED
JI Clin. Transl. Med.
PD JUL
PY 2024
VL 14
IS 7
AR e1779
DI 10.1002/ctm2.1779
PG 6
WC Oncology; Medicine, Research & Experimental
WE Science Citation Index Expanded (SCI-EXPANDED)
SC Oncology; Research & Experimental Medicine
GA ZC5Z9
UT WOS:001273118400001
PM 39032166
OA gold
DA 2025-03-13
ER

PT J
AU Huang, QY
   Wu, LY
   Wang, Y
   Kong, XY
   Xiao, XH
   Huang, QY
   Li, M
   Zhai, YJ
   Shi, FX
   Zhao, RC
   Zhong, JP
   Xiong, LX
AF Huang, Qingyun
   Wu, Longyuan
   Wang, Yi
   Kong, Xinyu
   Xiao, Xinhua
   Huang, Qiyuan
   Li, Miao
   Zhai, Yujia
   Shi, Fuxiu
   Zhao, Ruichen
   Zhong, Junpei
   Xiong, Lixia
TI Caveolin-1-deficient fibroblasts promote migration, invasion, and
   stemness via activating the TGF-β/Smad signaling pathway in breast
   cancer cells
SO ACTA BIOCHIMICA ET BIOPHYSICA SINICA
LA English
DT Article
DE caveolin 1; cancer-associated fibroblasts; breast neoplasms;
   epithelial-mesenchymal transition; transforming growth factor-beta
ID EPITHELIAL-MESENCHYMAL TRANSITION; EXPRESSION; GROWTH; MICROENVIRONMENT;
   METASTASIS; PROGRESSION; PROLIFERATION; HETEROGENEITY; EMT
AB Cancer-associated fibroblasts (CAFs) represent one of the main components in the tumor stroma and play a key role in breast cancer progression. Transforming growth factor-beta (TGF-beta) has been established to mediate breast cancer metastasis by regulating the epithelial-mesenchymal transition (EMT) and stemness of cancer cells. Caveolin-1 (CAV-1) is a scaffold protein of caveolae that is related to the proliferation and metabolism of cancer cells. It is now well demonstrated that CAV-1 deficiency in the tumor stroma is positively correlated with distant metastasis, but the mechanism remains unclear. Here, we explore whether CAV-1-deficient fibroblasts play an essential role in the EMT and stemness of breast cancer cells (BCCs) through TGF-beta signaling. We establish a specific small interfering RNA (siRNA) to inhibit CAV-1 expression in fibroblasts and coculture them with BCCs to investigate the effect of CAV-1-deficient fibroblasts and the tumor microenvironment on breast cancer progression. This study refreshingly points out that CAV-1 deficiency in fibroblasts enhances TGF-beta 1 secretion and then activates the TGF-beta 1/Smad signaling pathway of BCCs, thus promoting the metastasis and stemness of BCCs. Collectively, our findings indicate an unexpected role of CAV-1 deficiency in fibroblasts and the tumor microenvironment as a permissive factor, which is regulated by the TGF-beta 1 signaling pathway in BCCs.
C1 [Huang, Qingyun; Wu, Longyuan; Wang, Yi; Kong, Xinyu; Huang, Qiyuan; Li, Miao; Zhai, Yujia; Shi, Fuxiu; Zhao, Ruichen; Zhong, Junpei; Xiong, Lixia] Nanchang Univ, Med Coll, Dept Pathophysiol, Nanchang 330006, Jiangxi, Peoples R China.
   [Xiao, Xinhua] Nanchang Univ, Affiliated Hosp 1, Nanchang 330006, Jiangxi, Peoples R China.
   [Xiong, Lixia] Fujian Prov Univ, Key Lab Funct & Clin Translat Med, Xiamen 361023, Peoples R China.
C3 Nanchang University; Nanchang University; Fuzhou University
RP Xiong, LX (corresponding author), Nanchang Univ, Med Coll, Dept Pathophysiol, Nanchang 330006, Jiangxi, Peoples R China.; Xiong, LX (corresponding author), Fujian Prov Univ, Key Lab Funct & Clin Translat Med, Xiamen 361023, Peoples R China.
EM xionglixia@ncu.edu.cn
RI zhai, yujia/KPB-0449-2024; Huang, Rachel/KXQ-5304-2024
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NR 52
TC 3
Z9 3
U1 3
U2 10
PU SCIENCE PRESS
PI BEIJING
PA 16 DONGHUANGCHENGGEN NORTH ST, Building 5, Room 411, BEIJING, 100009,
   PEOPLES R CHINA
SN 1672-9145
EI 1745-7270
J9 ACTA BIOCH BIOPH SIN
JI Acta Biochim. Biophys. Sin.
PD NOV
PY 2022
VL 54
IS 11
BP 1587
EP 1598
PG 12
WC Biochemistry & Molecular Biology; Biophysics
WE Science Citation Index Expanded (SCI-EXPANDED)
SC Biochemistry & Molecular Biology; Biophysics
GA 7O9YP
UT WOS:000908370800003
PM 36604141
OA Green Published, gold
DA 2025-03-13
ER

PT J
AU Tsuyada, A
   Chow, A
   Wu, J
   Somlo, G
   Chu, PG
   Loera, S
   Luu, TH
   Li, AXJ
   Wu, XW
   Ye, W
   Chen, SA
   Zhou, WY
   Yu, Y
   Wang, YZ
   Ren, XB
   Li, H
   Scherle, P
   Kuroki, Y
   Wang, SE
AF Tsuyada, Akihiro
   Chow, Amy
   Wu, Jun
   Somlo, George
   Chu, Peiguo
   Loera, Sofia
   Luu, Thehang
   Li, Arthur Xuejun
   Wu, Xiwei
   Ye, Wei
   Chen, Shiuan
   Zhou, Weiying
   Yu, Yang
   Wang, Yuan-Zhong
   Ren, Xiubao
   Li, Hui
   Scherle, Peggy
   Kuroki, Yukio
   Wang, Shizhen Emily
TI CCL2 Mediates Cross-talk between Cancer Cells and Stromal Fibroblasts
   That Regulates Breast Cancer Stem Cells
SO CANCER RESEARCH
LA English
DT Article
ID MONOCYTE CHEMOATTRACTANT PROTEIN-1; MAMMARY STEM/PROGENITOR CELLS;
   GENE-EXPRESSION SIGNATURE; SOLID TUMORS; SURVIVAL; CHEMOKINES; PARACRINE
AB Cancer stem cells (CSC) play critical roles in cancer initiation, progression, and therapeutic refractoriness. Although many studies have focused on the genes and pathways involved in stemness, characterization of the factors in the tumor microenvironment that regulate CSCs is lacking. In this study, we investigated the effects of stromal fibroblasts on breast cancer stem cells. We found that compared with normal fibroblasts, primary cancer-associated fibroblasts (CAF) and fibroblasts activated by cocultured breast cancer cells produce higher levels of chemokine (C-C motif) ligand 2 (CCL2), which stimulates the stem cell-specific, sphere-forming phenotype in breast cancer cells and CSC self-renewal. Increased CCL2 expression in activated fibroblasts required STAT3 activation by diverse breast cancer-secreted cytokines, and in turn, induced NOTCH1 expression and the CSC features in breast cancer cells, constituting a cancer-stroma-cancer signaling circuit. In a xenograft model of paired fibroblasts and breast cancer tumor cells, loss of CCL2 significantly inhibited tumorigenesis and NOTCH1 expression. In addition, upregulation of both NOTCH1 and CCL2 was associated with poor differentiation in primary breast cancers, further supporting the observation that NOTCH1 is regulated by CCL2. Our findings therefore suggest that CCL2 represents a potential therapeutic target that can block the cancer-host communication that prompts CSC-mediated disease progression. Cancer Res; 72(11); 2768-79. (C)2012 AACR.
C1 [Tsuyada, Akihiro; Chow, Amy; Chen, Shiuan; Zhou, Weiying; Yu, Yang; Wang, Yuan-Zhong; Wang, Shizhen Emily] Beckman Res Inst City Hope, Div Tumor Cell Biol, Duarte, CA 91010 USA.
   [Wu, Jun] City Hope Beckman Res Inst, Div Comparat Med, Duarte, CA USA.
   [Somlo, George; Luu, Thehang] City Hope Beckman Res Inst, Dept Med Oncol, Duarte, CA USA.
   [Chu, Peiguo; Loera, Sofia] City Hope Beckman Res Inst, Dept Pathol, Duarte, CA USA.
   [Li, Arthur Xuejun; Ye, Wei] City Hope Beckman Res Inst, Dept Informat Sci, Duarte, CA USA.
   [Wu, Xiwei] City Hope Beckman Res Inst, Bioinformat Core Facil, Duarte, CA USA.
   [Wu, Xiwei] Med Ctr, Duarte, CA USA.
   [Tsuyada, Akihiro; Kuroki, Yukio] Sapporo Med Univ, Dept Biol Mol, Sapporo, Hokkaido, Japan.
   [Tsuyada, Akihiro] Sapporo Med Univ, Grad Sch Med, Sapporo, Hokkaido, Japan.
   [Yu, Yang; Ren, Xiubao; Li, Hui] Tianjin Canc Hosp, Dept Immunol & Biotherapy, Tianjin, Peoples R China.
   [Scherle, Peggy] Incyte Corp, Wilmington, DE USA.
C3 City of Hope; Beckman Research Institute of City of Hope; City of Hope;
   Beckman Research Institute of City of Hope; City of Hope; Beckman
   Research Institute of City of Hope; City of Hope; Beckman Research
   Institute of City of Hope; City of Hope; Beckman Research Institute of
   City of Hope; City of Hope; Beckman Research Institute of City of Hope;
   Sapporo Medical University; Sapporo Medical University; Tianjin Medical
   University; Incyte
RP Wang, SE (corresponding author), Beckman Res Inst City Hope, Div Tumor Cell Biol, 1500 E Duarte Rd,KCRB Room 2007, Duarte, CA 91010 USA.
EM ewang@coh.org
RI Wu, Jian/H-9404-2019; Wang, Yuanzhong/I-5963-2014; Flicek,
   Paul/JOZ-9351-2023
OI Wu, Jun/0000-0003-1834-9596; Wang, Yuanzhong/0000-0001-5739-9065; Wang,
   Shizhen Emily/0000-0002-5036-8175; Zhou, Weiying/0000-0001-8057-8379
FU National Cancer Institute (NCI) [R00 CA125892, P30 CA033572]; National
   Natural Science Foundation of China [30872986, 81171983]
FX The project described was supported by the National Cancer Institute
   (NCI) grant number R00 CA125892 (S.E. Wang) and P30 CA033572, and by the
   National Natural Science Foundation of China grant number 30872986 (X.
   Ren) and 81171983 (H. Li).
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NR 39
TC 321
Z9 349
U1 1
U2 58
PU AMER ASSOC CANCER RESEARCH
PI PHILADELPHIA
PA 615 CHESTNUT ST, 17TH FLOOR, PHILADELPHIA, PA 19106-4404 USA
SN 0008-5472
J9 CANCER RES
JI Cancer Res.
PD JUN 1
PY 2012
VL 72
IS 11
BP 2768
EP 2779
DI 10.1158/0008-5472.CAN-11-3567
PG 12
WC Oncology
WE Science Citation Index Expanded (SCI-EXPANDED)
SC Oncology
GA 986NJ
UT WOS:000307348000010
PM 22472119
OA Green Accepted, Green Submitted
DA 2025-03-13
ER

PT J
AU Folgueira, MAAK
   Maistro, S
   Katayama, MLH
   Roela, RA
   Mundim, FGL
   Nanogaki, S
   de Bock, GH
   Brentani, MM
AF Azevedo Koike Folgueira, Maria Aparecida
   Maistro, Simone
   Hirata Katayama, Maria Lucia
   Roela, Rosimeire Aparecida
   Lopes Mundim, Fiorita Gonzales
   Nanogaki, Suely
   de Bock, Geertruida H.
   Brentani, M. Mitzi
TI Markers of breast cancer stromal fibroblasts in the primary tumour site
   associated with lymph node metastasis: a systematic review including our
   case series
SO BIOSCIENCE REPORTS
LA English
DT Review
DE breast cancer; cancer-associated fibroblasts; caveolin 1; lymph node
   metastasis; MMP13; podoplanin
ID INVASIVE DUCTAL CARCINOMA; GENE-EXPRESSION; PROGNOSTIC-SIGNIFICANCE;
   PROLIFERATIVE ACTIVITY; PLASMINOGEN-ACTIVATOR; CAVEOLIN-1 EXPRESSION;
   TENASCIN-C; IN-SITU; CELLS; PODOPLANIN
AB CAFs (cancer-associated fibroblasts), the most abundant cell type in breast cancer stroma, produce a plethora of chemokines, growth factors and ECM (extracellular matrix) proteins, that may contribute to dissemination and metastasis. Axillary nodes are the first metastatic site in breast cancer; however, to the present date, there is no consensus of which specific proteins, synthesized by CAFs, might be related with lymph node involvement. The purpose of this study was to perform a systematic review of CAF biomarkers associated with the presence of regional metastasis. PubMed was searched using the words: 'breast cancer' and 'lymph node' and fibroblast or stroma or microenvironment. After exclusions, eight studies evaluating biomarkers immunoexpression in CAFs and lymph node status were selected. Biomarkers evaluated in these studies may be divided in two groups, according to their ontology: extracellular matrix components [MMP13 (matrix metalloproteinase 13), TIMP2 (tissue inhibitor of metalloproteinases-2), THBS1 (thrombospondin 1), LGALS1 (lectin, galactoside-binding, soluble, 1)] and response to wounding [PDPN (podoplanin), PLAU (plasminogen activator, urokinase), PLAUR (plasminogen activator, urokinase receptor), CAV1 (caveolin 1), THBS1, LGALS1]. A positive expression of MMP13 and LGALS1 in CAFs was associated with enhanced OR (odds ratio) for regional metastasis. Contrariwise, CAV1 positive staining of fibroblasts was associated with decreased OR for nodal involvement. Expression of MMP13, PDPN and CAV1 was further tested in a new series of 65 samples of invasive ductal breast carcinomas by immunohistochemistry and no association between biomarkers expression in CAFs and nodal status was found. It was suggested that breast cancer subtypes may differentially affect CAFs behaviour. It would be interesting to evaluate the prognostic significance of these biomarkers in CAFs from different tumour types.
C1 [Azevedo Koike Folgueira, Maria Aparecida; Maistro, Simone; Hirata Katayama, Maria Lucia; Roela, Rosimeire Aparecida; Brentani, M. Mitzi] Univ Sao Paulo LIM 24, Fac Med, Dept Radiol & Oncol Disciplina Oncol, Sao Paulo, Brazil.
   [de Bock, Geertruida H.] Univ Groningen, Univ Med Ctr Groningen, Dept Epidemiol, Groningen, Netherlands.
   [Nanogaki, Suely] Hosp AC Camargo Fund Antonio Prudente, Dept Anat Patol, Sao Paulo, Brazil.
   [Lopes Mundim, Fiorita Gonzales] Univ Vale Sapuca, Dept Patol, Pouso Alegre, MG, Brazil.
C3 University of Groningen; A.C.Camargo Cancer Center
RP Brentani, MM (corresponding author), Univ Sao Paulo LIM 24, Fac Med, Dept Radiol & Oncol Disciplina Oncol, Sao Paulo, Brazil.
EM mbrentani@lim24.fm.usp.br
RI Koike Folgueira, Maria Aparecida/V-3139-2019; Roela,
   Rosimeire/AAC-9377-2021; Katayama, Maria Lucia/AAU-8579-2020; Brentani,
   Maria/E-8017-2012; de Bock, Geertruida H./F-6529-2014; Maistro,
   Simone/N-5272-2015; Azevedo Koike Folgueira, Maria Aparecida/H-9558-2018
OI de Bock, Geertruida H./0000-0003-3104-4471; Maistro,
   Simone/0000-0002-0937-2391; Azevedo Koike Folgueira, Maria
   Aparecida/0000-0001-9269-8052
FU FAPESP [0910088-7]
FX This work was supported by the FAPESP [grant no. 0910088-7].
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NR 52
TC 41
Z9 54
U1 0
U2 10
PU PORTLAND PRESS LTD
PI LONDON
PA CHARLES DARWIN HOUSE, 12 ROGER STREET, LONDON WC1N 2JU, ENGLAND
SN 0144-8463
EI 1573-4935
J9 BIOSCIENCE REP
JI Biosci. Rep.
PY 2013
VL 33
BP 921
EP 929
AR e00085
DI 10.1042/BSR20130060
PN 6
PG 9
WC Biochemistry & Molecular Biology; Cell Biology
WE Science Citation Index Expanded (SCI-EXPANDED)
SC Biochemistry & Molecular Biology; Cell Biology
GA 286DR
UT WOS:000329446200007
PM 24229053
OA Green Published, gold, Green Submitted
DA 2025-03-13
ER

PT J
AU Li, KD
   Liu, T
   Chen, J
   Ni, HY
   Li, WH
AF Li, Kangdi
   Liu, Ting
   Chen, Jie
   Ni, Huying
   Li, Wenhua
TI Survivin in breast cancer-derived exosomes activates fibroblasts by
   up-regulating SOD1, whose feedback promotes cancer proliferation and
   metastasis
SO JOURNAL OF BIOLOGICAL CHEMISTRY
LA English
DT Article
DE breast cancer; myofibroblasts; exosome; survivin; SOD1; breast cancer;
   tumor microenvironment; exosome (vesicle)
ID EXTRACELLULAR VESICLES; TUMOR MICROENVIRONMENT; STROMAL FIBROBLASTS;
   TARGETING SURVIVIN; CELLS; EXPRESSION; MECHANISMS; PARACRINE
AB Cancer-associated fibroblasts (CAFs) play a critical role in the coevolution of breast tumor cells and their microenvironment by modifying cellular compartments and regulating cancer cell functions via stromal-epithelial dialogue. However, the relationship and interaction between stromal and epithelial cells is still poorly understood. Herein, we revealed that breast cancer cells have a stronger ability to activate fibroblasts and transform them into myofibroblasts (CAF-like) than normal breast epithelial cells, and this stronger ability occurs through paracrine signaling. In turn, myofibroblasts promote the proliferation, epithelial-to-mesenchymal transition (EMT), and stemness of breast cancer cells. Detailed regulatory mechanisms showed that, compared with normal cells, Survivin is overexpressed in breast cancer cells and secreted extracellularly in the form of exosomes, which are then internalized by fibroblasts. Breast cancer cell-derived survivin up-regulates SOD1 expression in fibroblasts and then converts them into myofibroblasts, conversely inducing breast cancer progressionin vitroandin vivo. Thus, our results indicate that survivin acts as an activator of the tumor microenvironment and that SOD1 up-regulation in fibroblasts can promote breast cancer progression. These results suggest that targeting survivin and SOD1 may be a potential therapeutic strategy for breast cancer.
C1 [Li, Kangdi; Liu, Ting; Chen, Jie; Ni, Huying; Li, Wenhua] Wuhan Univ, Coll Life Sci, Hubei Key Lab Cell Homeostasis, Wuhan, Peoples R China.
C3 Wuhan University
RP Li, WH (corresponding author), Wuhan Univ, Coll Life Sci, Hubei Key Lab Cell Homeostasis, Wuhan, Peoples R China.
EM whli@whu.edu.cn
FU National Natural Science Foundation of China [81472684]
FX This project was supported by National Natural Science Foundation of
   China Grant 81472684 (to W. L.).
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NR 47
TC 58
Z9 59
U1 1
U2 12
PU ELSEVIER
PI AMSTERDAM
PA RADARWEG 29, 1043 NX AMSTERDAM, NETHERLANDS
EI 1083-351X
J9 J BIOL CHEM
JI J. Biol. Chem.
PD OCT 2
PY 2020
VL 295
IS 40
BP 13737
EP 13752
DI 10.1074/jbc.RA120.013805
PG 16
WC Biochemistry & Molecular Biology
WE Science Citation Index Expanded (SCI-EXPANDED)
SC Biochemistry & Molecular Biology
GA OB4MB
UT WOS:000578444100004
PM 32709750
OA Green Published, hybrid
DA 2025-03-13
ER

PT J
AU Giorello, MB
   Martinez, LM
   Borzone, FR
   Padin, MD
   Mora, MF
   Sevic, I
   Alaniz, L
   Calcagno, MD
   Garcia-Rivello, H
   Wernicke, A
   Labovsky, V
   Chasseing, NA
AF Giorello, Maria Belen
   Martinez, Leandro Marcelo
   Borzone, Francisco Raul
   Padin, Maria del Rosario
   Mora, Maria Florencia
   Sevic, Ina
   Alaniz, Laura
   Calcagno, Maria de Lujan
   Garcia-Rivello, Hernan
   Wernicke, Alejandra
   Labovsky, Vivian
   Chasseing, Norma Alejandra
TI CD105 expression in cancer-associated fibroblasts: a biomarker for bone
   metastasis in early invasive ductal breast cancer patients
SO FRONTIERS IN CELL AND DEVELOPMENTAL BIOLOGY
LA English
DT Article
DE cancer-associated fibroblasts; CD105; breast cancer; prognosis factor;
   bone metastasis
ID TUMOR-STROMA; PROGNOSTIC-SIGNIFICANCE; CARCINOMA; CELLS; DIAGNOSIS; CD31
AB Introduction: Bone metastasis is one of the causes that mainly decrease survival in patients with advanced breast cancer. Therefore, it is essential to find prognostic markers for the occurrence of this type of metastasis during the early stage of the disease. Currently, cancer-associated fibroblasts, which represent 80% of the fibroblasts present in the tumor microenvironment, are an interesting target for studying new biomarkers and developing alternative therapies. This study evaluated the prognostic significance of the CD105 expression in cancer-associated fibroblasts in early breast cancer patients.Methods: Immunohistochemistry was used to assess CD105 expression in invasive ductal breast carcinomas (n = 342), analyzing its association with clinical and pathological characteristics.Results: High CD105 expression in cancer-associated fibroblasts was associated with an increased risk of metastatic occurrence (p = 0.0003), particularly bone metastasis (p = 0.0005). Furthermore, high CD105 expression was associated with shorter metastasis-free survival, bone metastasis-free survival, and overall survival (p = 0.0002, 0.0006, and 0.0002, respectively). CD105 expression also constituted an independent prognostic factor for metastasis-free survival, bone metastasis-free survival, and overall survival (p = 0.0003, 0.0006, and 0.0001, respectively).Discussion: The high CD105 expression in cancer-associated fibroblasts is an independent prognostic marker for bone metastasis in early breast cancer patients. Therefore, the evaluation of CD105(+) CAFs could be crucial to stratify BCPs based on their individual risk profile for the development of BM, enhancing treatment strategies and outcomes.
C1 [Giorello, Maria Belen; Borzone, Francisco Raul; Labovsky, Vivian; Chasseing, Norma Alejandra] Consejo Nacl Invest Cient & Tecn, Inst Biol & Med Expt IBYME, Lab Inmunohematol, Buenos Aires, Argentina.
   [Martinez, Leandro Marcelo] Weill Cornell Med Coll, Dept Med, Div Hematol & Med Oncol, New York, NY USA.
   [Padin, Maria del Rosario; Mora, Maria Florencia; Garcia-Rivello, Hernan; Wernicke, Alejandra] Hosp Italiano Buenos Aires, Dept Anat Patol, Buenos Aires, Argentina.
   [Sevic, Ina; Alaniz, Laura] Ctr Invest Basicas & Aplicadas CIBA, Lab Microambiente Tumoral, Junin, Argentina.
   [Calcagno, Maria de Lujan] Univ Buenos Aires, Fac Farm & Bioquim, Buenos Aires, Argentina.
C3 Consejo Nacional de Investigaciones Cientificas y Tecnicas (CONICET);
   Institute of Biology & Experimental Medicine; Cornell University; Weill
   Cornell Medicine; University of Buenos Aires; University of Buenos Aires
   Hospital; Hospital Italiano de Buenos Aires; University of Buenos Aires
RP Giorello, MB; Chasseing, NA (corresponding author), Consejo Nacl Invest Cient & Tecn, Inst Biol & Med Expt IBYME, Lab Inmunohematol, Buenos Aires, Argentina.
EM mbgiorello@gmail.com; achasseing@ibyme.conicet.gov.ar
RI Sevic, Ina/ABF-2898-2021; Mora, Maria/C-9753-2009; Alaniz,
   Laura/AAM-2676-2020
FU FONCYT, Argentina [PICT 2017- 2501]
FX This research was supported by the FONCYT, Argentina (PICT 2017-#2501).
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NR 52
TC 3
Z9 3
U1 1
U2 4
PU FRONTIERS MEDIA SA
PI LAUSANNE
PA AVENUE DU TRIBUNAL FEDERAL 34, LAUSANNE, CH-1015, SWITZERLAND
SN 2296-634X
J9 FRONT CELL DEV BIOL
JI Front. Cell. Dev. Biol.
PD AUG 31
PY 2023
VL 11
AR 1250869
DI 10.3389/fcell.2023.1250869
PG 16
WC Cell Biology; Developmental Biology
WE Science Citation Index Expanded (SCI-EXPANDED)
SC Cell Biology; Developmental Biology
GA R6WS5
UT WOS:001065745600001
PM 37719885
OA gold, Green Published
DA 2025-03-13
ER

PT J
AU Ye, JY
   Baer, JM
   Faget, DV
   Morikis, VA
   Ren, QH
   Melam, A
   Delgado, AP
   Luo, XM
   Bagchi, SM
   Belle, JI
   Campos, E
   Friedman, M
   Veis, DJ
   Knudsen, ES
   Witkiewicz, AK
   Powers, S
   Longmore, GD
   DeNardo, DG
   Stewart, SA
AF Ye, Jiayu
   Baer, John M.
   Faget, Douglas V.
   Morikis, Vasilios A.
   Ren, Qihao
   Melam, Anupama
   Delgado, Ana Paula
   Luo, Xianmin
   Bagchi, Satarupa Mullick
   Belle, Jad I.
   Campos, Edward
   Friedman, Michael
   Veis, Deborah J.
   Knudsen, Erik S.
   Witkiewicz, Agnieszka K.
   Powers, Scott
   Longmore, Gregory D.
   DeNardo, David G.
   Stewart, Sheila A.
TI Senescent CAFs Mediate Immunosuppression and Drive Breast Cancer
   Progression
SO CANCER DISCOVERY
LA English
DT Article
ID T-CELLS; SINGLE-CELL; FIBROBLASTS; EXPRESSION; RECEPTOR; ENVIRONMENT;
   ACTIVATION; CLEARANCE; PHENOTYPE; GROWTH
AB Cellular senescence arises in a specific subset of breast cancer myofibroblastic CAFs that modulate the ECM to potently limit NK cell function and thus could be an important therapeutic target to limit breast cancer progression.
   The tumor microenvironment (TME) profoundly influences tumorigenesis, with gene expression in the breast TME capable of predicting clinical outcomes. The TME is complex and includes distinct cancer-associated fibroblast (CAF) subtypes whose contribution to tumorigenesis remains unclear. Here, we identify a subset of myofibroblast CAFs (myCAF) that are senescent (senCAF) in mouse and human breast tumors. Utilizing the MMTV-PyMT;INK-ATTAC (INK) mouse model, we found that senCAF-secreted extracellular matrix specifically limits natural killer (NK) cell cytotoxicity to promote tumor growth. Genetic or pharmacologic senCAF elimination unleashes NK cell killing, restricting tumor growth. Finally, we show that senCAFs are present in HER2+, ER+, and triple-negative breast cancer and in ductal carcinoma in situ (DCIS) where they predict tumor recurrence. Together, these findings demonstrate that senCAFs are potently tumor promoting and raise the possibility that targeting them by senolytic therapy could restrain breast cancer development.Significance: senCAFs limit NK cell-mediated killing, thereby contributing to breast cancer progression. Thus, targeting senCAFs could be a clinically viable approach to limit tumor progression.See related article by Belle et al., p. 1324.
C1 [Ye, Jiayu; Faget, Douglas V.; Ren, Qihao; Melam, Anupama; Luo, Xianmin; Bagchi, Satarupa Mullick; Campos, Edward; Friedman, Michael; Stewart, Sheila A.] Washington Univ, Sch Med, Dept Cell Biol & Physiol, 660 South Euclid Ave,Campus Box 8228, St Louis, MO 63110 USA.
   [Baer, John M.; Morikis, Vasilios A.; Belle, Jad I.; Longmore, Gregory D.; DeNardo, David G.; Stewart, Sheila A.] Washington Univ, Sch Med, Dept Med, St Louis, MO USA.
   [Delgado, Ana Paula] SUNY Stony Brook, Grad Program Genet, Stony Brook, NY USA.
   [Campos, Edward] Washington Univ, Sch Med, Med Scientist Training Program, St Louis, MO USA.
   [Veis, Deborah J.] Washington Univ, Sch Med, Dept Pathol & Immunol, St Louis, MO USA.
   [Knudsen, Erik S.; Witkiewicz, Agnieszka K.] Roswell Pk Comprehens Canc Ctr, Dept Mol & Cellular Biol, Buffalo, NY USA.
   [Powers, Scott] Renaissance Sch Med, Dept Pathol, Stony Brook, NY USA.
   [Powers, Scott] Renaissance Sch Med, Canc Ctr, Stony Brook, NY USA.
   [Longmore, Gregory D.; DeNardo, David G.; Stewart, Sheila A.] Washington Univ, Sch Med, ICCE Inst, St Louis, MO USA.
   [Longmore, Gregory D.; DeNardo, David G.; Stewart, Sheila A.] Washington Univ, Sch Med, Siteman Canc Ctr, St Louis, MO USA.
C3 Washington University (WUSTL); Washington University (WUSTL); State
   University of New York (SUNY) System; Stony Brook University; Washington
   University (WUSTL); Washington University (WUSTL); Roswell Park
   Comprehensive Cancer Center; State University of New York (SUNY) System;
   Stony Brook University; Stony Brook University Hospital; State
   University of New York (SUNY) System; Stony Brook University; Stony
   Brook University Hospital; Washington University (WUSTL); Washington
   University (WUSTL); Siteman Cancer Center
RP Stewart, SA (corresponding author), Washington Univ, Sch Med, Dept Cell Biol & Physiol, 660 South Euclid Ave,Campus Box 8228, St Louis, MO 63110 USA.
EM sheila.stewart@wustl.edu
RI Ren, Qihao/HDN-5402-2022; Stewart, Sheila/C-5213-2012
OI Baer, John/0000-0002-8758-0030; Melam, Anupama/0000-0002-1000-5273;
   Delgado, Ana Paula/0000-0002-1219-4311; Belle, Jad/0000-0001-8944-9792;
   Ren, Qihao/0000-0001-5178-1829; , Michael Friedman/0009-0001-9341-7571;
   Ye, Jiayu/0000-0001-7987-6360; Mullick Bagchi,
   Satarupa/0009-0009-7091-7360; Faget, Douglas/0000-0002-2452-0962
FU Washington University School of Medicine; Children's Discovery Institute
   of Washington University; St. Louis Children's Hospital
   [CDI-CORE-2015-505, CDI-CORE-2019-813]; Foundation for Barnes-Jewish
   Hospital [3770, 4642]; NIH [R01 AG059244, CA217208]; Office of the
   Assistant Secretary of Defense for Health Affairs, through the Breast
   Cancer Research Program [BC181712]; Siteman Cancer Center Investment
   Program (NCI Cancer Center Support Grant) [P30CA091842]; Fashion
   Footwear Association of New York; Alvin J. Siteman Cancer Center Siteman
   Investment Program - Foundation for Barnes-Jewish Hospital, Cancer
   Frontier Fund; NIH MSTP under the Medical Scientist Training Program of
   Washington University School of Medicine [CA113275]; Cancer Biology
   Pathway of Siteman Cancer Center - NCI T32 grant; Cancer Biology Pathway
   of Siteman Cancer Center - NIH F31 grant [CA271721-01]; Bristol Meyer
   Squibb; Blueprint Medicine;  [F31 DK122633];  [F32 CA275212-01];  [R01
   CA21720605];  [R01 CA223758];  [CA254060];  [R01CA247362];  [T32
   GM7200-49]
FX We would like to thank Dr. Todd Fehniger and Pamela Wong for their
   support and guidance in NK cytotoxicity assays. We thank Dr. Edna
   Cukierman for advice on in vitro ECM generation. We also thank Siteman
   Flow Cytometry Core for help with sorting; Julie Prior and Katie Duncan
   in the Molecular Imaging Center for their help with bioluminescence
   imaging; Dr. Roberta Faccio and Seunghyun Lee for providing RMA-S cell
   lines and suggestions on in vitro NK cytotoxicity assays; the Genome
   Technology Access Center in the Department of Genetics at Washington
   University School of Medicine for help with sequencing, alignment, and
   genomic data analysis; Washington University Center for Cellular imaging
   (WUCCI), which is supported by Washington University School of Medicine,
   The Children's Discovery Institute of Washington University and St.
   Louis Children's Hospital (CDI-CORE-2015-505 and CDI-CORE-2019-813), and
   the Foundation for Barnes-Jewish Hospital (3770 and 4642) for support on
   performing second-harmonic generation imaging. In addition, we would
   like to acknowledge Dr. Lorenzo Galluzzi for his suggestions on NK cell
   flow cytometry panel. This work was supported by NIH grants R01
   AG059244, CA217208 (S.A. Stewart), The U.S. Army Medical Research
   Acquisition Activity, 820 Chandler Street, Fort Detrick, MD 21702-5014,
   is the awarding and administrating acquisition office, and this was
   supported in part by the Office of the Assistant Secretary of Defense
   for Health Affairs, through the Breast Cancer Research Program, under
   award No. BC181712. Opinions, interpretations, conclusions, and
   recommendations are those of the authors and are not necessarily
   endorsed by the Department of Defense. This work was also supported by
   the Siteman Cancer Center Investment Program (NCI Cancer Center Support
   Grant P30CA091842, Fashion Footwear Association of New York, and the
   Alvin J. Siteman Cancer Center Siteman Investment Program (supported by
   the Foundation for Barnes-Jewish Hospital, Cancer Frontier Fund) to S.A.
   Stewart. J. Ye was supported by Cancer Biology Pathway of Siteman Cancer
   Center, which was funded by an NCI T32 grant CA113275, and NIH F31 grant
   CA271721-01. J.M. Baer was supported by F31 DK122633. V.A. Morikis was
   supported by F32 CA275212-01. S. Powers and A.P. Delgado were supported
   by R01 CA21720605. G.D. Longmore was supported by R01 CA223758 and
   CA254060. A. K. Witkiewicz and E. S. Knudsen were supported by
   R01CA247362 and received sponsored research funding from Bristol Meyer
   Squibb and Blueprint Medicine. E. Campos was supported by NIH MSTP T32
   GM7200-49 under the Medical Scientist Training Program of Washington
   University School of Medicine.
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NR 74
TC 17
Z9 17
U1 7
U2 8
PU AMER ASSOC CANCER RESEARCH
PI PHILADELPHIA
PA 615 CHESTNUT ST, 17TH FLOOR, PHILADELPHIA, PA 19106-4404 USA
SN 2159-8274
EI 2159-8290
J9 CANCER DISCOV
JI Cancer Discov.
PD JUL 1
PY 2024
VL 14
IS 7
BP 1302
EP 1323
DI 10.1158/2159-8290.CD-23-0426
PG 22
WC Oncology
WE Science Citation Index Expanded (SCI-EXPANDED)
SC Oncology
GA XI0D7
UT WOS:001260926600014
PM 38683161
DA 2025-03-13
ER

PT J
AU Barcus, CE
   Hwang, PY
   Morikis, V
   Brenot, A
   Pence, P
   Clarke, M
   Longmore, GD
AF Barcus, Craig E.
   Hwang, Priscilla Y.
   Morikis, Vasilios
   Brenot, Audrey
   Pence, Patrick
   Clarke, Maria
   Longmore, Gregory D.
TI Tyrosine kinase-independent actions of DDR2 in tumor cells and
   cancer-associated fibroblasts influence tumor invasion, migration and
   metastasis
SO JOURNAL OF CELL SCIENCE
LA English
DT Article
DE DDR2; Cancer-associated fibroblasts; Kinase independent; Metastasis;
   Paracrine actions
ID DOMAIN RECEPTOR 2; ACTIVATED PROTEIN-KINASE; BREAST-CANCER; LUNG-CANCER;
   PHASE-II; DASATINIB; PHOSPHORYLATION; EXPRESSION; SNAIL1; STIMULATION
AB Both tumor cell-intrinsic signals and tumor cell-extrinsic signals from cells within the tumor microenvironment influence tumor cell dissemination and metastasis. The fibrillar collagen receptor tyrosine kinase (RTK) discoidin domain receptor 2 (DDR2) is essential for breast cancer metastasis in mouse models, and high expression of DDR2 in tumor and tumor stromal cells is strongly associated with poorer clinical outcomes. DDR2 tyrosine kinase activity has been hypothesized to be required for the metastatic activity of DDR2; however, inhibition of DDR2 tyrosine kinase activity, along with that of other RTKs, has failed to provide clinically relevant responses in metastatic patients. Here, we show that tyrosine kinase activity-independent action of DDR2 in tumor cells can support Matrigel invasion and in vivo metastasis. Paracrine actions of DDR2 in tumor cells and cancer-associated fibroblasts (CAFs) also support tumor invasion, migration and lung colonization in vivo. These data suggest that tyrosine kinase-independent functions of DDR2 could explain failures of tyrosine kinase inhibitor treatment in metastatic breast cancer patients and highlight the need for alternative therapeutic strategies that inhibit both tyrosine kinase-dependent and -independent actions of RTKs in the treatment of breast cancer.
C1 [Barcus, Craig E.; Hwang, Priscilla Y.; Morikis, Vasilios; Brenot, Audrey; Pence, Patrick; Clarke, Maria; Longmore, Gregory D.] Washington Univ, ICCE Inst, St Louis, MO 63110 USA.
   [Barcus, Craig E.; Hwang, Priscilla Y.; Morikis, Vasilios; Brenot, Audrey; Pence, Patrick; Clarke, Maria; Longmore, Gregory D.] Washington Univ, Dept Med Oncol, St Louis, MO 63110 USA.
   [Hwang, Priscilla Y.] Virginia Commonwealth Univ, Coll Engn, Richmond, VA 23284 USA.
C3 Washington University (WUSTL); Washington University (WUSTL); Virginia
   Commonwealth University
RP Longmore, GD (corresponding author), Washington Univ, ICCE Inst, St Louis, MO 63110 USA.; Longmore, GD (corresponding author), Washington Univ, Dept Med Oncol, St Louis, MO 63110 USA.
EM glongmore@wustl.edu
OI Pence, Patrick/0000-0002-2970-9342
FU National Institutes of Health [R01 CA223758, U54CA210173, T32
   CA113275-10]; American Cancer Society [ACS 133574-PF-19-204-01-CSM, ACS
   131342-PF-17-23801-CSM]
FX This work was supported by the National Institutes of Health (R01
   CA223758 and U54CA210173 to G.D.L., T32 CA113275-10 to C.E.B.) and by
   the American Cancer Society (ACS 133574-PF-19-204-01-CSM to C.E.B and
   ACS 131342-PF-17-23801-CSM to P.Y.H.). Deposited in PMC for immediate
   release.
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NR 55
TC 15
Z9 16
U1 0
U2 12
PU COMPANY BIOLOGISTS LTD
PI CAMBRIDGE
PA BIDDER BUILDING, STATION RD, HISTON, CAMBRIDGE CB24 9LF, ENGLAND
SN 0021-9533
EI 1477-9137
J9 J CELL SCI
JI J. Cell Sci.
PD OCT
PY 2021
VL 134
IS 19
AR jcs258431
DI 10.1242/jcs.258431
PG 13
WC Cell Biology
WE Science Citation Index Expanded (SCI-EXPANDED)
SC Cell Biology
GA WJ3HU
UT WOS:000708939100004
PM 34477203
OA hybrid, Green Published
DA 2025-03-13
ER

PT J
AU Rivas, EI
   Linares, J
   Zwick, M
   Gómez-Llonin, A
   Guiu, M
   Labernadie, A
   Badia-Ramentol, J
   Lladó, A
   Bardia, L
   Pérez-Núñez, I
   Martínez-Ciarpaglini, C
   Tarazona, N
   Sallent-Aragay, A
   Garrido, M
   Celià-Terrassa, T
   Burgués, O
   Gomis, RR
   Albanell, J
   Calon, A
AF Rivas, Elisa, I
   Linares, Jenniffer
   Zwick, Melissa
   Gomez-Llonin, Andrea
   Guiu, Marc
   Labernadie, Anna
   Badia-Ramentol, Jordi
   Llado, Anna
   Bardia, Lidia
   Perez-Nunez, Ivan
   Martinez-Ciarpaglini, Carolina
   Tarazona, Noelia
   Sallent-Aragay, Anna
   Garrido, Marta
   Celia-Terrassa, Toni
   Burgues, Octavio
   Gomis, Roger R.
   Albanell, Joan
   Calon, Alexandre
TI Targeted immunotherapy against distinct cancer-associated fibroblasts
   overcomes treatment resistance in refractory HER2+breast tumors
SO NATURE COMMUNICATIONS
LA English
DT Article
ID HER2-POSITIVE BREAST-CANCER; INFILTRATING LYMPHOCYTES; ENRICHMENT
   ANALYSIS; TRASTUZUMAB; EXPRESSION; THERAPY; CELLS; ACTIVATION; SURVIVAL;
   EFFICACY
AB A substantial proportion of HER2+ breast cancer patients do not benefit from HER2-targeted therapy. Here, the authors identify a population of cancer-associated fibroblasts involved in the suppression of trastuzumab-induced ADCC that can be pharmacologically targeted to raise treatment effectiveness in unresponsive tumors.
   About 50% of human epidermal growth factor receptor 2 (HER2)+ breast cancer patients do not benefit from HER2-targeted therapy and almost 20% of them relapse after treatment. Here, we conduct a detailed analysis of two independent cohorts of HER2+ breast cancer patients treated with trastuzumab to elucidate the mechanisms of resistance to anti-HER2 monoclonal antibodies. In addition, we develop a fully humanized immunocompetent model of HER2+ breast cancer recapitulating ex vivo the biological processes that associate with patients' response to treatment. Thanks to these two approaches, we uncover a population of TGF-beta-activated cancer-associated fibroblasts (CAF) specific from tumors resistant to therapy. The presence of this cellular subset related to previously described myofibroblastic (CAF-S1) and podoplanin+ CAF subtypes in breast cancer associates with low IL2 activity. Correspondingly, we find that stroma-targeted stimulation of IL2 pathway in unresponsive tumors restores trastuzumab anti-cancer efficiency. Overall, our study underscores the therapeutic potential of exploiting the tumor microenvironment to identify and overcome mechanisms of resistance to anti-cancer treatment.
C1 [Rivas, Elisa, I; Linares, Jenniffer; Zwick, Melissa; Gomez-Llonin, Andrea; Badia-Ramentol, Jordi; Perez-Nunez, Ivan; Sallent-Aragay, Anna; Garrido, Marta; Celia-Terrassa, Toni; Albanell, Joan; Calon, Alexandre] Hosp del Mar Med Res Inst IMIM, Canc Res Program, Barcelona, Spain.
   [Guiu, Marc; Llado, Anna; Bardia, Lidia; Gomis, Roger R.] Barcelona Inst Sci & Technol BIST, Inst Res Biomed IRB Barcelona, Barcelona, Spain.
   [Labernadie, Anna] Barcelona Inst Sci & Technol BIST, Inst Bioengn Catalonia IBEC, Barcelona, Spain.
   [Martinez-Ciarpaglini, Carolina; Tarazona, Noelia; Burgues, Octavio] Univ Valencia, INCLIVA Biomed Res Inst, Dept Med Oncol, Valencia, Spain.
   [Albanell, Joan] Hosp del Mar, Med Oncol Dept, Barcelona, Spain.
   [Albanell, Joan] Univ Pompeu Fabra, Barcelona, Spain.
   [Albanell, Joan] Ctr Invest Biomed Red Oncol CIBERONC ISCIII, Madrid, Spain.
C3 Hospital del Mar Research Institute; Hospital del Mar; Barcelona
   Institute of Science & Technology; Institute for Research in Biomedicine
   - IRB Barcelona; Barcelona Institute of Science & Technology; Institut
   de Bioenginyeria de Catalunya; University of Barcelona; University of
   Valencia; Hospital del Mar Research Institute; Hospital del Mar; Pompeu
   Fabra University
RP Calon, A (corresponding author), Hosp del Mar Med Res Inst IMIM, Canc Res Program, Barcelona, Spain.
EM acalon@imim.es
RI TARAZONA, NOELIA/ISU-2610-2023; Labernadie, Anna/LXA-0348-2024; Linares,
   Jenniffer/KBA-3662-2024; Calon, Alexandre/GPK-2061-2022; Gomis,
   Roger/E-9788-2016; Celia-Terrassa, Toni/M-4808-2014
OI Zwick, Melissa/0009-0000-1482-2062; Celia-Terrassa,
   Toni/0000-0002-0615-8744; Calon, Alexandre/0000-0002-3398-6131; Martinez
   Ciarpaglini, Carolina/0000-0002-8797-2114; Perez-Nunez,
   Ivan/0000-0002-2907-1991; Llado Equisoain, Anna/0000-0001-5884-7114;
   Bardia, Lidia/0000-0003-2232-683X; Linares,
   Jenniffer/0000-0001-9373-8781
FU Instituto de Salud Carlos III (ISCIII) - European Union [PI17/00211,
   PI20/00011, CP16/00151]; ISCIII [CIBERONC CB16/12/00241, PI18/00006,
   PI21/00002]; Generalitat de Catalunya [2017 SGR 507]; European Community
   through the Regional Development Funding Program; Instituto de Salud
   Carlos III - European Union [MS16/00151, CPII21/00012]; Fundacio Privada
   Cellex; Spanish Association against Cancer (AECC) [6884]
FX This work has been supported by grants from Instituto de Salud Carlos
   III (ISCIII) co-funded by the European Union (PI17/00211, PI20/00011,
   CP16/00151; Spanish Ministry of Economy and Competitiveness) to A.C.
   This work was also supported by ISCIII (CIBERONC CB16/12/00241,
   PI18/00006, PI21/00002), Generalitat de Catalunya (no. 2017 SGR 507) and
   the European Community through the Regional Development Funding Program
   to J.A. A.C. is the recipient of Miguel Servet research contracts from
   Instituto de Salud Carlos III co-funded by the European Union
   (MS16/00151, CPII21/00012). E.R. fellowship was funded by the Fundacio
   Privada Cellex. J.L. is the recipient of a Junior Clinician fellowship
   from the Spanish Association against Cancer (AECC; 6884).
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NR 76
TC 35
Z9 35
U1 7
U2 35
PU NATURE PORTFOLIO
PI BERLIN
PA HEIDELBERGER PLATZ 3, BERLIN, 14197, GERMANY
EI 2041-1723
J9 NAT COMMUN
JI Nat. Commun.
PD SEP 9
PY 2022
VL 13
IS 1
AR 5310
DI 10.1038/s41467-022-32782-3
PG 16
WC Multidisciplinary Sciences
WE Science Citation Index Expanded (SCI-EXPANDED)
SC Science & Technology - Other Topics
GA 4M3BV
UT WOS:000853200800002
PM 36085201
OA gold, Green Published
DA 2025-03-13
ER

PT J
AU Paulsson, J
   Rydén, L
   Strell, C
   Frings, O
   Tobin, NP
   Fornander, T
   Bergh, J
   Landberg, G
   Stål, O
   Östman, A
AF Paulsson, Janna
   Ryden, Lisa
   Strell, Carina
   Frings, Oliver
   Tobin, Nicholas P.
   Fornander, Tommy
   Bergh, Jonas
   Landberg, Goran
   Stal, Olle
   Ostman, Arne
TI High expression of stromal PDGFRβ is associated with reduced benefit of
   tamoxifen in breast cancer
SO JOURNAL OF PATHOLOGY CLINICAL RESEARCH
LA English
DT Article
DE breast cancer; tamoxifen; tumour stroma; PDGFR beta
ID TERM-FOLLOW-UP; GROWTH-FACTOR; TUMOR MICROENVIRONMENT; ADJUVANT
   TAMOXIFEN; RECEPTOR EXPRESSION; RESISTANCE; CHEMOTHERAPY; FIBROBLASTS;
   SENSITIVITY; INHIBITION
AB Cancer-associated fibroblasts (CAFs) regulate tumour growth, metastasis and response to treatment. Recent studies indicate the existence of functionally distinct CAF subsets. Suggested mechanisms whereby CAFs can impact on treatment response include paracrine signalling affecting cancer cell drug sensitivity and effects on tumour drug uptake. PDGFR beta is an important regulator of fibroblasts. Experimental studies have linked PDGFR beta-positive fibroblasts to metastasis and also to reduced tumour drug uptake. This study has investigated the potential role of PDGFR beta-positive fibroblasts in response to adjuvant tamoxifen treatment of breast cancer. Analyses of two breast cancer collections from randomised studies analysing adjuvant tamoxifen treatment in early breast cancer demonstrated significant benefit of tamoxifen in the group with low stromal PDGFR beta, which was not observed in the group with high stromal PDGFR beta. In general terms these findings provide novel evidence, derived from analyses of randomised clinical studies, of response-predictive capacity of a marker-defined subset of CAFs and, more specifically, identify stromal PDGFR beta as a marker related to tamoxifen benefit in early breast cancer.
C1 [Paulsson, Janna; Strell, Carina; Frings, Oliver; Tobin, Nicholas P.; Fornander, Tommy; Bergh, Jonas; Ostman, Arne] Karolinska Inst, Canc Ctr Karolinska, Dept Oncol Pathol, Stockholm, Sweden.
   [Ryden, Lisa] Lund Univ, Dept Clin Sci, Div Surg, Lund, Sweden.
   [Ryden, Lisa] Skane Univ Hosp, Dept Surg, Lund, Sweden.
   [Bergh, Jonas] Karolinska Univ Hosp, Radiumhemmet, Stockholm, Sweden.
   [Landberg, Goran] Univ Gothenburg, Sahlgrenska Canc Ctr, Dept Pathol, Gothenburg, Sweden.
   [Stal, Olle] Linkoping Univ, Oncol, Dept Clin & Expt Med, Linkoping, Sweden.
C3 Karolinska Institutet; Lund University; Lund University; Skane
   University Hospital; Karolinska Institutet; Karolinska University
   Hospital; University of Gothenburg; Linkoping University
RP Östman, A (corresponding author), Karolinska Inst, Canc Ctr Karolinska, Dept Oncol Pathol, Stockholm, Sweden.
EM arne.ostman@ki.se
RI Tobin, Nicholas/AAE-9806-2019
OI Strell, Carina/0000-0002-3783-7256; Bergh, Jonas/0000-0001-5526-1847;
   Tobin, Nicholas/0000-0003-2343-9772; Ryden, Lisa/0000-0001-7515-3130
FU Swedish Research Council (STARGET network); Breast Cancer Theme Center
   (BRECT) at Karolinska Institutet; Swedish Cancer Society; Radiumhemmet;
   Stockholm County Council (ALF); Karolinska Institutet-Astra Zeneca; Knut
   and Alice Wallenberg grant; Swedish Breast Cancer Association; Percy
   Falks stiftelse for forskning betraffande prostatacancer och brostcancer
FX Members of the AO group are acknowledged for support and constructive
   criticism throughout the study. The AO and JB groups are supported by
   grants from the Swedish Research Council (STARGET network), the Breast
   Cancer Theme Center (BRECT) at Karolinska Institutet, Swedish Cancer
   Society, The research funds at Radiumhemmet and Stockholm County Council
   (ALF) and Karolinska Institutet-Astra Zeneca. The JB group is also
   supported by Knut and Alice Wallenberg grant and The Swedish Breast
   Cancer Association. OS and LR are also supported by the Swedish Cancer
   Society. Additional funding was obtained from 'Percy Falks stiftelse for
   forskning betraffande prostatacancer och brostcancer'.
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NR 26
TC 31
Z9 39
U1 0
U2 9
PU WILEY
PI HOBOKEN
PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA
EI 2056-4538
J9 J PATHOL CLIN RES
JI J. Pathol. Clin. Res.
PD JAN
PY 2017
VL 3
IS 1
BP 38
EP 43
DI 10.1002/cjp2.56
PG 6
WC Pathology
WE Science Citation Index Expanded (SCI-EXPANDED)
SC Pathology
GA FH0PX
UT WOS:000410844100004
PM 28138400
OA Green Published
DA 2025-03-13
ER

PT J
AU Wu, YH
   Li, N
   Shang, J
   Jiang, JZ
   Liu, XL
AF Wu, Yunhao
   Li, Nu
   Shang, Jin
   Jiang, Jiazi
   Liu, Xiaoliang
TI Identification of cancer-associated fibroblast subtypes and prognostic
   model development in breast cancer: role of the RUNX1/SDC1 axis in
   promoting invasion and metastasis
SO CELL BIOLOGY AND TOXICOLOGY
LA English
DT Article
DE Cancer-associated fibroblasts; Breast cancer; Molecular subtypes;
   Predictive model; RUNX1/SDC1 axis; Targeted therapy
ID CELL; ANGIOGENESIS
AB In this study, we identified cancer-associated fibroblast (CAF) molecular subtypes and developed a CAF-based prognostic model for breast cancer (BRCA). The heterogeneity of cancer-associated fibroblasts (CAFs) and their significant involvement in the advancement of BRCA were discovered employing single-cell RNA sequencing. Notably, we discovered that the RUNX1/SDC1 axis enhances BRCA cell invasion and metastasis. RUNX1 transcriptionally upregulates SDC1, which facilitates extracellular matrix remodeling and promotes tumor cell migration. This finding highlights the vital contribution of CAFs to the tumor microenvironment and provides new potential targets for therapeutic intervention. The predictive model showcased remarkable precision in anticipating patient outcomes and could guide personalized treatment strategies.
C1 [Wu, Yunhao] China Med Univ, Pancreat & Thyroid Ward, Dept Gen Surg, Shengjing Hosp, Shenyang 110004, Peoples R China.
   [Li, Nu] China Med Univ, Dept Breast Surg, Hosp 1, Shenyang 110004, Peoples R China.
   [Shang, Jin] China Med Univ, Dept Radiol, Shengjing Hosp, Shenyang 110004, Peoples R China.
   [Jiang, Jiazi; Liu, Xiaoliang] China Med Univ, Dept Emergency, Hosp 1, 155 Nanjing Rd, Shenyang 110001, Liaoning, Peoples R China.
C3 China Medical University; China Medical University; China Medical
   University; China Medical University
RP Jiang, JZ; Liu, XL (corresponding author), China Med Univ, Dept Emergency, Hosp 1, 155 Nanjing Rd, Shenyang 110001, Liaoning, Peoples R China.
EM wuyh9149@outlook.com; 20081177@cmu.edu.cn; 895495103@qq.com;
   jzjiang@cmu.edu.cn; shenhai.85@163.com
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NR 57
TC 0
Z9 0
U1 4
U2 4
PU SPRINGER
PI DORDRECHT
PA VAN GODEWIJCKSTRAAT 30, 3311 GZ DORDRECHT, NETHERLANDS
SN 0742-2091
EI 1573-6822
J9 CELL BIOL TOXICOL
JI Cell Biol. Toxicol.
PD JAN 3
PY 2025
VL 41
IS 1
AR 21
DI 10.1007/s10565-024-09950-w
PG 27
WC Cell Biology; Toxicology
WE Science Citation Index Expanded (SCI-EXPANDED)
SC Cell Biology; Toxicology
GA R1O7O
UT WOS:001389237400001
PM 39753834
OA hybrid
DA 2025-03-13
ER

PT J
AU Al-Harbi, B
   Aboussekhra, A
AF Al-Harbi, Bothaina
   Aboussekhra, Abdelilah
TI Cucurbitacin I (JSI-124)-dependent inhibition of STAT3 permanently
   suppresses the pro-carcinogenic effects of active breast
   cancer-associated fibroblasts
SO MOLECULAR CARCINOGENESIS
LA English
DT Article
DE breast cancer; cancer&#8208; associated fibroblasts; JSI&#8208; 124;
   STAT3
AB Active cancer-associated fibroblasts (CAFs), which constitute the most preponderant cell type in breast tumors, contribute actively to all aspects of cancer progression, stimulate recurrence, and restrain drug sensitivity. In the present study, we tested the effect of the selective JAK/STAT3 inhibitor cucurbitacin I (JSI-124) on active breast CAFs. We have shown that JSI-124 at non-cytotoxic concentration (20 nM) can inhibit the IL-6/STAT3/NF-kappa B positive feedback loop in breast myofibroblasts, which enabled persistent inactivation of these cells. Interestingly, JSI-124 treatment suppressed the paracrine promotion of the epithelial-to-mesenchymal transition (EMT) process and the pro-migratory/-invasive and -proliferative effects of CAFs on breast cancer cells in vitro. Similarly, JSI-124 inhibited the capacity of CAF cells in promoting tumor growth, EMT, stemness as well as angiogenesis in orthotopic humanized breast cancer tumors. Together, these findings indicate that JSI-124-dependent inhibition of STAT3 could be of great therapeutic value for the treatment of breast cancer through targeting cancer cells as well as their growth supportive stromal fibroblasts and blood vessels. This could pave the path to developing a precise CAF-targeted anticancer therapy.
C1 [Al-Harbi, Bothaina; Aboussekhra, Abdelilah] King Faisal Specialist Hosp & Res Ctr, Dept Mol Oncol, MBC 03,POB 3354, Riyadh 11211, Saudi Arabia.
   [Al-Harbi, Bothaina] King Saud bin Abdulaziz Univ Hlth Sci, King Abdullah Int Med Res Ctr, Expt Med Dept, MNGHA, Riyadh 11426, Saudi Arabia.
C3 King Faisal Specialist Hospital & Research Center; King Saud Bin
   Abdulaziz University for Health Sciences; Ministry of National Guard -
   Health Affairs
RP Aboussekhra, A (corresponding author), King Faisal Specialist Hosp & Res Ctr, Dept Mol Oncol, MBC 03,POB 3354, Riyadh 11211, Saudi Arabia.
EM aboussekhra@kfshrc.edu.sa
RI Aboussekhra, Abdelilah/JCD-8138-2023
FU Research Center Administration; RAC [2170006]; King Faisal Specialist
   Hospital & Research Center
FX We are thankful to the Comparative Medicine staff for their help with
   animal experiments. We also appreciate the continuous support of the
   Research Center Administration. This study was performed under
   RAC#2170006, and was supported in totality by the King Faisal Specialist
   Hospital & Research Center.
CR Al-Harbi B, 2021, MOL CARCINOGEN, V60, P242, DOI 10.1002/mc.23287
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NR 20
TC 12
Z9 13
U1 0
U2 4
PU WILEY
PI HOBOKEN
PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA
SN 0899-1987
EI 1098-2744
J9 MOL CARCINOGEN
JI Mol. Carcinog.
PD APR
PY 2021
VL 60
IS 4
BP 242
EP 251
DI 10.1002/mc.23287
EA FEB 2021
PG 10
WC Biochemistry & Molecular Biology; Oncology
WE Science Citation Index Expanded (SCI-EXPANDED)
SC Biochemistry & Molecular Biology; Oncology
GA QV3NY
UT WOS:000620721800001
PM 33621387
DA 2025-03-13
ER

PT J
AU Zhang, WF
   Wang, J
   Liu, C
   Li, Y
   Sun, CG
   Wu, JB
   Wu, QB
AF Zhang, Wenfeng
   Wang, Jia
   Liu, Cun
   Li, Ye
   Sun, Changgang
   Wu, Jibiao
   Wu, Qibiao
TI Crosstalk and plasticity driving between cancer-associated fibroblasts
   and tumor microenvironment: significance of breast cancer metastasis
SO JOURNAL OF TRANSLATIONAL MEDICINE
LA English
DT Review
DE Breast cancer; Cancer-associated fibroblasts; Tumor microenvironment;
   Metastasis
ID NERVE GROWTH-FACTOR; EPITHELIAL-MESENCHYMAL TRANSITION; VEGF-INDEPENDENT
   ANGIOGENESIS; TGF-BETA; STROMAL FIBROBLASTS; LUNG METASTASIS; NICHE
   FORMATION; LYMPH-NODE; CARCINOMA; PROMOTES
AB Cancer-associated fibroblasts (CAFs) are the most abundant stromal cell population in breast tumors. A functionally diverse population of CAFs increases the dynamic complexity of the tumor microenvironment (TME). The intertwined network of the TME facilitates the interaction between activated CAFs and breast cancer cells, which can lead to the proliferation and invasion of breast cells. Considering the special transmission function of CAFs, the aim of this review is to summarize and highlight the crosstalk between CAFs and breast cancer cells in the TME as well as the relationship between CAFs and extracellular matrix (ECM), soluble cytokines, and other stromal cells in the metastatic state. The crosstalk between cancer-associated fibroblasts and tumor microenvironment also provides a plastic therapeutic target for breast cancer metastasis. In the course of the study, the inhibitory effects of different natural compounds on targeting CAFs and the advantages of different drug combinations were summarized. CAFs are also widely used in the diagnosis and treatment of breast cancer. The cumulative research on this phenomenon supports the establishment of a targeted immune microenvironment as a possible breakthrough in the prevention of invasive metastasis of breast cancer.
C1 [Zhang, Wenfeng; Wang, Jia; Li, Ye; Sun, Changgang; Wu, Qibiao] Macau Univ Sci & Technol, State Key Lab Qual Res Chinese Med, Ave Wai Long, Taipa 999078, Macau, Peoples R China.
   [Zhang, Wenfeng; Wang, Jia; Li, Ye; Sun, Changgang; Wu, Qibiao] Macau Univ Sci & Technol, Fac Chinese Med, Ave Wai Long, Taipa 999078, Macau, Peoples R China.
   [Zhang, Wenfeng; Liu, Cun; Sun, Changgang] Weifang Med Univ, Coll Tradit Chinese Med, Weifang 261000, Peoples R China.
   [Zhang, Wenfeng; Wang, Jia; Wu, Jibiao] Shandong Univ Tradit Chinese Med, Coll Tradit Chinese Med, Jinan 250355, Peoples R China.
   [Sun, Changgang] Weifang Tradit Chinese Hosp, Dept Oncol, Weifang 261000, Peoples R China.
C3 Macau University of Science & Technology; Macau University of Science &
   Technology; Shandong Second Medical University; Shandong University of
   Traditional Chinese Medicine
RP Sun, CG; Wu, QB (corresponding author), Macau Univ Sci & Technol, State Key Lab Qual Res Chinese Med, Ave Wai Long, Taipa 999078, Macau, Peoples R China.; Sun, CG; Wu, QB (corresponding author), Macau Univ Sci & Technol, Fac Chinese Med, Ave Wai Long, Taipa 999078, Macau, Peoples R China.; Sun, CG (corresponding author), Weifang Med Univ, Coll Tradit Chinese Med, Weifang 261000, Peoples R China.; Wu, JB (corresponding author), Shandong Univ Tradit Chinese Med, Coll Tradit Chinese Med, Jinan 250355, Peoples R China.; Sun, CG (corresponding author), Weifang Tradit Chinese Hosp, Dept Oncol, Weifang 261000, Peoples R China.
EM scgdoctor@126.com; wujibiao1963@163.com; qbwu@must.edu.mo
OI Wu, Qibiao/0000-0002-1670-1050; Sun, Changgang/0000-0003-0778-8788
FU National Natural Science Foundation of China [82305000, 82174222,
   81973677]; Shandong Provincial Natural Science Foundation
   [ZR2021LZY015]; Qingdao Science and Technology demonstration Project for
   the benefit of the people [23-2-8-smjk-1-nsh]
FX This work was supported by funds from the National Natural Science
   Foundation of China (Grant Number:82305000,82174222, 81973677), the
   Shandong Provincial Natural Science Foundation (Grant Number:
   ZR2021LZY015) and Qingdao Science and Technology demonstration Project
   for the benefit of the people (Grant Number:23-2-8-smjk-1-nsh).
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NR 152
TC 13
Z9 13
U1 2
U2 18
PU BMC
PI LONDON
PA CAMPUS, 4 CRINAN ST, LONDON N1 9XW, ENGLAND
EI 1479-5876
J9 J TRANSL MED
JI J. Transl. Med.
PD NOV 17
PY 2023
VL 21
IS 1
AR 827
DI 10.1186/s12967-023-04714-2
PG 21
WC Medicine, Research & Experimental
WE Science Citation Index Expanded (SCI-EXPANDED)
SC Research & Experimental Medicine
GA Y7TR5
UT WOS:001107253100008
PM 37978384
OA Green Published, gold
DA 2025-03-13
ER

PT J
AU Joo, EH
   Kim, S
   Park, D
   Lee, TS
   Park, WY
   Han, KY
   Lee, JE
AF Joo, Eun Hye
   Kim, Sangmin
   Park, Donghyun
   Lee, Taeseob
   Park, Woong-Yang
   Han, Kyung Yeon
   Lee, Jeong Eon
TI Migratory Tumor Cells Cooperate with Cancer Associated Fibroblasts in
   Hormone Receptor-Positive and HER2-Negative Breast Cancer
SO INTERNATIONAL JOURNAL OF MOLECULAR SCIENCES
LA English
DT Article
DE scRNA-seq; SIDR-seq; transcriptome; CNV alteration; breast cancer; tumor
   microenvironment
ID GENE; SUBTYPES; SIGNATURES; DIVERSITY; REVEALS; RISK
AB Hormone receptor-positive and HER2-negative breast cancer (HR+/HER2-BC) is the most common type with a favorable prognosis under endocrine therapy. However, it still demonstrates unpredictable progression and recurrences influenced by high tumoral diversity and microenvironmental status. To address these heterogeneous molecular characteristics of HR+/HER2-BC, we aimed to simultaneously characterize its transcriptomic landscape and genetic architecture at the same resolution. Using advanced single-cell RNA and DNA sequencing techniques together, we defined four distinct tumor subtypes. Notably, the migratory tumor subtype was closely linked to genomic alterations of EGFR, related to the tumor-promoting behavior of IL6-positive inflammatory tumor-associated fibroblast, and contributing to poor prognosis. Our study comprehensively utilizes integrated analysis to uncover the complex dynamics of this breast cancer subtype, highlighting the pivotal role of the migratory tumor subtype in influencing surrounding cells. This sheds light on potential therapeutic targets by offering enhanced insights for HR+/HER2-BC treatment.
C1 [Joo, Eun Hye; Park, Woong-Yang; Han, Kyung Yeon] Samsung Genome Inst, Samsung Med Ctr, Seoul 06351, South Korea.
   [Joo, Eun Hye; Park, Woong-Yang] Sungkyunkwan Univ, Samsung Adv Inst Hlth Sci & Technol, Dept Hlth Sci & Technol, Seoul 06355, South Korea.
   [Kim, Sangmin; Lee, Jeong Eon] Samsung Med Ctr, Dept Breast Canc Ctr, Seoul 06351, South Korea.
   [Kim, Sangmin; Lee, Jeong Eon] Sungkyunkwan Univ, Samsung Med Ctr, Sch Med, Dept Surg, Seoul 06351, South Korea.
   [Park, Donghyun] Planit Healthcare Inc, Seoul 06235, South Korea.
   [Lee, Taeseob] Sungkyunkwan Univ, Samsung Adv Inst Hlth Sci & Technol, Dept Digital Hlth, Seoul 06355, South Korea.
   [Park, Woong-Yang] Sungkyunkwan Univ, Sch Med, Dept Mol Cell Biol, Suwon 16419, South Korea.
C3 Sungkyunkwan University (SKKU); Samsung Medical Center; Samsung;
   Sungkyunkwan University (SKKU); Samsung Medical Center; Sungkyunkwan
   University (SKKU); Samsung Medical Center; Sungkyunkwan University
   (SKKU); Samsung Medical Center; Sungkyunkwan University (SKKU); Samsung
   Medical Center; Sungkyunkwan University (SKKU)
RP Han, KY (corresponding author), Samsung Genome Inst, Samsung Med Ctr, Seoul 06351, South Korea.; Lee, JE (corresponding author), Samsung Med Ctr, Dept Breast Canc Ctr, Seoul 06351, South Korea.; Lee, JE (corresponding author), Sungkyunkwan Univ, Samsung Med Ctr, Sch Med, Dept Surg, Seoul 06351, South Korea.
EM thegracejoo@gmail.com; sangmin3005.kim@samsung.com;
   eastwise37@gmail.com; leets1984@gmail.com; woongyang@skku.edu;
   ky2.han@samsung.com; jeongeon.lee@samsung.com
RI Lee, Jeeyun/I-7171-2015
OI Park, Woong-Yang/0000-0003-4234-0380; Kim, Sangmin/0000-0003-3466-8634;
   Joo, Eun Hye/0000-0002-7171-4807
FU Korea Health Industry Development Institute (KHIDI)
FX We thank all the patients for the tissue donation in this study. We
   thank all the technicians from the Samsung Genome Institute for their
   help with the library preparation and sequencing. Part of the
   bioinformatics analyses was carried out on the high-performance
   computing environment of the Samsung Genome Institute.
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NR 60
TC 0
Z9 0
U1 2
U2 2
PU MDPI
PI BASEL
PA ST ALBAN-ANLAGE 66, CH-4052 BASEL, SWITZERLAND
SN 1661-6596
EI 1422-0067
J9 INT J MOL SCI
JI Int. J. Mol. Sci.
PD JUN
PY 2024
VL 25
IS 11
AR 5876
DI 10.3390/ijms25115876
PG 17
WC Biochemistry & Molecular Biology; Chemistry, Multidisciplinary
WE Science Citation Index Expanded (SCI-EXPANDED)
SC Biochemistry & Molecular Biology; Chemistry
GA UA2Y0
UT WOS:001245288600001
PM 38892065
OA Green Published, gold
DA 2025-03-13
ER

PT J
AU Croizer, H
   Mhaidly, R
   Kieffer, Y
   Gentric, G
   Djerroudi, L
   Leclere, R
   Pelon, F
   Robley, C
   Bohec, M
   Meng, A
   Meseure, D
   Romano, E
   Baulande, S
   Peltier, A
   Vincent-Salomon, A
   Mechta-Grigoriou, F
AF Croizer, Hugo
   Mhaidly, Rana
   Kieffer, Yann
   Gentric, Geraldine
   Djerroudi, Lounes
   Leclere, Renaud
   Pelon, Floriane
   Robley, Catherine
   Bohec, Mylene
   Meng, Arnaud
   Meseure, Didier
   Romano, Emanuela
   Baulande, Sylvain
   Peltier, Agathe
   Vincent-Salomon, Anne
   Mechta-Grigoriou, Fatima
TI Deciphering the spatial landscape and plasticity of immunosuppressive
   fibroblasts in breast cancer
SO NATURE COMMUNICATIONS
LA English
DT Article
ID SINGLE-CELL; GENE-EXPRESSION; MICROENVIRONMENT; TRANSITION; GROWTH;
   TISSUE
AB Although heterogeneity of FAP+ Cancer-Associated Fibroblasts (CAF) has been described in breast cancer, their plasticity and spatial distribution remain poorly understood. Here, we analyze trajectory inference, deconvolute spatial transcriptomics at single-cell level and perform functional assays to generate a high-resolution integrated map of breast cancer (BC), with a focus on inflammatory and myofibroblastic (iCAF/myCAF) FAP+ CAF clusters. We identify 10 spatially-organized FAP+ CAF-related cellular niches, called EcoCellTypes, which are differentially localized within tumors. Consistent with their spatial organization, cancer cells drive the transition of detoxification-associated iCAF (Detox-iCAF) towards immunosuppressive extracellular matrix (ECM)-producing myCAF (ECM-myCAF) via a DPP4- and YAP-dependent mechanism. In turn, ECM-myCAF polarize TREM2+ macrophages, regulatory NK and T cells to induce immunosuppressive EcoCellTypes, while Detox-iCAF are associated with FOLR2+ macrophages in an immuno-protective EcoCellType. FAP+ CAF subpopulations accumulate differently according to the invasive BC status and predict invasive recurrence of ductal carcinoma in situ (DCIS), which could help in identifying low-risk DCIS patients eligible for therapeutic de-escalation.
   The heterogeneity of cancer associated fibroblasts (CAFs) in breast cancer has been previously described. Here the authors provide further insights into the spatial landscape and plasticity of immunosuppressive fibroblasts in breast cancer.
C1 [Croizer, Hugo; Mhaidly, Rana; Kieffer, Yann; Gentric, Geraldine; Djerroudi, Lounes; Pelon, Floriane; Robley, Catherine; Meng, Arnaud; Peltier, Agathe; Mechta-Grigoriou, Fatima] PSL Res Univ, Inst Curie, Stress & Canc Lab, Equipe Labelisee Ligue Natl Canc, 26, Rue Ulm, F-75248 Paris, France.
   [Croizer, Hugo; Mhaidly, Rana; Kieffer, Yann; Gentric, Geraldine; Djerroudi, Lounes; Pelon, Floriane; Robley, Catherine; Meng, Arnaud; Peltier, Agathe; Mechta-Grigoriou, Fatima] Inserm, U830, 26 Rue Ulm, F-75005 Paris, France.
   [Djerroudi, Lounes; Leclere, Renaud; Meseure, Didier; Vincent-Salomon, Anne] Inst Curie Hosp Grp, Dept Diagnost & Theragnost Med, 26 Rue Ulm, F-75248 Paris, France.
   [Bohec, Mylene; Baulande, Sylvain] PSL Res Univ, Inst Curie, ICGex Next Generat Sequencing Platform, F-75005 Paris, France.
   [Bohec, Mylene; Baulande, Sylvain] PSL Res Univ, Inst Curie, Single Cell Initiat, F-75005 Paris, France.
   [Romano, Emanuela] Inst Curie, Ctr Canc Immunotherapy, Dept Med Oncol, 26 Rue Ulm, F-75248 Paris, France.
C3 UNICANCER; Universite PSL; Institut Curie; Universite PSL; UNICANCER;
   Institut Curie; Institut National de la Sante et de la Recherche
   Medicale (Inserm); UNICANCER; Universite PSL; Institut Curie; UNICANCER;
   Universite PSL; Institut Curie; UNICANCER; Universite PSL; Institut
   Curie; UNICANCER; Universite PSL; Institut Curie
RP Mechta-Grigoriou, F (corresponding author), PSL Res Univ, Inst Curie, Stress & Canc Lab, Equipe Labelisee Ligue Natl Canc, 26, Rue Ulm, F-75248 Paris, France.; Mechta-Grigoriou, F (corresponding author), Inserm, U830, 26 Rue Ulm, F-75005 Paris, France.
EM fatima.mechta-grigoriou@curie.fr
RI Peltier, Agathe/GWU-7535-2022; Djerroudi, Lounes/MAH-7676-2025
OI Bohec, Mylene/0000-0002-6530-596X; CROIZER, hugo/0009-0009-4817-9875;
   Gentric, Geraldine/0000-0002-7558-8705; Leclere,
   Renaud/0000-0001-8737-6817
FU Equipex [13683]; France Genomic Consortium [TRANS2022080005422];
   Foundation for Medical Research (FRM) [PC201317]; Foundation de France;
   Institut National du Cancer; INCa; Ligue Nationale Contre le Cancer
   (LNCC, Labelisation); Inserm [INCa-16786]; ITMO Cancer of Aviesan;
   Foundation ARC; European TRANSCAN-3 ERA-NET CHRYSALIS (ARCPARTN) and
   Magnolia [INCa-11692]; ANR as part of the PIA France 2030; CASSIOPEIA
   RHU [INCa-16101];  [ANR-10-EQPX-03];  [ANR-21-RHUS-0002]; 
   [ANR-10-INBS-09-08];  [00119142/WB-2021-36276];  [INCa-DGOS-9963]
FX We are grateful to Laetitia Fuhrmann, Charlotte Martinat and Andreia
   Goncalves for collecting clinical data of the patients (SIRIC,
   INCa-DGOS-4654); Laetitia Lesage and Andre Nicolas for their help at the
   experimental pathology platform and Coralie Guerin and Lea Guyonnet at
   the cytometry core. The ICGex NGS platform was supported by the
   ANR-10-EQPX-03 (Equipex) and ANR-10-INBS-09-08 (France Genomic
   Consortium) grants. H.C. is supported by the Foundation for Medical
   Research (FRM, grant number 13683), and R.M. by the Foundation de France
   (00119142/WB-2021-36276). G.G. and F.M.-G. are permanent scientists at
   Inserm. Y.K. is supported by the Institut National du Cancer and INCa
   (INCa-DGOS-9963; INCa-11692). The experimental work was supported by
   grants from the Ligue Nationale Contre le Cancer (LNCC, Labelisation),
   Inserm (PC201317), INCa (CaLYS INCa-11692, CAFHeros INCa-16101), ITMO
   Cancer of Aviesan (2021-2030 cancer control strategy framework,
   Pre-Caution), SIGN'it 2019 from the Foundation ARC, the European
   TRANSCAN-3 ERA-NET CHRYSALIS (ARCPARTN-TRANS2022080005422) and Magnolia
   (INCa-16786), and the ANR as part of the PIA France 2030 with the
   funding of the CASSIOPEIA RHU (ANR-21-RHUS-0002). F.M.-G. acknowledges
   the "French Pink Ribbon Association" and the "Simone and Cino del Duca
   Foundation" for attribution of their respective Grand Prix, as well as
   the FRM for the Rozen Price and the LNCC for the Duquesne Price. F.M.-G.
   is very grateful to all her funders for providing support throughout the
   years.
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NR 105
TC 15
Z9 15
U1 3
U2 16
PU NATURE PORTFOLIO
PI BERLIN
PA HEIDELBERGER PLATZ 3, BERLIN, 14197, GERMANY
EI 2041-1723
J9 NAT COMMUN
JI Nat. Commun.
PD APR 1
PY 2024
VL 15
IS 1
AR 2806
DI 10.1038/s41467-024-47068-z
PG 28
WC Multidisciplinary Sciences
WE Science Citation Index Expanded (SCI-EXPANDED)
SC Science & Technology - Other Topics
GA MT1I7
UT WOS:001195790900019
PM 38561380
OA gold
DA 2025-03-13
ER

PT J
AU Hosein, AN
   Livingstone, J
   Buchanan, M
   Reid, JF
   Hallett, M
   Basik, M
AF Hosein, Abdel Nasser
   Livingstone, Julie
   Buchanan, Marguerite
   Reid, James F.
   Hallett, Michael
   Basik, Mark
TI A functional <i>in vitro</i> model of heterotypic interactions reveals a
   role for interferon-positive carcinoma associated fibroblasts in breast
   cancer
SO BMC CANCER
LA English
DT Article
DE Stroma; Carcinoma-associated fibroblasts; Breast cancer; Interferon
ID STROMAL FIBROBLASTS; GROWTH-INHIBITION; TUMOR-GROWTH; TGF-BETA;
   EXPRESSION; RESISTANCE; SIGNATURE; CELLS; PROTEINS; S100A2
AB Background: Cancer-associated fibroblasts (CAFs) play an important role in breast cancer pathogenesis by paracrine regulation of breast cancer cell biology. Several in vitro and mouse models have characterized the role of cell contact and cytokine molecules mediating this relationship, although few reports have used human CAFs from breast tumors.
   Methods: Primary breast CAF cultures were established and gene expression profiles analysed in order to guide subsequent co-culture models. We used a combination of colorimetric proliferation assays and gene expression profiling to determine the effect of CAFs on the MCF-7 breast cancer cell in an indirect co-culture system.
   Results: Using gene expression profiling, we found that a subgroup of breast CAFs are positive for a type one interferon response, confirming previous reports of an activated type one interferon response in whole tumor datasets. Interferon positive breast cancer patients show a poor prognostic outcome in an independent microarray dataset. In addition, CAFs positive for the type one interferon response promoted the growth of the MCF-7 breast cancer cell line in an indirect co-culture model. The addition of a neutralizing antibody against the ligand mediating the type one response in fibroblasts, interferon-beta, reverted this co-culture phenotype. CAFs not expressing the interferon response genes also promoted the growth of the MCF-7 breast cancer cell line but this phenotype was independent of the type one fibroblast interferon ligand.
   Conclusions: Primary breast CAFs show inter-patient molecular heterogeneity as evidenced by interferon response gene elements activated in a subgroup of CAFs, which result in paracrine pro-proliferative effects in a breast cancer cell line co-culture model.
C1 [Hosein, Abdel Nasser; Buchanan, Marguerite; Basik, Mark] Sir Mortimer B Davis Jewish Hosp, Lady Davis Inst Med Res, Montreal, PQ, Canada.
   [Hosein, Abdel Nasser] McGill Univ, Dept Pharmacol & Therapeut, Montreal, PQ, Canada.
   [Basik, Mark] McGill Univ, Dept Oncol, Montreal, PQ, Canada.
   [Basik, Mark] McGill Univ, Dept Surg, Montreal, PQ H3A 2T5, Canada.
   [Livingstone, Julie; Hallett, Michael] McGill Ctr Bioinformat, Montreal, PQ, Canada.
   [Reid, James F.] Fdn IFOM Ist FIRC Oncol Mol, Milan, Italy.
   [Basik, Mark] Lady Davis Inst, Dept Oncol, Montreal, PQ H3T 1E2, Canada.
C3 Lady Davis Institute; IFOM - FIRC Institute of Molecular Oncology; Lady
   Davis Institute
RP Basik, M (corresponding author), Sir Mortimer B Davis Jewish Hosp, Lady Davis Inst Med Res, Montreal, PQ, Canada.
EM mark.basik@mcgill.ca
RI Hosein, Abdel/KGM-7325-2024
OI Hallett, Michael/0000-0001-6738-6786; Livingstone,
   Julie/0000-0002-8424-3768; Hosein, Abdel/0000-0003-1567-6700
FU FRQS Reseau de Recherche sur le Cancer; Jewish General Hospital
   Foundation-Weekend to End Breast Cancer Fund
FX We would like to thank the FRQS Reseau de Recherche sur le Cancer and
   the Jewish General Hospital Foundation-Weekend to End Breast Cancer Fund
   for their generous funding of this work.
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NR 37
TC 20
Z9 21
U1 0
U2 12
PU BMC
PI LONDON
PA CAMPUS, 4 CRINAN ST, LONDON N1 9XW, ENGLAND
SN 1471-2407
J9 BMC CANCER
JI BMC Cancer
PD MAR 15
PY 2015
VL 15
AR 130
DI 10.1186/s12885-015-1117-0
PG 11
WC Oncology
WE Science Citation Index Expanded (SCI-EXPANDED)
SC Oncology
GA CD8IH
UT WOS:000351337900001
PM 25884794
OA gold, Green Published
DA 2025-03-13
ER

PT J
AU Martínez-López, A
   Infante, G
   Mendiburu-Eliçabe, M
   Machuca, A
   Antón, OM
   González-Fernández, M
   Luque-García, JL
   Clarke, RB
   Castillo-Lluva, S
AF Martinez-Lopez, Angelica
   Infante, Guiomar
   Mendiburu-Elicabe, Marina
   Machuca, Andres
   Anton, Olga M.
   Gonzalez-Fernandez, Monica
   Luque-Garcia, Jose L.
   Clarke, Robert B.
   Castillo-Lluva, Sonia
TI SUMOylation regulates the aggressiveness of breast cancer-associated
   fibroblasts
SO CELLULAR ONCOLOGY
LA English
DT Article; Early Access
DE CAFs; Breast cancer; SUMOylation; Ginkgolic acid; SILAC
ID CARCINOMA-ASSOCIATED FIBROBLASTS; SUMO CONJUGATION; CELL; TUMOR;
   METASTASIS; MATRIX; RAC1
AB BackgroundCancer-associated fibroblasts (CAFs) are the most abundant stromal cellular component in the tumor microenvironment (TME). CAFs contribute to tumorigenesis and have been proposed as targets for anticancer therapies. Similarly, dysregulation of SUMO machinery components can disrupt the balance of SUMOylation, contributing to tumorigenesis and drug resistance in various cancers, including breast cancer. We explored the role of SUMOylation in breast CAFs and evaluated its potential as a therapeutic strategy in breast cancer.MethodsWe used pharmacological and genetic approaches to analyse the functional crosstalk between breast tumor cells and CAFs. We treated breast CAFs with the SUMO1 inhibitor ginkgolic acid (GA) at two different concentrations and conditioned media was used to analyse the proliferation, migration, and invasion of breast cancer cells from different molecular subtypes. Additionally, we performed quantitative proteomics (SILAC) to study the differential signalling pathways expressed in CAFs treated with low or high concentrations of GA. We confirmed these results both in vitro and in vivo. Moreover, we used samples from metastatic breast cancer patients to evaluate the use of GA as a therapeutic strategy.ResultsInhibition of SUMOylation with ginkgolic acid (GA) induces death in breast cancer cells but does not affect the viability of CAFs, indicating that CAFs are resistant to this therapy. While CAF viability is unaffected, CAF-conditioned media (CM) is altered by GA, impacting tumor cell behaviour in different ways depending on the overall degree to which SUMO1-SUMOylated proteins are dysregulated. Breast cancer cell lines exhibited a concentration-dependent response to conditioned media (CM) from CAFs. At a low concentration of GA (10 mu M), there was an increase in proliferation, migration and invasion of breast cancer cells. However, at a higher concentration of GA (30 mu M), these processes were inhibited. Similarly, analysis of tumor development revealed that at 10 mu M of GA, the tumors were heavier and there was a greater degree of metastasis compared to the tumors treated with the higher concentration of GA (30 mu M). Moreover, some of these effects could be explained by an alteration in the activity of the GTPase Rac1 and the activation of the AKT signalling pathway. The results obtained using SILAC suggest that different concentrations of GA affected cellular processes differentially, possibly influencing the secretome of CAFs. Treatment of metastatic breast cancer with GA demonstrated the use of SUMOylation inhibition as an alternative therapeutic strategy.ConclusionThe study highlights the importance of SUMOylation in the tumor microenvironment, specifically in cancer-associated fibroblasts (CAFs). Targeting SUMOylation in CAFs affects their signalling pathways and secretome in a concentration-dependent manner, regulating the protumorigenic properties of CAFs.
C1 [Martinez-Lopez, Angelica; Infante, Guiomar; Anton, Olga M.; Gonzalez-Fernandez, Monica; Castillo-Lluva, Sonia] Univ Complutense Madrid, Fac Ciencias Quim, Dept Bioquim & Biol Mol, Madrid, Spain.
   [Martinez-Lopez, Angelica; Infante, Guiomar; Anton, Olga M.; Castillo-Lluva, Sonia] Inst Invest Sanit San Carlos IdISSC, Madrid, Spain.
   [Mendiburu-Elicabe, Marina] Univ Complutense Madrid, Fac Ciencias Matemat, Dept Estadist & Invest Operat, Madrid, Spain.
   [Machuca, Andres; Luque-Garcia, Jose L.] Univ Complutense Madrid, Fac Ciencias Quim, Dept Quim Analit, Madrid, Spain.
   [Clarke, Robert B.] Univ Manchester, Fac Biol Med & Hlth, Div Canc Sci, Manchester Breast Ctr, Manchester, England.
C3 Complutense University of Madrid; Complutense University of Madrid;
   Complutense University of Madrid; University of Manchester
RP Castillo-Lluva, S (corresponding author), Univ Complutense Madrid, Fac Ciencias Quim, Dept Bioquim & Biol Mol, Madrid, Spain.; Castillo-Lluva, S (corresponding author), Inst Invest Sanit San Carlos IdISSC, Madrid, Spain.
EM sonica01@ucm.es
RI Lopez, Angelica/JTS-8187-2023; CASTILLO-LLUVA, SONIA/AAA-1776-2020
OI Martinez-Lopez, Angelica/0000-0001-9407-1368; Castillo-LLuva,
   Sonia/0000-0001-5357-7178
FU Ministerio de Economa y Competitividad
FX We thank Paloma Bragado and Akira Orimo for providing us with the NF and
   CAF cells. We thank the Breast Biology Group for all their support with
   the management of patient samples and Professor Ron Hay for providing
   the SUMO2 antibody.
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NR 53
TC 0
Z9 0
U1 3
U2 3
PU SPRINGER
PI DORDRECHT
PA VAN GODEWIJCKSTRAAT 30, 3311 GZ DORDRECHT, NETHERLANDS
SN 2211-3428
EI 2211-3436
J9 CELL ONCOL
JI Cell. Oncol.
PD 2024 OCT 21
PY 2024
DI 10.1007/s13402-024-01005-w
EA OCT 2024
PG 17
WC Oncology; Cell Biology; Pathology
WE Science Citation Index Expanded (SCI-EXPANDED)
SC Oncology; Cell Biology; Pathology
GA J5B3Q
UT WOS:001337211100001
PM 39432155
OA hybrid
DA 2025-03-13
ER

PT J
AU Romano, V
   Ruocco, MR
   Carotenuto, P
   Barbato, A
   Venuta, A
   Acampora, V
   De Lella, S
   Vigliar, E
   Iaccarino, A
   Troncone, G
   Calì, G
   Insabato, L
   Russo, D
   Franco, B
   Masone, S
   Velotti, N
   Accurso, A
   Pellegrino, T
   Fiume, G
   Belviso, I
   Montagnani, S
   Avagliano, A
   Arcucci, A
AF Romano, Veronica
   Ruocco, Maria Rosaria
   Carotenuto, Pietro
   Barbato, Anna
   Venuta, Alessandro
   Acampora, Vittoria
   De Lella, Sabrina
   Vigliar, Elena
   Iaccarino, Antonino
   Troncone, Giancarlo
   Cali, Gaetano
   Insabato, Luigi
   Russo, Daniela
   Franco, Brunella
   Masone, Stefania
   Velotti, Nunzio
   Accurso, Antonello
   Pellegrino, Tommaso
   Fiume, Giuseppe
   Belviso, Immacolata
   Montagnani, Stefania
   Avagliano, Angelica
   Arcucci, Alessandro
TI Generation and Characterization of a Tumor Stromal Microenvironment and
   Analysis of Its Interplay with Breast Cancer Cells: An In Vitro Model to
   Study Breast Cancer-Associated Fibroblast Inactivation
SO INTERNATIONAL JOURNAL OF MOLECULAR SCIENCES
LA English
DT Article
DE breast cancer; breast cancer-associated fibroblasts; aggregates; breast
   cancer cells; deactivation; conditioned medium
ID SPHEROIDS; MYOFIBROBLASTS; METASTASIS; DIFFERENTIATION; PROGRESSION;
   ROLES
AB Breast cancer-associated fibroblasts (BCAFs), the most abundant non-cancer stromal cells of the breast tumor microenvironment (TME), dramatically sustain breast cancer (BC) progression by interacting with BC cells. BCAFs, as well as myofibroblasts, display an up regulation of activation and inflammation markers represented by alpha-smooth muscle actin (alpha-SMA) and cyclooxygenase 2 (COX-2). BCAF aggregates have been identified in the peripheral blood of metastatic BC patients. We generated an in vitro stromal model consisting of human primary BCAFs grown as monolayers or 3D cell aggregates, namely spheroids and reverted BCAFs, obtained from BCAF spheroids reverted to 2D cell adhesion growth after 216 h of 3D culture. We firstly evaluated the state of activation and inflammation and the mesenchymal status of the BCAF monolayers, BCAF spheroids and reverted BCAFs. Then, we analyzed the MCF-7 cell viability and migration following treatment with conditioned media from the different BCAF cultures. After 216 h of 3D culture, the BCAFs acquired an inactivated phenotype, associated with a significant reduction in alpha-SMA and COX-2 protein expression. The deactivation of the BCAF spheroids at 216 h was further confirmed by the cytostatic effect exerted by their conditioned medium on MCF-7 cells. Interestingly, the reverted BCAFs also retained a less activated phenotype as indicated by alpha-SMA protein expression reduction. Furthermore, the reverted BCAFs exhibited a reduced pro-tumor phenotype as indicated by the anti-migratory effect exerted by their conditioned medium on MCF-7 cells. The deactivation of BCAFs without drug treatment is possible and leads to a reduced capability of BCAFs to sustain BC progression in vitro. Consequently, this study could be a starting point to develop new therapeutic strategies targeting BCAFs and their interactions with cancer cells.
C1 [Romano, Veronica; Venuta, Alessandro; Acampora, Vittoria; De Lella, Sabrina; Vigliar, Elena; Iaccarino, Antonino; Troncone, Giancarlo; Belviso, Immacolata; Montagnani, Stefania; Avagliano, Angelica; Arcucci, Alessandro] Univ Naples Federico II, Dept Publ Hlth, I-80131 Naples, Italy.
   [Ruocco, Maria Rosaria] Univ Naples Federico II, Dept Mol Med & Med Biotechnol, I-80131 Naples, Italy.
   [Carotenuto, Pietro; Barbato, Anna; Franco, Brunella] Telethon Inst Genet & Med, TIGEM, I-80078 Naples, Italy.
   [Carotenuto, Pietro; Franco, Brunella] Univ Naples Federico II, Dept Translat Med Sci, Med Genet, I-80131 Naples, Italy.
   [Cali, Gaetano] Natl Council Res, IEOS Ist Endocrinol & Oncol Sperimentale G Salvat, I-80131 Naples, Italy.
   [Insabato, Luigi; Russo, Daniela] Univ Naples Federico II, Sch Med, Dept Adv Biomed Sci, Anat Pathol Unit, Naples 80131, Italy.
   [Franco, Brunella] Scuola Super Merid, Sch Adv Studies, I-80138 Naples, Italy.
   [Masone, Stefania] Univ Naples Federico II, Dept Clin Med & Surg, I-80131 Naples, Italy.
   [Velotti, Nunzio] Univ Naples Federico II, Dept Adv Biochem Sci, I-80131 Naples, Italy.
   [Accurso, Antonello] Univ Naples Federico II, Dept Gen Oncol Bariatr & Endocrine Metab Surg, Naples 80131, Italy.
   [Pellegrino, Tommaso] Azienda Osped Univ Federico II, DAI Chirurg Gen Endocrinol Ortopedia & Riabilitaz, I-80131 Naples, Italy.
   [Fiume, Giuseppe] Magna Graecia Univ Catanzaro, Dept Expt & Clin Med, I-88100 Catanzaro, Italy.
C3 University of Naples Federico II; University of Naples Federico II;
   Fondazione Telethon; Telethon Institute of Genetics & Medicine (TIGEM);
   University of Naples Federico II; Consiglio Nazionale delle Ricerche
   (CNR); University of Naples Federico II; University of Naples Federico
   II; University of Naples Federico II; University of Naples Federico II;
   Magna Graecia University of Catanzaro
RP Avagliano, A; Arcucci, A (corresponding author), Univ Naples Federico II, Dept Publ Hlth, I-80131 Naples, Italy.
EM veronica.romano@unina.it; mariarosaria.ruocco2@unina.it;
   p.carotenuto@tigem.it; a.barbato@tigem.it; alessandro.venuta@unina.it;
   vit.acampora@studenti.unina.it; sab.delella@studenti.unina.it;
   elena.vigliar@unina.it; antonino.iaccarino@unina.it;
   giancarlo.troncone@unina.it; g.cali@ieos.cnr.it;
   luigi.insabato@unina.it; daniela.russo@unina.it;
   brunella.franco@unina.it; stefania.masone@unina.it;
   nunzio.velotti@gmail.com; antonello.accurso@unina.it;
   tommaso.pellegrino@unina.it; fiume@unicz.it;
   immacolata.belviso@unina.it; stefania.montagnani@unina.it;
   angelica.avagliano@unina.it; alessandro.arcucci2@unina.it
RI Toprak, Omer/ABA-5812-2020; Belviso, Immacolata/AAI-4676-2021; masone,
   stefania/I-5077-2012; Arcucci, Alessandro/AAV-7902-2020; Venuta,
   Alessandro/LFS-5762-2024; Avagliano, Angelica/ABI-2247-2020; Romano,
   Veronica/AAM-4208-2020; Vigliar, Elena/L-2174-2019; BARBATO,
   ANNA/IQR-8362-2023; Velotti, Nunzio/O-2060-2015
OI Carotenuto, Pietro/0000-0002-6622-183X; BARBATO,
   ANNA/0000-0002-5706-7244; CALI', GAETANO/0000-0003-2901-2374; Vigliar,
   Elena/0000-0003-2856-9023; FIUME, Giuseppe/0000-0002-5414-6190; Velotti,
   Nunzio/0000-0002-3478-6270; Russo, Daniela/0000-0002-6961-3695;
   Troncone, Giancarlo/0000-0003-1630-5805
FU POR CAMPANIA FESR 2014/2020 grant [CUP B61G18000470007]; Italian
   Association for Cancer Research (AIRC) [IG17711/2015, IG 2021/26414];
   Marie Sklodowska-Curie Career Re-Integration fellowship - AIRC; European
   Union [800924]
FX P.C. and B.F. are kindly supported by the POR CAMPANIA FESR 2014/2020
   grant (Project title: "Dalla genomica alla terapia di tumori rari" and
   "Combattere la resistenza tumorale: piattaforma integrate
   multidisciplinare per un approccio tecnologico innovativo alle
   oncoterapie; CUP B61G18000470007") and by the Italian Association for
   Cancer Research (AIRC) (grant No. IG17711/2015 and IG 2021/26414). P.C.
   is a current recipient of a Marie Sklodowska-Curie Career Re-Integration
   fellowship funded by the AIRC and the European Union's Horizon 2020
   research and innovation programme (Grant agreement No. 800924).
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NR 67
TC 5
Z9 5
U1 1
U2 9
PU MDPI
PI BASEL
PA ST ALBAN-ANLAGE 66, CH-4052 BASEL, SWITZERLAND
SN 1661-6596
EI 1422-0067
J9 INT J MOL SCI
JI Int. J. Mol. Sci.
PD JUN
PY 2022
VL 23
IS 12
AR 6875
DI 10.3390/ijms23126875
PG 21
WC Biochemistry & Molecular Biology; Chemistry, Multidisciplinary
WE Science Citation Index Expanded (SCI-EXPANDED)
SC Biochemistry & Molecular Biology; Chemistry
GA 2P2WW
UT WOS:000819609200001
PM 35743318
OA Green Published, gold
DA 2025-03-13
ER

PT J
AU Li, HL
   Lin, XG
   Yang, D
   Chen, ZY
   Wang, XT
   Re, FT
   Wei, JJ
   Chen, JP
AF Li, Hualing
   Lin, Xueguang
   Yang, Di
   Chen, Zhangyue
   Wang, Xiaotong
   Re, Fati
   Wei, Junjie
   Chen, Juping
TI Cancer-associated fibroblasts support bone tropic metastasis by acting
   as coordinators between the tumor microenvironment and bone matrix in
   breast cancer
SO NEOPLASMA
LA English
DT Review
DE CAFs; breast cancer; bone metastasis; microenvironment; CXCL12; cancer
   stem cells; exosome; microRNA
ID EPITHELIAL-MESENCHYMAL TRANSITION; CARCINOMA-ASSOCIATED FIBROBLASTS;
   STEM-CELLS; DOWN-REGULATION; EXTRACELLULAR VESICLES; COLORECTAL-CANCER;
   TGF-BETA; EXOSOMES; PROMOTE; GROWTH
AB Bone is a common site of metastasis for various types of cancer cells, including breast cancer, and the consequent skeleton-related events observed in patients are severe and often fatal. Currently, it is widely accepted that cancer-associated fibroblasts (CAFs) confer a metastasis-promoting property to breast cancer cells. Furthermore, clinical observations suggest that CAFs mediate the bone tropism of metastatic breast cancer cells. Therefore, a deeper understanding of the mechanism by which CAFs are involved in the bone-tropic metastasis of breast cancer can facilitate the study of the novel and effective therapeutic drugs for the corresponding targets. In this review, we focused on the coordinator role of CAFs in remolding breast cancer cells and remodeling the bone marrow during metastasis. We discussed the potential roles of the CXCL12/CXCR4 axis, the CAFs-CSCs reinforcing loop, and exosomes in this malignant process. In summary, in agreement with Paget's theory, CAFs play a pivotal role in bone colonization by breast cancer cells by providing a "fertile soil" for the "selected seeds" by influencing tumor-intrinsic characteristics and microenvironment (ME).
C1 [Li, Hualing; Lin, Xueguang; Yang, Di; Chen, Zhangyue; Wang, Xiaotong; Wei, Junjie; Chen, Juping] Yangzhou Univ, Med Coll, Inst Translat Med, Yangzhou, Jiangsu, Peoples R China.
   [Li, Hualing; Lin, Xueguang; Yang, Di; Chen, Zhangyue; Wang, Xiaotong; Chen, Juping] Yangzhou Univ, Jiangsu Key Lab Expt & Translat Noncoding RNA Res, Yangzhou, Jiangsu, Peoples R China.
   [Li, Hualing; Chen, Juping] Yangzhou Univ, Jiangsu Coinnovat Ctr Prevent & Control Important, Yangzhou, Jiangsu, Peoples R China.
   [Re, Fati] Yangzhou Univ, Jiangsu Key Lab Zoonosis, Yangzhou, Jiangsu, Peoples R China.
C3 Yangzhou University; Yangzhou University; Yangzhou University; Yangzhou
   University
RP Chen, JP (corresponding author), Yangzhou Univ, Med Coll, Inst Translat Med, Yangzhou, Jiangsu, Peoples R China.; Chen, JP (corresponding author), Yangzhou Univ, Jiangsu Key Lab Expt & Translat Noncoding RNA Res, Yangzhou, Jiangsu, Peoples R China.; Chen, JP (corresponding author), Yangzhou Univ, Jiangsu Coinnovat Ctr Prevent & Control Important, Yangzhou, Jiangsu, Peoples R China.
EM hlli@yzu.edu.cn
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NR 87
TC 7
Z9 9
U1 2
U2 20
PU AEPRESS SRO
PI BRATISLAVA
PA BAJZOVA 7, BRATISLAVA, 821 08, SLOVAKIA
SN 0028-2685
EI 1338-4317
J9 NEOPLASMA
JI Neoplasma
PY 2021
VL 68
IS 1
BP 10
EP 22
DI 10.4149/neo_2020_200905N951
PG 13
WC Oncology
WE Science Citation Index Expanded (SCI-EXPANDED)
SC Oncology
GA SS6QT
UT WOS:000661880800002
PM 33231088
OA Bronze
DA 2025-03-13
ER

PT J
AU Fan, JJ
   Sha, T
   Ma, BL
AF Fan, Jingjing
   Sha, Tong
   Ma, Binlin
TI Cancer-Derived Extracellular Vesicle ITGB2 Promotes the Progression of
   Triple-Negative Breast Cancer via the Activation of Cancer-Associated
   Fibroblasts
SO GLOBAL CHALLENGES
LA English
DT Article; Early Access
DE cancer-associated fibroblast; extracellular vesicle; integrin beta 2;
   triple-negative breast cancer; tumor microenvironment
ID POOR-PROGNOSIS; GENE SIGNATURE; CELLS; EXPRESSION; BIOMARKERS;
   RESISTANCE; INTEGRINS; LNCRNAS; LFA-1
AB Breast cancer is the most prevalent cancer and a leading cause of death among women globally, posing a significant public health challenge. Triple-negative breast cancer (TNBC), an aggressive subtype accounting for 15-20% of all breast cancers, lacks targeted therapies due to the absence of hormone receptors and HER2, resulting in poor prognosis and high recurrence rates. This study investigates the role of cancer-derived extracellular vesicle (EV) integrin beta-2 (ITGB2) in TNBC progression. These findings reveal that ITGB2 is significantly overexpressed in TNBC tissues and serum EVs, correlating with advanced tumor stages and poor patient survival. ITGB2 enhances TNBC progression by activating cancer-associated fibroblasts (CAFs) within the tumor microenvironment, promoting tumor growth, migration, and invasion. Mechanistic studies demonstrate that EV ITGB2 facilitates CAF activation, driving tumor-stroma interactions that support TNBC progression. These results highlight ITGB2 as a potential biomarker and therapeutic target in TNBC, emphasizing the need for novel interventions to combat this challenging breast cancer subtype.
C1 [Fan, Jingjing; Sha, Tong; Ma, Binlin] Xinjiang Med Univ, Affiliated Canc Hosp, Xinjiang Key Lab Oncol, Urumqi 830011, Peoples R China.
   [Fan, Jingjing; Sha, Tong; Ma, Binlin] Clin Med Res Ctr Breast & Thyroid Tumor Xinjiang, Urumqi 830011, Peoples R China.
C3 Xinjiang Medical University
RP Ma, BL (corresponding author), Xinjiang Med Univ, Affiliated Canc Hosp, Xinjiang Key Lab Oncol, Urumqi 830011, Peoples R China.; Ma, BL (corresponding author), Clin Med Res Ctr Breast & Thyroid Tumor Xinjiang, Urumqi 830011, Peoples R China.
EM fjjsunny@xjmu.edu.cn
FU Youth Science and Technology Elite Talent Program, Xinjiang Medical
   University [XYD2024910]; Tianshan Talents Cultivation Program Technology
   and Innovation Leading Talents Project [2023TSYCLJ0039]; National
   Natural Science Foundation of China [82260549]
FX This project is supported by the Youth Science and Technology Elite
   Talent Program, Xinjiang Medical University (Project No. XYD2024910),
   the "Tianshan Talents Cultivation Program" Technology and Innovation
   Leading Talents Project (Grant No. 2023TSYCLJ0039) and the National
   Natural Science Foundation of China (Grant No. 82260549).
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NR 54
TC 0
Z9 0
U1 1
U2 1
PU WILEY-V C H VERLAG GMBH
PI WEINHEIM
PA POSTFACH 101161, 69451 WEINHEIM, GERMANY
EI 2056-6646
J9 GLOB CHALL
JI Glob. Chall.
PD 2025 JAN 23
PY 2025
DI 10.1002/gch2.202400235
EA JAN 2025
PG 11
WC Multidisciplinary Sciences
WE Science Citation Index Expanded (SCI-EXPANDED)
SC Science & Technology - Other Topics
GA T0Y0G
UT WOS:001402356800001
DA 2025-03-13
ER

PT J
AU Mercier, I
   Casimiro, MC
   Wang, CG
   Rosenberg, AL
   Quong, J
   Minkeu, A
   Allen, KG
   Danilo, C
   Sotgia, F
   Bonuccelli, G
   Jasmin, JF
   Xu, H
   Bosco, E
   Aronow, B
   Witkiewicz, A
   Pestell, RG
   Knudsen, ES
   Lisanti, MP
AF Mercier, Isabelle
   Casimiro, Mathew C.
   Wang, Chenguang
   Rosenberg, Anne L.
   Quong, Judy
   Minkeu, Alimatou
   Allen, Kathleen G.
   Danilo, Christiane
   Sotgia, Federica
   Bonuccelli, Gloria
   Jasmin, Jean-Francois
   Xu, Huan
   Bosco, Emily
   Aronow, Bruce
   Witkiewicz, Agnieszka
   Pestell, Richard G.
   Knudsen, Erik S.
   Lisanti, Michael P.
TI Human breast cancer-associated fibroblasts (CAFs) show caveolin-1
   downregulation and RB tumor suppressor functional inactivation -
   Implications for the response to hormonal therapy
SO CANCER BIOLOGY & THERAPY
LA English
DT Article
DE caveolin-1; invasive breast cancer; mammary fibroblasts
ID ONCOGENICALLY TRANSFORMED-CELLS; ANCHORAGE-INDEPENDENT GROWTH; MALIGNANT
   BREAST; STROMAL CELLS; IN-VIVO; PROGRESSION; EXPRESSION; TUMORIGENESIS;
   TISSUE; PROLIFERATION
AB It is becoming increasingly apparent that the tumor micro-environment plays a critical role in human breast cancer onset and progression. Therefore, we isolated cancer-associated fibroblasts (CAFs) from human breast cancer lesions and studied their properties, as compared with normal mammary fibroblasts (NFs) isolated from the same patient. Here, we demonstrate that 8 out of 11 CAFs show dramatic downregulation of caveolin-1 (Cav-1) protein expression; Cav-1 is a well-established marker that is normally decreased during the oncogenic transformation of fibroblasts. Next, we performed gene expression profiling studies (DNA microarray) and established a CAF gene expression signature. Interestingly, the expression signature associated with CAFs encompasses a large number of genes that are regulated via the RB-pathway. The CAF gene signature is also predictive of poor clinical outcome in breast cancer patients that were treated with tamoxifen mono-therapy, indicating that CAFs may be useful for predicting the response to hormonal therapy. Finally, we show that replacement of Cav-1 expression in CAFs (using a cell-permeable peptide approach) is sufficient to revert their hyper-proliferative phenotype and prevent RB hyper-phosphorylation. Taken together, these studies highlight the critical role of Cav-1 downregulation in maintaining the abnormal phenotype of human breast cancer-associated fibroblasts.
C1 [Mercier, Isabelle; Casimiro, Mathew C.; Wang, Chenguang; Quong, Judy; Minkeu, Alimatou; Danilo, Christiane; Sotgia, Federica; Bonuccelli, Gloria; Jasmin, Jean-Francois; Pestell, Richard G.; Knudsen, Erik S.; Lisanti, Michael P.] Thomas Jefferson Univ, Kimmel Canc Ctr, Dept Canc Biol, Philadelphia, PA 19107 USA.
   [Mercier, Isabelle; Casimiro, Mathew C.; Wang, Chenguang; Quong, Judy; Minkeu, Alimatou; Danilo, Christiane; Sotgia, Federica; Bonuccelli, Gloria; Jasmin, Jean-Francois; Pestell, Richard G.; Knudsen, Erik S.; Lisanti, Michael P.] Thomas Jefferson Univ, Dept Med Oncol, Philadelphia, PA 19107 USA.
   [Mercier, Isabelle; Casimiro, Mathew C.; Wang, Chenguang; Quong, Judy; Minkeu, Alimatou; Danilo, Christiane; Sotgia, Federica; Bonuccelli, Gloria; Jasmin, Jean-Francois; Pestell, Richard G.; Knudsen, Erik S.; Lisanti, Michael P.] Thomas Jefferson Univ, Stem Cell Biol & Regenerat Med Ctr, Philadelphia, PA 19107 USA.
   [Rosenberg, Anne L.; Allen, Kathleen G.] Thomas Jefferson Univ, Dept Surg, Philadelphia, PA 19107 USA.
   [Witkiewicz, Agnieszka] Thomas Jefferson Univ, Dept Pathol Anat & Cell Biol, Philadelphia, PA 19107 USA.
   [Xu, Huan; Bosco, Emily; Aronow, Bruce] Cincinnati Childrens Hosp, Med Ctr, Cincinnati, OH USA.
C3 Thomas Jefferson University; Thomas Jefferson University; Thomas
   Jefferson University; Thomas Jefferson University; Thomas Jefferson
   University; Cincinnati Children's Hospital Medical Center
RP Lisanti, MP (corresponding author), Thomas Jefferson Univ, Kimmel Canc Ctr, Dept Canc Biol, 233 S 10th St, Philadelphia, PA 19107 USA.
EM michael.lisanti@kimmelcancercenter.org
RI Aronow, Bruce/F-8438-2012; Mercier, Isabelle/C-5775-2011; Pestell,
   Richard/JQW-3484-2023; Jasmin, Jean-Francois/C-5774-2011; Lisanti,
   Michael/C-6866-2013
OI Bonuccelli, Gloria/0000-0001-7576-5508; Tchafa,
   Alimatou/0000-0002-6490-803X; Sotgia, Federica/0000-0003-2826-4529
FU NIH/NCI [R01-CA-80250, R01-CA-098779, R01-CA-120876]; American
   Association for Cancer Research (AACR); Department of Defense-Breast
   Cancer Research Program; Susan G. Komen Breast Cancer Foundation; Elsa
   U. Pardee Foundation; W. W. Smith Charitable Trust; American Cancer
   Society (ACS); Pennsylvania Department of Health
FX M.P.L. and his laboratory were supported by grants from the NIH/NCI
   (R01-CA-80250; R01-CA-098779; R01-CA-120876), the American Association
   for Cancer Research ( AACR), and the Department of Defense-Breast Cancer
   Research Program (Synergistic Idea Award). I. M. was supported by a
   Post-doctoral Fellowship from the Susan G. Komen Breast Cancer
   Foundation. F. S. was supported by grants from the Elsa U. Pardee
   Foundation, the W. W. Smith Charitable Trust, and a Research Scholar
   Grant from the American Cancer Society (ACS). J.F.J. was supported by a
   Career Catalyst Award from the Susan G. Komen Breast Cancer Foundation.
   This project is funded, in part, under a grant with the Pennsylvania
   Department of Health (to M.P.L.). The Department specifically disclaims
   responsibility for any analyses, interpretations or conclusions.
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NR 44
TC 133
Z9 151
U1 0
U2 8
PU TAYLOR & FRANCIS INC
PI PHILADELPHIA
PA 530 WALNUT STREET, STE 850, PHILADELPHIA, PA 19106 USA
SN 1538-4047
EI 1555-8576
J9 CANCER BIOL THER
JI Cancer Biol. Ther.
PD AUG
PY 2008
VL 7
IS 8
BP 1212
EP 1225
DI 10.4161/cbt.7.8.6220
PG 14
WC Oncology
WE Science Citation Index Expanded (SCI-EXPANDED)
SC Oncology
GA 342HI
UT WOS:000258774800009
PM 18458534
OA Green Accepted, Bronze
DA 2025-03-13
ER

PT J
AU Fu, ZX
   Song, PM
   Li, DB
   Yi, CH
   Chen, HR
   Ruan, SQ
   Shi, Z
   Xu, WH
   Fu, XH
   Zheng, S
AF Fu, Zhixuan
   Song, Peiming
   Li, Dongbo
   Yi, Chenghao
   Chen, Huarong
   Ruan, Shuqin
   Shi, Zhong
   Xu, Wenhong
   Fu, Xianhua
   Zheng, Shu
TI Cancer-associated fibroblasts from invasive breast cancer have an
   attenuated capacity to secrete collagens
SO INTERNATIONAL JOURNAL OF ONCOLOGY
LA English
DT Article
DE cancer-associated fibroblasts; extracellular matrix; tumor
   microenvironment; mass spectrometry; desmoplasia
ID TUMOR MICROENVIRONMENT; DESMOPLASTIC RESPONSE; STROMAL CELLS;
   ACTIVATION; MYOFIBROBLASTS; GROWTH; EXPRESSION; PROTEIN;
   DIFFERENTIATION; CARCINOMA
AB Normal fibroblasts produce extracellular matrix (ECM) components that form the structural framework of tissues. Cancer-associated fibroblasts (CAFs) with an activated phenotype mainly contribute to ECM deposition and construction of cancer masses. However, the stroma of breast cancer tissues has been shown to be more complicated, and the mechanisms through which CAFs influence ECM deposition remain elusive. In this study, we found that the activated fibroblast marker a-smooth muscle actin (alpha-SMA) was only present in the stroma of breast cancer tissue, and the CAFs isolated from invasive breast cancer sample remained to be activated and proliferative in passages. To further assess the difference between CAFs and normal breast fibroblasts (NFs), MALDI TOF/TOF-MS was used to analyze the secretory proteins of primary CAFs and NFs. In total, 2,903 and 3,023 proteins were identified. Mass spectrum quantitative assay and data analysis for extracellular proteins indicated that the CAFs produce less collagens and matrix-degrading enzymes compared with NFs. This finding was confirmed by western blot analysis. Furthermore, we discovered that reduced collagen deposition was present in the stroma of invasive breast cancer. These studies showed that although CAFs from invasive breast cancer possess an activated phenotype, they secreted less collagen and induced less ECM deposition in cancer stroma. In cancer tissue, the remodeling of stromal structure and tumor microenvironment might, therefore, be attributed to the biological changes in CAFs including their protein expression profile.
C1 [Fu, Zhixuan; Song, Peiming; Yi, Chenghao; Chen, Huarong; Ruan, Shuqin; Shi, Zhong; Xu, Wenhong; Fu, Xianhua; Zheng, Shu] Zhejiang Univ, Sch Med, Key Lab Canc Prevent & Intervent, China Natl Minist Educ,Affiliated Hosp 2, Hangzhou 310009, Zhejiang, Peoples R China.
   [Fu, Zhixuan] Zhejiang Canc Hosp, Dept Surg Oncol, Hangzhou 310022, Zhejiang, Peoples R China.
   [Li, Dongbo] Zhengzhou Univ, Dept Geriatr, Affiliated Hosp 1, Cardiovasc Ward, Zhengzhou 450052, Henan, Peoples R China.
C3 Zhejiang University; Zhejiang Cancer Hospital; Zhengzhou University
RP Zheng, S (corresponding author), Zhejiang Univ, Coll Med, Key Lab Canc Prevent & Intervent, China Natl Minist Educ,Affiliated Hosp 2, Hangzhou 310009, Zhejiang, Peoples R China.
EM zhengshu@zju.edu.cn
RI Fu, Zhixuan/KHC-7075-2024; Chen, Huarong/ABH-8561-2020
OI chen, huarong/0000-0003-2192-1864
FU National Natural Science Foundation of China [83172210, 30973382]
FX This study was supported by a grant from the National Natural Science
   Foundation of China (nos. 83172210 and 30973382). We thank Dr Shanwei
   Wang and Dr Jiaping Peng for their technical support in pathology. We
   also thank Dr Jiekai Yu, Dr Jiawei Zhang and Dr Weiting Ge for their
   help in Mass Spectrometry and Laser Confocal technology.
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NR 36
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Z9 34
U1 3
U2 30
PU SPANDIDOS PUBL LTD
PI ATHENS
PA POB 18179, ATHENS, 116 10, GREECE
SN 1019-6439
EI 1791-2423
J9 INT J ONCOL
JI Int. J. Oncol.
PD OCT
PY 2014
VL 45
IS 4
BP 1479
EP 1488
DI 10.3892/ijo.2014.2562
PG 10
WC Oncology
WE Science Citation Index Expanded (SCI-EXPANDED)
SC Oncology
GA AQ1FT
UT WOS:000342528000017
PM 25070059
OA Bronze
DA 2025-03-13
ER

PT J
AU Nandi, A
   Debnath, R
   Nayak, A
   To, TKJ
   Thacker, G
   Reilly, M
   Gumber, S
   Karagounis, I
   Li, N
   Lengner, CJ
   Haldar, M
   Welm, AL
   Blanco, AM
   Thomas, C
   Chakrabarti, R
AF Nandi, Ajeya
   Debnath, Rahul
   Nayak, Anupma
   To, Tsun Ki Jerrick
   Thacker, Gatha
   Reilly, Megan
   Gumber, Sanjeev
   Karagounis, Ilias
   Li, Ning
   Lengner, Christopher J.
   Haldar, Malay
   Welm, Alana L.
   Blanco, Andres M.
   Thomas, Christoforos
   Chakrabarti, Rumela
TI Dll1-Mediated Notch Signaling Drives Tumor Cell Cross-talk with
   Cancer-Associated Fibroblasts to Promote Radioresistance in Breast
   Cancer
SO CANCER RESEARCH
LA English
DT Article
ID EPITHELIAL-MESENCHYMAL TRANSITION; RESISTANCE; LUNG; RADIATION;
   MICROENVIRONMENT; METASTASIS; MECHANISMS; CHEMORESISTANCE; RADIOTHERAPY;
   PATTERNS
AB Resistance to radiotherapy is a major obstacle for effective cancer treatment. Both cancer-associated fibroblasts (CAF) within the tumor microenvironment (TME) and Notch signaling are impli-cated in radioresistance, but their potential interrelationship is unclear. Here, we report that irradiated samples obtained from luminal breast cancer patient tumors express higher levels of the Notch ligand Dll1 and have a greater number of aSMA-and FAP-expressing activated CAFs. Single cell transcriptomic profiles fur-ther revealed enrichment of an alpha SMA(+) myofibroblastic subpopu-lation of CAF in Dll1(+) tumors. In murine and human patient-derived xenograft models, Dll1(+) tumor cells were more radio-resistant than Dll1(-) tumor cells, and genetic and pharmacologic blocking of Dll1-mediated Notch signaling decreased the number of Dll1(+) cancer stem cells (CSC) and CAFs and increased Dll1(+)tumor cell radiosensitivity. Dll1(+) cells recruited CAFs in an IL6-dependent fashion and promoted Wnt ligand secretion by Notch2/3-expres-sing CAFs, thereby driving Wnt/beta-catenin-dependent increases in Dll1(+) CSC function to promote metastasis. Treatment with the porcupine inhibitor LGK-974 that inhibits Wnt ligand secretion or pharmacologic blockade of IL6 or Dll1 suppressed CAF-dependent enhancement of Dll1(+) CSC function and metastasis in radioresis-tant tumors. Together, these findings reveal an essential cross-talk between Dll1(+) cancer cells and CAFs, which promotes metastasis and radioresistance, which could be therapeutically exploited to improve the outcome of patients with breast cancer.
   Significance: Dll1(+) breast cancer cells activate Notch signaling in cancer-associated fibroblasts that increases Wnt ligand secretion and leads to beta-catenin-driven radioresistance and metastasis, opening new therapeutic avenues for breast cancer.
C1 [Nandi, Ajeya; Debnath, Rahul; Reilly, Megan; Li, Ning; Lengner, Christopher J.; Blanco, Andres M.; Thomas, Christoforos] Univ Penn, Dept Biomed Sci, Philadelphia, PA USA.
   [Nayak, Anupma; To, Tsun Ki Jerrick] Univ Penn, Dept Pathol & Lab Med, Perelman Sch Med, Philadelphia, PA USA.
   [Thacker, Gatha] Sylvester Comprehens Cancer Ctr, Miller Sch Med, Dept Surg, Miami, FL USA.
   [Gumber, Sanjeev] Emory Univ, Sch Med, Dept Pathol & Lab Med, Atlanta, GA USA.
   [Karagounis, Ilias; Thomas, Christoforos] Univ Penn, Perelman Sch Med, Dept Radiat Oncol, Philadelphia, PA USA.
   [Lengner, Christopher J.; Blanco, Andres M.; Chakrabarti, Rumela] Univ Penn, Inst Regenerat Med, Philadelphia, PA USA.
   [Welm, Alana L.] Univ Utah, Huntsman Canc Inst, Dept Oncol Sci, Salt Lake City, UT USA.
   [Chakrabarti, Rumela] Univ Miami Hlth Syst, Sylvester Comprehens Canc Ctr, Dept Surg, Miller Sch Med, 1501 NW 10th Ave,5th Floor, Miami, FL 33136 USA.
C3 University of Pennsylvania; University of Pennsylvania; Emory
   University; University of Pennsylvania; University of Pennsylvania; Utah
   System of Higher Education; University of Utah; Huntsman Cancer
   Institute
RP Chakrabarti, R (corresponding author), Univ Miami Hlth Syst, Sylvester Comprehens Canc Ctr, Dept Surg, Miller Sch Med, 1501 NW 10th Ave,5th Floor, Miami, FL 33136 USA.
EM rxc1335@med.miami.edu
RI Karagounis, Ilias/A-6497-2013; Menéndez Blanco, Andrés/ABH-3737-2020;
   Debnath, Rahul/AAD-7615-2022; Thacker, Gatha/IAQ-2070-2023
OI Debnath, Rahul/0000-0001-5910-3993; Thacker, Gatha/0000-0002-6378-4442;
   Li, Ning/0000-0001-5997-5556; Karagounis, Ilias V./0000-0003-1642-1996;
   Lengner, Christopher/0000-0002-0574-5189; Gumber,
   Sanjeev/0000-0001-9048-2717
FU NCI [U54CA224076]; Department of Defense Breast Cancer Research Program
   Era of Hope Scholar Award [W81XWH1210077]; American Cancer Society [RSG
   DDC-133604]; Emerson Collective Fund-University of Pennsylvania
   [20200315113131]; NCI-R01 [R01CA237243]; U.S. Department of Defense
   (DOD) [W81XWH1210077] Funding Source: U.S. Department of Defense (DOD)
FX The authors thank Dr. Leslie King and Snahlata Singh (School of
   Veterinary Medicine, University of Pennsylvania) and Dr. Ioannis I.
   Verginadis (Perelman University School of Medicine, University of
   Pennsylvania) for critical comments and helpful discussions. They thank
   Dr. Ellen Pure for FAP antibodies used in flow cytometry analyses and
   helpful discussions. The authors thank Dr. Christian W. Siebel for
   providing anti-DLL1 antibody and critical comments. They thank Eastern
   Division of the Cooperative Human Tissue Network (CHTN), UPENN for
   providing human breast cancer fixed tissues and fresh tumor tissues from
   patients. The authors thank Penn Vet Comparative Pathology Core,
   Children's Hospital of Philadelphia (CHOP) histology core, and Perelman
   School of Medicine histology core for their assistance with embedding
   and sectioning of tumor samples and Penn Vet imaging core for providing
   confocal microscopy service. They also thank the members of SARRP
   radiation machine in Department of Radiation Oncology, Flow Cytometry
   core at UPENN and Children's Hospital of Philadelphia (CHOP) for all
   flow-based experiments. The authors thank PSOM Next-Generation
   Sequencing Core for running single-cell RNA sequencing. They also thank
   Novogene Corporation, Inc. for bulk mRNA sequencing and analyses.
   Generation of human PDX tumors was supported by NCI U54CA224076 to A. L.
   Welm and Department of Defense Breast Cancer Research Program Era of
   Hope Scholar Award W81XWH1210077 to A.L. Welm. This work was supported
   by grants from American Cancer Society (RSG DDC-133604), Emerson
   Collective Fund-University of Pennsylvania (20200315113131), and NCI-R01
   (R01CA237243) grants to R. Chakrabarti.
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NR 62
TC 25
Z9 26
U1 1
U2 25
PU AMER ASSOC CANCER RESEARCH
PI PHILADELPHIA
PA 615 CHESTNUT ST, 17TH FLOOR, PHILADELPHIA, PA 19106-4404 USA
SN 0008-5472
EI 1538-7445
J9 CANCER RES
JI Cancer Res.
PD OCT 15
PY 2022
VL 82
IS 20
DI 10.1158/0008-5472.CAN-21-1225
PG 16
WC Oncology
WE Science Citation Index Expanded (SCI-EXPANDED)
SC Oncology
GA 5Q9DC
UT WOS:000874122300001
PM 36007109
OA Green Accepted, Green Submitted
DA 2025-03-13
ER

PT J
AU Suh, J
   Kim, D
   Lee, YH
   Jang, JH
   Surh, YJ
AF Suh, Jinyoung
   Kim, Do-Hee
   Lee, Yeon-Hwa
   Jang, Jeong-Hoon
   Surh, Young-Joon
TI Fibroblast growth factor-2, derived from cancer-associated fibroblasts,
   stimulates growth and progression of human breast cancer cells via FGFR1
   signaling
SO MOLECULAR CARCINOGENESIS
LA English
DT Article
DE breast cancer; cancer-associated fibroblasts; fibroblast growth factor
   2; fibroblast growth factor receptor 1; tumor microenvironment
ID EPITHELIAL-MESENCHYMAL TRANSITION; STROMAL FIBROBLASTS; TGF-BETA;
   CLINICAL-SIGNIFICANCE; COLORECTAL-CANCER; POOR-PROGNOSIS; TUMOR-GROWTH;
   EXPRESSION; RECEPTORS; INDUCE
AB Cancer-associated fibroblasts (CAFs) constitute a major compartment of the tumor microenvironment. In the present study, we investigated the role for CAFs in breast cancer progression and underlying molecular mechanisms. Human breast cancer MDA-MB-231 cells treated with the CAF-conditioned media manifested a more proliferative phenotype, as evidenced by enhanced messenger RNA (mRNA) expression of Cyclin D1, c-Myc, and proliferating cell nuclear antigen. Analysis of data from The Cancer Genome Atlas revealed that fibroblast growth factor-2 (FGF2) expression was well correlated with the presence of CAFs. We noticed that the mRNA level of FGF2 in CAFs was higher than that in normal fibroblasts. FGF2 exerts its biological effects through interaction with FGF receptor 1 (FGFR1). In the breast cancer tissue array, 42% estrogen receptor-negative patients coexpressed FGF2 and FGFR1, whereas only 19% estrogen receptor-positive patients exhibited coexpression. CAF-stimulated MDA-MB-231 cell migration and invasiveness were abolished when FGF2-neutralizing antibody was added to the conditioned media of CAFs. In a xenograft mouse model, coinjection of MDA-MB-231 cells with activated fibroblasts expressing FGF2 dramatically enhanced tumor growth, and this was abrogated by silencing of FGFR1 in cancer cells. In addition, treatment of MDA-MB-231 cells with FGF2 enhanced expression of Cyclin D1, a key molecule involved in cell cycle progression. FGF2-induced cell migration and upregulation of Cyclin D1 were abolished by siRNA-mediated FGFR1 silencing. Taken together, the above findings suggest that CAFs promote growth, migration and invasion of MDA-MB-231 cells via the paracrine FGF2-FGFR1 loop in the breast tumor microenvironment.
C1 [Suh, Jinyoung; Lee, Yeon-Hwa; Jang, Jeong-Hoon; Surh, Young-Joon] Seoul Natl Univ, Tumor Microenvironm Global Core Res Ctr, Seoul 08826, South Korea.
   [Suh, Jinyoung; Lee, Yeon-Hwa; Jang, Jeong-Hoon; Surh, Young-Joon] Seoul Natl Univ, Pharmaceut Sci Res Inst, Seoul 08826, South Korea.
   [Kim, Do-Hee] Kyonggi Univ, Coll Convergence & Integrated Sci, Dept Chem, Suwon, Gyeonggi Do, South Korea.
   [Surh, Young-Joon] Seoul Natl Univ, Grad Sch Convergence Sci & Technol, Dept Mol Med & Biopharmaceut Sci, Seoul, South Korea.
   [Surh, Young-Joon] Seoul Natl Univ, Canc Res Inst, Seoul, South Korea.
C3 Seoul National University (SNU); Seoul National University (SNU);
   Kyonggi University; Seoul National University (SNU); Seoul National
   University (SNU)
RP Surh, YJ (corresponding author), Seoul Natl Univ, Tumor Microenvironm Global Core Res Ctr, Seoul 08826, South Korea.; Surh, YJ (corresponding author), Seoul Natl Univ, Pharmaceut Sci Res Inst, Seoul 08826, South Korea.
EM surh@snu.ac.kr
RI Jang, Jeong/AAO-8249-2020
FU National Research Foundation of Korea [2011-0030001]
FX National Research Foundation of Korea, Grant/Award Number: 2011-0030001
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NR 52
TC 52
Z9 56
U1 2
U2 20
PU WILEY
PI HOBOKEN
PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA
SN 0899-1987
EI 1098-2744
J9 MOL CARCINOGEN
JI Mol. Carcinog.
PD SEP
PY 2020
VL 59
IS 9
BP 1028
EP 1040
DI 10.1002/mc.23233
EA JUN 2020
PG 13
WC Biochemistry & Molecular Biology; Oncology
WE Science Citation Index Expanded (SCI-EXPANDED)
SC Biochemistry & Molecular Biology; Oncology
GA MS8BK
UT WOS:000541037800001
PM 32557854
DA 2025-03-13
ER

PT J
AU Boesch, M
   Onder, L
   Cheng, HW
   Novkovic, M
   Mörbe, U
   Sopper, S
   Gastl, G
   Jochum, W
   Ruhstaller, T
   Knauer, M
   Ludewig, B
AF Boesch, Maximilian
   Onder, Lucas
   Cheng, Hung-Wei
   Novkovic, Mario
   Morbe, Urs
   Sopper, Sieghart
   Gastl, Guenther
   Jochum, Wolfram
   Ruhstaller, Thomas
   Knauer, Michael
   Ludewig, Burkhard
TI Interleukin 7-expressing fibroblasts promote breast cancer growth
   through sustenance of tumor cell stemness
SO ONCOIMMUNOLOGY
LA English
DT Article
DE Breast cancer; tumor microenvironment; interleukin 7; cancer-associated
   fibroblast; cancer stem cells; Cxcl12
ID STROMAL CELLS; RETICULAR CELLS; MOUSE MODEL; METASTASIS; HETEROGENEITY;
   ACTIVATION; IDENTIFICATION; POPULATION; RECEPTORS; SIGNALS
AB The tumor microenvironment harbors cancer-associated fibroblasts that function as major modulators of cancer progression. Here, we assessed to which extent distinct cancer-associated fibroblast subsets impact mammary carcinoma growth and cancer cell stemness in an orthotopic murine model. We found that fibroblasts expressing the Cre recombinase under the control of the interleukin 7 promoter occupied mainly the tumor margin where they physically interacted with tumor cells. Intratumoral ablation of interleukin 7-expressing fibroblasts impaired breast tumor growth and reduced the clonogenic potential of cancer cells. Moreover, cDNA expression profiling revealed a distinct oncogenic signature of interleukin 7-producing fibroblasts. In particular, Cxcl12 expression was strongly enhanced in interleukin 7-producing fibroblasts and cell type-specific genetic ablation and systemic pharmacological inhibition revealed that the CXCL12/CXCR4 axis impacts breast tumor cell stemness. Elevated expression of CXCL12 and other stem cell factors in primary human breast cancer-associated fibroblasts indicates that certain fibroblast populations support tumor cell stemness and thereby promote breast cancer growth.
C1 [Boesch, Maximilian; Onder, Lucas; Cheng, Hung-Wei; Novkovic, Mario; Morbe, Urs; Ludewig, Burkhard] Kantonsspital St Gallen, Inst Immunobiol, Rorschacherstr 95, CH-9007 St Gallen, Switzerland.
   [Sopper, Sieghart; Gastl, Guenther] Med Univ Innsbruck, Internal Med 5, Anichstr 35, Innsbruck, Austria.
   [Jochum, Wolfram] Kantonsspital St Gallen, Inst Pathol, Rorschacherstr 95, St Gallen, Switzerland.
   [Ruhstaller, Thomas; Knauer, Michael] Kantonsspital St Gallen, Breast Ctr, Rorschacherstr 95, St Gallen, Switzerland.
C3 Kantonsspital St. Gallen; Institute of Immunobiology, St. Gallen;
   Medical University of Innsbruck; Kantonsspital St. Gallen; Kantonsspital
   St. Gallen
RP Ludewig, B (corresponding author), Kantonsspital St Gallen, Inst Immunobiol, Rorschacherstr 95, CH-9007 St Gallen, Switzerland.
EM Burkhard.Ludewig@kssg.ch
RI Knauer, Michael/AAR-6162-2021; Mörbe, Urs/GPX-7383-2022; Sopper,
   Sieghart/I-3155-2018; Bösch, Ph.D., Maximilian/LCE-6964-2024
OI Morbe, Urs Michael/0000-0001-8747-437X; Sopper,
   Sieghart/0000-0003-2265-1974; Novkovic, Mario/0000-0001-7654-5777
FU Austrian Science Fund (FWF) [J-3807]; Krebsliga Ostschweiz; Human
   Frontiers Science Program [RGP0034/2016]
FX This work was supported by the Austrian Science Fund (FWF) under grant
   number J-3807 (Erwin Schrodinger Fellowship awarded to Maximilian
   Boesch), by the Krebsliga Ostschweiz (to Burkhard Ludewig) and the Human
   Frontiers Science Program (RGP0034/2016).
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NR 57
TC 37
Z9 40
U1 0
U2 7
PU TAYLOR & FRANCIS INC
PI PHILADELPHIA
PA 530 WALNUT STREET, STE 850, PHILADELPHIA, PA 19106 USA
SN 2162-402X
J9 ONCOIMMUNOLOGY
JI OncoImmunology
PY 2018
VL 7
IS 4
AR e1414129
DI 10.1080/2162402X.2017.1414129
PG 12
WC Oncology; Immunology
WE Science Citation Index Expanded (SCI-EXPANDED)
SC Oncology; Immunology
GA GA4CP
UT WOS:000428277500028
PM 29632733
OA gold, Green Published
DA 2025-03-13
ER

PT J
AU Kundu, M
   Butti, R
   Panda, VK
   Malhotra, D
   Das, S
   Mitra, T
   Kapse, P
   Gosavi, SW
   Kundu, GC
AF Kundu, Moumita
   Butti, Ramesh
   Panda, Venketesh K.
   Malhotra, Diksha
   Das, Sumit
   Mitra, Tandrima
   Kapse, Prachi
   Gosavi, Suresh W.
   Kundu, Gopal C.
TI Modulation of the tumor microenvironment and mechanism of
   immunotherapy-based drug resistance in breast cancer
SO MOLECULAR CANCER
LA English
DT Review
DE Breast cancer; Tumor microenvironment; Cancer-associated fibroblast;
   Tumor-associated macrophage; Immune resistance; Therapeutic approach
ID VIVO CRISPR SCREENS; PHASE-II TRIAL; SINGLE-CELL; MACROPHAGE
   POLARIZATION; FIBROBLAST ACTIVATION; PHOTODYNAMIC THERAPY; ANTIGEN
   PRESENTATION; BLOCKADE RESISTANCE; ANTITUMOR IMMUNITY; COLORECTAL-CANCER
AB Breast cancer, the most frequent female malignancy, is often curable when detected at an early stage. The treatment of metastatic breast cancer is more challenging and may be unresponsive to conventional therapy. Immunotherapy is crucial for treating metastatic breast cancer, but its resistance is a major limitation. The tumor microenvironment (TME) is vital in modulating the immunotherapy response. Various tumor microenvironmental components, such as cancer-associated fibroblasts (CAFs), tumor-associated macrophages (TAMs), and myeloid-derived suppressor cells (MDSCs), are involved in TME modulation to cause immunotherapy resistance. This review highlights the role of stromal cells in modulating the breast tumor microenvironment, including the involvement of CAF-TAM interaction, alteration of tumor metabolism leading to immunotherapy failure, and other latest strategies, including high throughput genomic screening, single-cell and spatial omics techniques for identifying tumor immune genes regulating immunotherapy response. This review emphasizes the therapeutic approach to overcome breast cancer immune resistance through CAF reprogramming, modulation of TAM polarization, tumor metabolism, and genomic alterations.
C1 [Kundu, Moumita; Panda, Venketesh K.; Malhotra, Diksha; Mitra, Tandrima; Kundu, Gopal C.] KIIT Deemed Univ, Sch Biotechnol, Bhubaneswar 751024, India.
   [Butti, Ramesh] Univ Texas Southwestern Med Ctr, Dept Internal Med, Div Hematol & Oncol, Dallas, TX 75235 USA.
   [Das, Sumit] Natl Ctr Cell Sci, Savitribai Phule Pune Univ Campus, Pune 411007, India.
   [Kapse, Prachi; Gosavi, Suresh W.] Savitribai Phule Pune Univ, Sch Basic Med Sci, Pune 411007, India.
   [Kundu, Gopal C.] KIIT Deemed Univ, Kalinga Inst Med Sci KIMS, Bhubaneswar 751024, India.
   [Kundu, Moumita] Brainware Univ, Dept Pharmaceut Technol, Kolkata 700125, West Bengal, India.
C3 Kalinga Institute of Industrial Technology (KIIT); University of Texas
   System; University of Texas Southwestern Medical Center Dallas;
   Department of Biotechnology (DBT) India; National Centre for Cell
   Science, Pune (NCCS); Savitribai Phule Pune University; Kalinga
   Institute of Industrial Technology (KIIT)
RP Kundu, GC (corresponding author), KIIT Deemed Univ, Sch Biotechnol, Bhubaneswar 751024, India.; Kundu, GC (corresponding author), KIIT Deemed Univ, Kalinga Inst Med Sci KIMS, Bhubaneswar 751024, India.
EM gopalc.kundu@kiit.ac.in
RI Kundu, Moumita/IVV-3094-2023; Butti, Ramesh/ABF-7762-2021; PANDA,
   VENKETESH/AAE-6695-2021
OI KUNDU, MOUMITA/0000-0003-1416-720X; Das, Sumit/0000-0002-8170-5525;
   PANDA, VENKETESH K./0000-0002-6633-2898
FU DST INSPIRE Fellowship Program
FX We acknowledge Ms. Angitha N. Nath for editing the manuscript.
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NR 342
TC 29
Z9 30
U1 18
U2 31
PU BMC
PI LONDON
PA CAMPUS, 4 CRINAN ST, LONDON N1 9XW, ENGLAND
EI 1476-4598
J9 MOL CANCER
JI Mol. Cancer
PD MAY 7
PY 2024
VL 23
IS 1
AR 92
DI 10.1186/s12943-024-01990-4
PG 27
WC Biochemistry & Molecular Biology; Oncology
WE Science Citation Index Expanded (SCI-EXPANDED)
SC Biochemistry & Molecular Biology; Oncology
GA PQ1F5
UT WOS:001215448200002
PM 38715072
OA gold
DA 2025-03-13
ER

PT J
AU Zang, CB
   Eucker, J
   Habbel, P
   Neumann, C
   Schulz, CO
   Bangemann, N
   Kissner, L
   Riess, H
   Liu, HY
AF Zang, Chuanbing
   Eucker, Jan
   Habbel, Piet
   Neumann, Christian
   Schulz, Carsten-Oliver
   Bangemann, Nikola
   Kissner, Lutz
   Riess, Hanno
   Liu, Hongyu
TI Targeting multiple tyrosine kinase receptors with Dovitinib blocks
   invasion and the interaction between tumor cells and cancer-associated
   fibroblasts in breast cancer
SO CELL CYCLE
LA English
DT Article
DE breast cancer; cancer-associated fibroblasts; chemokines; Dovitinib;
   FGF; invasion; PDGF
ID GROWTH-FACTOR RECEPTORS; XENOGRAFT MODELS; POTENT INHIBITOR; METASTASIS;
   STROMA; ANGIOGENESIS; TUMORIGENESIS; PROGRESSION; CHEMOKINES; APOPTOSIS
AB A constitutive and dynamic interaction between tumor cells and their surrounding stroma is a prerequisite for tumor invasion and metastasis. Fibroblasts and myofibroblasts (collectively called cancer associated fibroblasts, CAFs) often represent the major cellular components of tumor stroma. Tumor cells secret different growth factors which induce CAFs proliferation and differentiation, and, consequently, CAFs secrete different chemokines, cytokines or growth factors which induce tumor cell invasion and metastasis. In this study we showed here that CAFs from breast cancer surgical specimens significantly induced the invasion of breast cancer cells in vitro. Most interestingly, the novel multiple tyrosine kinase inhibitor Dovitinib significantly blocked the CAFs-induced invasion of breast cancer cells by, at least in part, inhibition of the expression and secretion of CCL2, CCL5 and VEGF in CAFs. Inhibition of PI3K/Akt/mTOR signaling could be responsible for the effects of Dovitinib, since Dovitinib antagonized the promoted phosphorylated Akt after treatment with PDGF, FGF or breast cancer cell-conditioned media. Treatment with Dovitinib in combination with PI3K/Akt/mTOR signaling inhibitors Ly294002 or RAD001 resulted in additive inhibition of cell invasion. This is the first in vitro study to show that the multiple tyrosine kinase inhibitor has therapeutic activities against breast cancer metastasis by targeting both tumor cells and CAFs.
C1 [Zang, Chuanbing; Eucker, Jan; Habbel, Piet; Neumann, Christian; Schulz, Carsten-Oliver; Riess, Hanno; Liu, Hongyu] Charite, Div Hematol & Oncol, D-13353 Berlin, Germany.
   [Bangemann, Nikola; Kissner, Lutz] Charite, Breast Ctr, Clin Gynecol, D-13353 Berlin, Germany.
C3 Berlin Institute of Health; Free University of Berlin; Humboldt
   University of Berlin; Charite Universitatsmedizin Berlin; Berlin
   Institute of Health; Free University of Berlin; Humboldt University of
   Berlin; Charite Universitatsmedizin Berlin
RP Liu, HY (corresponding author), Charite, Div Hematol & Oncol, Charitepl 1, D-13353 Berlin, Germany.
EM hongyu.liu@charite.de
OI Eucker, Jan/0000-0002-6714-8056
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NR 37
TC 15
Z9 19
U1 1
U2 13
PU TAYLOR & FRANCIS INC
PI PHILADELPHIA
PA 530 WALNUT STREET, STE 850, PHILADELPHIA, PA 19106 USA
SN 1538-4101
EI 1551-4005
J9 CELL CYCLE
JI Cell Cycle
PD APR 15
PY 2015
VL 14
IS 8
BP 1291
EP 1299
DI 10.4161/15384101.2014.995050
PG 9
WC Cell Biology
WE Science Citation Index Expanded (SCI-EXPANDED)
SC Cell Biology
GA CG3GZ
UT WOS:000353168600025
PM 25714853
OA Bronze, Green Published
DA 2025-03-13
ER

PT J
AU Lai, YW
   Liu, ZW
   Lin, MH
   Yang, CC
   Chu, CY
   Chung, CH
   Lin, CW
AF Lai, Yi-Wen
   Liu, Zei-Wei
   Lin, Mei-Hsiang
   Yang, Ching-Chieh
   Chu, Cheng-Ying
   Chung, Chu-Hung
   Lin, Cheng-Wei
TI Melatonin increases Olaparib sensitivity and suppresses
   cancer-associated fibroblast infiltration via suppressing the
   LAMB3-CXCL2 axis in TNBC
SO PHARMACOLOGICAL RESEARCH
LA English
DT Article
DE Melatonin; Olaparib; LAMB3; CXCL2; Cancer-associated fibroblasts;
   Triple-negative breast cancer; Immune microenvironment
ID CELLS
AB Triple-negative breast cancer (TNBC) is the most malignant breast cancer subtype, characterized with high aggressiveness and a high recurrence rate. Olaparib is the first US Food and Drug Administration-approved poly(ADP ribose) polymerase (PARP) inhibitor (PARPi) to treat breast cancer patients with a germline BRCA1 or BRCA2 mutation. However, resistance to Olaparib treatment restricts the therapeutic effects, and thus novel therapeutics are urgently required. In the present study, we identified that the combination of melatonin and Olaparib synergistically enhanced the sensitivity of TNBC cells. Moreover, melatonin exerted promising antitumor activities in Olaparib-resistant cells, implying the potential for its clinical application. An RNA-sequencing analysis revealed that melatonin treatment downregulated laminin subunit beta 3 (LAMB3) expression. Genetic ablation of LAMB3 significantly increased Olaparib sensitivity, and subsequently suppressed proliferation, epithelial-to-mesenchymal transition (EMT)-related gene expressions, and aggressiveness of breast cancer cells. Accordingly, LAMB3 expression was positively correlated with C-X-C motif chemokine ligand 2 (CXCL2), and they collaboratively promoted cancer-associated fibroblast (CAF) infiltration. An in vivo study demonstrated that combined treatment with melatonin and Olaparib showed enhanced inhibitory efficacy against tumor growth, LAMB3 expression, CXCL2 levels, and CAF infiltration compared to single treatment groups, and combined treatment with melatonin and Olaparib significantly ameliorated the immunosuppressive tumor microenvironment. These findings illustrate a promising therapeutic strategy using melatonin to overcome Olaparib resistance and activate antitumor immunity via attenuating the LAMB3-CXCL2 axis in breast cancer patients.
C1 [Lai, Yi-Wen; Chung, Chu-Hung; Lin, Cheng-Wei] Taipei Med Univ, Grad Inst Med Sci, Coll Med, Taipei, Taiwan.
   [Lai, Yi-Wen; Liu, Zei-Wei; Chung, Chu-Hung; Lin, Cheng-Wei] Taipei Med Univ, Coll Med, Sch Med, Dept Biochem & Mol Cell Biol, 250 Wu Xing St, Taipei 11031, Taiwan.
   [Lin, Mei-Hsiang] Taipei Med Univ, Coll Pharm, Sch Pharm, Taipei, Taiwan.
   [Yang, Ching-Chieh] Chi Mei Med Ctr, Dept Radiat Oncol, Tainan, Taiwan.
   [Yang, Ching-Chieh] Chia Nan Univ Pharm & Sci, Dept Pharm, Tainan, Taiwan.
   [Yang, Ching-Chieh] Natl Sun Yat Sen Univ, Coll Med, Sch Med, Kaohsiung, Taiwan.
   [Chu, Cheng-Ying] Taipei Med Univ, CRISPR Gene Targeting Core Lab, Taipei, Taiwan.
   [Lin, Cheng-Wei] Kaohsiung Med Univ, Dept Biomed Sci & Environm Biol, Kaohsiung, Taiwan.
C3 Taipei Medical University; Taipei Medical University; Taipei Medical
   University; Chi Mei Hospital; Chia Nan University of Pharmacy & Science;
   National Sun Yat Sen University; Taipei Medical University; Kaohsiung
   Medical University
RP Lin, CW (corresponding author), Taipei Med Univ, Coll Med, Sch Med, Dept Biochem & Mol Cell Biol, 250 Wu Xing St, Taipei 11031, Taiwan.
EM cwlin@tmu.edu.tw
FU Ministry of Science and Technology, Taiwan [NSTC112-2320-B-038-046-MY3,
   MOST111-2320-B-038-019, MOST110-2320-B-038-021, MOST111-2314-B-038-081];
   Ministry of Science and Technology, Taiwan (T-Star Cancer Center)
   [NSTC113-2634-F-039-001]; Chi Mei Medical Center [110CM-TMU-01,
   111CM-TMU-01, 112CM-TMU-01]
FX This study was supported by grants from the Ministry of Science and
   Technology, Taiwan (NSTC112-2320-B-038-046-MY3, MOST111-2320-B-038-019,
   MOST110-2320-B-038-021, MOST111-2314-B-038-081, T-Star Cancer Center
   NSTC113-2634-F-039-001) and Chi Mei Medical Center (110CM-TMU-01,
   111CM-TMU-01, 112CM-TMU-01) .
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NR 49
TC 0
Z9 0
U1 17
U2 17
PU ACADEMIC PRESS LTD- ELSEVIER SCIENCE LTD
PI LONDON
PA 24-28 OVAL RD, LONDON NW1 7DX, ENGLAND
SN 1043-6618
EI 1096-1186
J9 PHARMACOL RES
JI Pharmacol. Res.
PD NOV
PY 2024
VL 209
AR 107429
DI 10.1016/j.phrs.2024.107429
EA SEP 2024
PG 14
WC Pharmacology & Pharmacy
WE Science Citation Index Expanded (SCI-EXPANDED)
SC Pharmacology & Pharmacy
GA H7B7V
UT WOS:001324964300001
PM 39306019
OA hybrid
DA 2025-03-13
ER

PT J
AU Niemiec, JA
   Adamczyk, A
   Ambicka, A
   Mucha-Malecka, A
   Wysocki, WM
   Rys, J
AF Niemiec, Joanna A.
   Adamczyk, Agnieszka
   Ambicka, Aleksandra
   Mucha-Malecka, Anna
   Wysocki, Wojciech M.
   Rys, Janusz
TI Triple-negative, Basal Marker-expressing, and High-grade Breast
   Carcinomas are Characterized by High Lymphatic Vessel Density and the
   Expression of Podoplanin in Stromal Fibroblasts
SO APPLIED IMMUNOHISTOCHEMISTRY & MOLECULAR MORPHOLOGY
LA English
DT Article
DE breast cancer; podoplanin; lymphatic vessel density; basal subtype;
   basal markers
ID CANCER-ASSOCIATED FIBROBLASTS; LYMPHOVASCULAR INVASION; MICROVESSEL
   DENSITY; POOR-PROGNOSIS; D2-40
AB Podoplanin, expressed in the lymphatic but not in the blood vessel endothelium, is widely used as a specific marker for lymphatic endothelial cells and lymphangiogenesis. The relation between lymphatic vessel density and breast cancer subtype or the expression of basal markers has not yet been investigated. We assessed lymphatic vessel density (LVD), blood vessel density, and the expression of podoplanin in stromal cancer-associated fibroblasts, in 156 invasive ductal breast cancers (T1, N1, M0). Afterwards, we assessed the relationship between the above-mentioned parameters and (i) breast cancer subtype (luminal vs. HER2 vs. triple negative), (ii) tumor grade (G1 vs. G2 vs. G3), (iii) the expression of cytokeratin (CK) 5/6, (iv) P-cadherin, (v) smooth muscle actin (SMA), and (vi) the pattern/intensity of stromal lymphocytic infiltration. We found a significantly higher LVD and podoplanin expression in stromal fibroblasts in (i) G3 tumors, (ii) triple-negative carcinomas, (iii) tumors expressing CK5/6, SMA, or P-cadherin, and (iv) neoplasms with stroma intensively infiltrated by lymphocytes. Moreover, we observed a significant inverse relationship between the expression of podoplanin in luminal A subtype, P-cadherin, CK5/6, and SMA-negative tumors and tumors without strong lymphocytic infiltration. A significantly higher percentage of tumors with strong lymphocytic infiltration was noted among G3 carcinomas. Breast carcinomas of different grades, subtypes, and basal marker expression are characterized by different composition of the stroma, that is different LVD, podoplanin expression in stromal fibroblasts, and the pattern/intensity of lymphocytic infiltration.
C1 [Niemiec, Joanna A.; Adamczyk, Agnieszka] Maria Sklodowska Curie Mem Inst Oncol, Ctr Oncol, Dept Appl Radiobiol, PL-31115 Krakow, Poland.
   [Ambicka, Aleksandra; Rys, Janusz] Maria Sklodowska Curie Mem Inst Oncol, Ctr Oncol, Dept Tumor Pathol, PL-31115 Krakow, Poland.
   [Mucha-Malecka, Anna] Maria Sklodowska Curie Mem Inst Oncol, Ctr Oncol, Dept Head & Neck Canc, PL-31115 Krakow, Poland.
   [Wysocki, Wojciech M.] Maria Sklodowska Curie Mem Inst Oncol, Ctr Oncol, Dept Surg Oncol, PL-31115 Krakow, Poland.
C3 Maria Sklodowska-Curie National Research Institute of Oncology; Maria
   Sklodowska-Curie National Research Institute of Oncology; Maria
   Sklodowska-Curie National Research Institute of Oncology; Maria
   Sklodowska-Curie National Research Institute of Oncology
RP Niemiec, JA (corresponding author), Maria Sklodowska Curie Mem Inst Oncol, Cracow Branch, Dept Appl Radiobiol, Ctr Oncol, Ul Garncarska 11, PL-31115 Krakow, Poland.
EM joanna@eikon.pl
RI Mucha-Małecka, Anna/GLR-2846-2022
OI Adamczyk, Agnieszka/0000-0002-0567-5731; Niemiec,
   Joanna/0000-0001-9403-7119; Mucha-Malecka, Anna/0000-0003-3135-1199
FU Polish Ministry of Science and Higher Education [NN 401 096 137]
FX Supported by Polish Ministry of Science and Higher Education; Grant
   number NN 401 096 137.
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NR 30
TC 17
Z9 18
U1 2
U2 11
PU LIPPINCOTT WILLIAMS & WILKINS
PI PHILADELPHIA
PA TWO COMMERCE SQ, 2001 MARKET ST, PHILADELPHIA, PA 19103 USA
SN 1541-2016
EI 1533-4058
J9 APPL IMMUNOHISTO M M
JI Appl. Immunohistochem.
PD JAN
PY 2014
VL 22
IS 1
BP 10
EP 16
DI 10.1097/PAI.0b013e318286030d
PG 7
WC Anatomy & Morphology; Medical Laboratory Technology; Pathology
WE Science Citation Index Expanded (SCI-EXPANDED)
SC Anatomy & Morphology; Medical Laboratory Technology; Pathology
GA 278IM
UT WOS:000328882800002
PM 23455186
DA 2025-03-13
ER

PT J
AU Li, Z
   Yu, JY
   Lv, CL
   Luo, ZH
AF Li, Zan
   Yu, Junyi
   Lv, Chunliu
   Luo, Zhenhua
TI Cancer-associated fibroblasts-derived lncRNA signature as a putative
   biomarker in breast cancer
SO FRONTIERS IN ONCOLOGY
LA English
DT Article
DE immunotherapy; lncRNA; prognosis; cancer-associated fibroblasts; breast
   cancer
ID MICROENVIRONMENT; PROLIFERATION; CAVEOLIN-1; MUTATIONS
AB Long noncoding RNAs (lncRNAs) have been reported to play a key role in regulating tumor microenvironment and immunity. Cancer-associated fibroblasts (CAFs) are abundant in many tumors. However, the functional and clinical significance of lncRNAs specifically expressed in CAFs has not been fully elucidated. In this study, we identified a list of 95 CAF-specific lncRNAs (FibLnc), including HHLA3, TP53TG1, ST7-AS1, LINC00536, ZNF503-AS1, MIR22HG, and MAPT-AS1, based on immune cell transcriptome expression profiling data. Based on the Cancer Genome Atlas and Gene Expression Omnibus datasets, we found that the FibLnc score predicted differences in overall patient survival and performed well in multiple datasets. FibLnc score was associated with the clinical stage of patients with breast cancer but did not significantly correlate with the PAM50 classification. Functional analysis showed that FibLnc was positively correlated with signaling pathways associated with malignant tumor progression. In addition, FibLnc was positively correlated with tumor mutational load and could predict immunotherapy response in patients with breast cancer receiving anti-PD-1 or anti-CTLA4 therapy. Our proposed FibLnc score was able to reflect the status of the immune environment and immunotherapeutic response in breast cancer, which could help explore potential therapeutic decisions and regulatory mechanisms of CAF-specific lncRNAs.
C1 [Li, Zan; Yu, Junyi; Lv, Chunliu; Luo, Zhenhua] Cent South Univ, Hunan Canc Hosp, Affiliated Canc Hosp, Dept Oncol Plast Surg,Xiangya Med Sch, Changsha, Hunan, Peoples R China.
C3 Central South University
RP Luo, ZH (corresponding author), Cent South Univ, Hunan Canc Hosp, Affiliated Canc Hosp, Dept Oncol Plast Surg,Xiangya Med Sch, Changsha, Hunan, Peoples R China.
EM luozhenhua@hnca.org.cn
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NR 43
TC 5
Z9 5
U1 0
U2 10
PU FRONTIERS MEDIA SA
PI LAUSANNE
PA AVENUE DU TRIBUNAL FEDERAL 34, LAUSANNE, CH-1015, SWITZERLAND
SN 2234-943X
J9 FRONT ONCOL
JI Front. Oncol.
PD NOV 2
PY 2022
VL 12
AR 1028664
DI 10.3389/fonc.2022.1028664
PG 11
WC Oncology
WE Science Citation Index Expanded (SCI-EXPANDED)
SC Oncology
GA 6H7QC
UT WOS:000885628100001
PM 36408190
OA Green Published, gold
DA 2025-03-13
ER

PT J
AU Ershaid, N
   Sharon, Y
   Doron, H
   Raz, Y
   Shani, O
   Cohen, N
   Monteran, L
   Leider-Trejo, L
   Ben-Shmuel, A
   Yassin, M
   Gerlic, M
   Ben-Baruch, A
   Pasmanik-Chor, M
   Apte, R
   Erez, N
AF Ershaid, Nour
   Sharon, Yoray
   Doron, Hila
   Raz, Yael
   Shani, Ophir
   Cohen, Noam
   Monteran, Lea
   Leider-Trejo, Leonor
   Ben-Shmuel, Amir
   Yassin, Muhammad
   Gerlic, Motti
   Ben-Baruch, Adit
   Pasmanik-Chor, Metsada
   Apte, Roni
   Erez, Neta
TI NLRP3 inflammasome in fibroblasts links tissue damage with inflammation
   in breast cancer progression and metastasis
SO NATURE COMMUNICATIONS
LA English
DT Article
ID CARCINOMA-ASSOCIATED FIBROBLASTS; TUMOR PROGRESSION; SUPPRESSOR-CELLS;
   GROWTH; EXPRESSION; OSTEOPONTIN; ACTIVATION; SECRETION; FIBROSIS
AB Cancer-Associated Fibroblasts (CAFs) were shown to orchestrate tumour-promoting inflammation in multiple malignancies, including breast cancer. However, the molecular pathways that govern the inflammatory role of CAFs are poorly characterised. In this study we found that fibroblasts sense damage-associated molecular patterns (DAMPs), and in response activate the NLRP3 inflammasome pathway, resulting in instigation of proinflammatory signalling and secretion of IL-1 beta. This upregulation was evident in CAFs in mouse and in human breast carcinomas. Moreover, CAF-derived inflammasome signalling facilitated tumour growth and metastasis, which was attenuated when NLRP3 or IL-1 beta were specifically ablated. Functionally, CAF-derived inflammasome promoted tumour progression and metastasis by modulating the tumour microenvironment towards an immune suppressive milieu and by upregulating the expression of adhesion molecules on endothelial cells. Our findings elucidate a mechanism by which CAFs promote breast cancer progression and metastasis, by linking the physiological tissue damage response of fibroblasts with tumour-promoting inflammation.
C1 [Ershaid, Nour; Sharon, Yoray; Doron, Hila; Raz, Yael; Shani, Ophir; Cohen, Noam; Monteran, Lea; Yassin, Muhammad; Erez, Neta] Tel Aviv Univ, Sackler Fac Med, Dept Pathol, Tel Aviv, Israel.
   [Raz, Yael] Tel Aviv Sourasky Med Ctr, Dept Obstet & Gynecol, Tel Aviv, Israel.
   [Leider-Trejo, Leonor] Tel Aviv Univ, Tel Aviv Sourasky Med Ctr, Dept Pathol, Tel Aviv, Israel.
   [Ben-Shmuel, Amir] Israel Inst Biol Res, Dept Infect Dis, Ness Ziona, Israel.
   [Gerlic, Motti] Tel Aviv Univ, Sackler Fac Med, Dept Clin Microbiol & Immunol, Tel Aviv, Israel.
   [Ben-Baruch, Adit] Tel Aviv Univ, Dept Cell Res & Immunol, Tel Aviv, Israel.
   [Pasmanik-Chor, Metsada] Tel Aviv Univ, George S Wise Fac Life Sci, Bioinformat Unit, Tel Aviv, Israel.
   [Apte, Roni] Ben Gurion Univ Negev, Shraga Segal Dept Microbiol Immunol & Genet, Beer Sheva, Israel.
C3 Tel Aviv University; Sackler Faculty of Medicine; Tel Aviv University;
   Sackler Faculty of Medicine; Tel Aviv Sourasky Medical Center; Tel Aviv
   University; Sackler Faculty of Medicine; Tel Aviv Sourasky Medical
   Center; Tel Aviv University; Sackler Faculty of Medicine; Tel Aviv
   University; Tel Aviv University; Ben Gurion University
RP Erez, N (corresponding author), Tel Aviv Univ, Sackler Fac Med, Dept Pathol, Tel Aviv, Israel.
EM netaerez@tauex.tau.ac.il
RI Erez, Neta/G-8584-2012; gerlic, mordechay/U-3484-2017
OI Yassin, Muhammad/0000-0002-3900-0775; gerlic,
   mordechay/0000-0001-9518-1833; Erez, Neta/0000-0001-6506-9074; Cohen,
   Noam/0009-0003-7047-8843; Monteran, Lea/0000-0002-7633-2090; Ershaid,
   Nour/0000-0002-6422-7728; Ben-Shmuel, Amir/0009-0001-7216-937X
FU European Research Council (ERC) under the European Union [637069];
   Israel Science Foundation [813/12]; Israel Cancer Association; Israel
   Cancer Research Fund; European Research Council (ERC) [637069] Funding
   Source: European Research Council (ERC)
FX This research was supported by grants to N.E. from the European Research
   Council (ERC) under the European Union's Horizon 2020 research and
   innovation programme (grant agreement No. 637069 MetCAF), from the
   Israel Science Foundation (#813/12), the Israel Cancer Association, and
   The Israel Cancer Research Fund (Research Career Development Award and
   Project Grant). We thank Ms. Hadar Cohen for her help with the revision
   process.
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NR 70
TC 213
Z9 224
U1 3
U2 49
PU NATURE PUBLISHING GROUP
PI LONDON
PA MACMILLAN BUILDING, 4 CRINAN ST, LONDON N1 9XW, ENGLAND
SN 2041-1723
J9 NAT COMMUN
JI Nat. Commun.
PD SEP 26
PY 2019
VL 10
AR 4375
DI 10.1038/s41467-019-12370-8
PG 15
WC Multidisciplinary Sciences
WE Science Citation Index Expanded (SCI-EXPANDED)
SC Science & Technology - Other Topics
GA JB0FR
UT WOS:000488227700004
PM 31558756
OA Green Published, gold
HC Y
HP N
DA 2025-03-13
ER

PT J
AU Chen, Y
   Zeng, C
   Zhan, Y
   Wang, H
   Jiang, X
   Li, W
AF Chen, Y.
   Zeng, C.
   Zhan, Y.
   Wang, H.
   Jiang, X.
   Li, W.
TI Aberrant low expression of p85α in stromal fibroblasts promotes breast
   cancer cell metastasis through exosome-mediated paracrine Wnt10b
SO ONCOGENE
LA English
DT Article
ID PHOSPHOINOSITIDE 3-KINASES; TUMOR-SUPPRESSOR; PI3K PATHWAY; TGF-BETA;
   ACQUISITION; GROWTH; TUMORIGENESIS; TRANSITIONS; ACTIVATION; MUTATIONS
AB P85 alpha, which acts as a tumour suppressor, is frequently found to be downregulated in various human cancers. However, the role of p85 alpha in the tumour microenvironment is unknown. Here, we report that aberrantly low expression of p85 alpha in breast cancer stroma is clinically relevant to breast cancer disease progression. Stromal fibroblasts can acquire the hallmarks of cancer-associated fibroblasts (CAFs) as a result of the loss of p85 alpha expression. Paracrine Wnt10b from p85 alpha-deficient fibroblasts can promote cancer progression via epithelial-to-mesenchymal transition (EMT) induced by the canonical Wnt pathway. Moreover, exosomes have a key role in paracrine Wnt10b transport from fibroblasts to breast cancer epithelial cells. Our results reveal that p85 alpha expression in stromal fibroblasts haves a crucial role in regulating breast cancer tumourigenesis and progression by modifying stromal-epithelial crosstalk and remodelling the tumour microenvironment. Therefore, p85 alpha can function as a tumour suppressor and represent a new candidate for diagnosis, prognosis and targeted therapy.
C1 [Chen, Y.; Zeng, C.; Zhan, Y.; Wang, H.; Li, W.] Wuhan Univ, Coll Life Sci, Hubei Key Lab Cell Homeostasis, Wuhan 430072, Hubei, Peoples R China.
   [Jiang, X.] Huazhong Univ Sci & Technol, Sch Life Sci & Technol, Sinofrance Lab Drug Screening, Key Lab Mol Biophys,Minist Educ, Wuhan, Hubei, Peoples R China.
C3 Wuhan University; Huazhong University of Science & Technology
RP Li, W (corresponding author), Wuhan Univ, Coll Life Sci, Hubei Key Lab Cell Homeostasis, Wuhan 430072, Hubei, Peoples R China.
EM whli@whu.edu.cn
FU National Basic Research Program of China [2014CB910603]; National
   Natural Science Foundation of China [81472684, 81072151]; Program for
   New Century Excellent Talents in University of Ministry of Education of
   China [NCET-13-0436]
FX We thank Professor Lewis C Cantley for the gift of the knockout cell
   lines. This study was supported by National Basic Research Program of
   China (2014CB910603), the National Natural Science Foundation of China
   (81472684, 81072151) and Program for New Century Excellent Talents in
   University of Ministry of Education of China (NCET-13-0436).
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NR 56
TC 100
Z9 109
U1 1
U2 14
PU SPRINGERNATURE
PI LONDON
PA CAMPUS, 4 CRINAN ST, LONDON, N1 9XW, ENGLAND
SN 0950-9232
EI 1476-5594
J9 ONCOGENE
JI Oncogene
PD AUG 17
PY 2017
VL 36
IS 33
BP 4692
EP 4705
DI 10.1038/onc.2017.100
PG 14
WC Biochemistry & Molecular Biology; Oncology; Cell Biology; Genetics &
   Heredity
WE Science Citation Index Expanded (SCI-EXPANDED)
SC Biochemistry & Molecular Biology; Oncology; Cell Biology; Genetics &
   Heredity
GA FD7JM
UT WOS:000407702400003
PM 28394344
OA Green Published, hybrid
DA 2025-03-13
ER

PT J
AU Chang, YH
   Ngo, NH
   Vuong, CK
   Yamashita, T
   Osaka, M
   Hiramatsu, Y
   Ohneda, O
AF Chang, Yun-Hsuan
   Ngo, Nhat-Hoang
   Vuong, Cat-Khanh
   Yamashita, Toshiharu
   Osaka, Motoo
   Hiramatsu, Yuji
   Ohneda, Osamu
TI Type 2 Diabetes Mellitus Promotes the Differentiation of Adipose
   Tissue-Derived Mesenchymal Stem Cells into Cancer-Associated
   Fibroblasts, Induced by Breast Cancer Cells
SO STEM CELLS AND DEVELOPMENT
LA English
DT Article
DE triple-negative breast cancer; metastasis; cancer-associated
   fibroblasts; adipose tissue-derived mesenchymal stem cells; type 2
   diabetes
ID CARCINOMA-ASSOCIATED FIBROBLASTS; PROGRESSION; METASTASIS
AB Triple-negative breast cancer (TNBC) is a highly aggressive and invasive type of breast cancer. In addition, type 2 diabetes mellitus (T2DM) is recognized as a risk factor for cancer metastasis, which is associated with mortality in patients with breast cancer. Cancer-associated fibroblasts (CAFs) generated from adipose tissue-derived mesenchymal stem cells (AT-MSCs) play a vital role in the progression of TNBC. However, to date, whether T2DM affects the ability of AT-MSCs to differentiate into CAFs is still unclear. In this study, we found that in coculture with TNBC cells [breast cancer cells (BCCs)] under hypoxic conditions, AT-MSCs derived from T2DM donors (dAT-MSCs) were facilitated to differentiate into CAFs, which showed fibroblastic morphology and the induced expression of fibroblastic markers, such as fibroblast activation protein, fibroblast-specific protein, and vimentin. This was involved in the higher expression of transforming growth factor beta receptor 2 (TGF beta R2) and the phosphorylation of Smad2/3. Furthermore, T2DM affected the fate and functions of CAFs derived from dAT-MSCs. While CAFs derived from AT-MSCs of healthy donors (AT-CAFs) exhibited the markers of inflammatory CAFs, those derived from dAT-MSCs (dAT-CAFs) showed the markers of myofibroblastic CAFs. Of note, in comparison with AT-CAFs, dAT-CAFs showed a higher ability to induce the proliferation and in vivo metastasis of BCCs, which was involved in the activation of the transforming growth factor beta (TGF beta)-Smad2/3 signaling pathway. Collectively, our study suggests that T2DM contributes to metastasis of BCCs by inducing the myofibroblastic CAFs differentiation of dAT-MSCs. In addition, targeting the TGF beta-Smad2/3 signaling pathway in dAT-MSCs may be useful in cancer therapy for TNBC patients with T2DM.
C1 [Chang, Yun-Hsuan; Ngo, Nhat-Hoang; Vuong, Cat-Khanh; Yamashita, Toshiharu; Ohneda, Osamu] Univ Tsukuba, Grad Sch Comprehens Human Sci, Lab Regenerat Med & Stem Cell Biol, Tsukuba, Japan.
   [Osaka, Motoo; Hiramatsu, Yuji] Univ Tsukuba, Dept Cardiovasc Surg, Tsukuba, Japan.
   [Ohneda, Osamu] Univ Tsukuba, Grad Sch Comprehens Human Sci, Lab Regenerat Med & Stem Cell Biol, 1-1-1 Tennoudai, Tsukuba, 3058575, Japan.
C3 University of Tsukuba; University of Tsukuba; University of Tsukuba
RP Ohneda, O (corresponding author), Univ Tsukuba, Grad Sch Comprehens Human Sci, Lab Regenerat Med & Stem Cell Biol, 1-1-1 Tennoudai, Tsukuba, 3058575, Japan.
EM oohneda@md.tsukuba.ac.jp
RI Chang, Hui/AGD-4270-2022
OI Vuong, Cat-Khanh/0000-0002-9252-181X
FU Grants-in-Aid for Scientific Research [21K06964] Funding Source: KAKEN
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NR 50
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U1 0
U2 12
PU MARY ANN LIEBERT, INC
PI NEW ROCHELLE
PA 140 HUGUENOT STREET, 3RD FL, NEW ROCHELLE, NY 10801 USA
SN 1547-3287
EI 1557-8534
J9 STEM CELLS DEV
JI Stem Cells Dev.
PD NOV 1
PY 2022
VL 31
IS 21-22
BP 659
EP 671
DI 10.1089/scd.2022.0086
EA JUL 2022
PG 13
WC Cell & Tissue Engineering; Hematology; Medicine, Research &
   Experimental; Transplantation
WE Science Citation Index Expanded (SCI-EXPANDED)
SC Cell Biology; Hematology; Research & Experimental Medicine;
   Transplantation
GA 6D2GY
UT WOS:000836904800001
PM 35734905
DA 2025-03-13
ER

PT J
AU Zheng, F
   Luo, YJ
   Liu, YQ
   Gao, YY
   Chen, WY
   Wei, K
AF Zheng, Fang
   Luo, Yujia
   Liu, Yuanqi
   Gao, Yuanyuan
   Chen, Wenyu
   Wei, Kun
TI Nano-baicalein facilitates chemotherapy in breast cancer by targeting
   tumor microenvironment
SO INTERNATIONAL JOURNAL OF PHARMACEUTICS
LA English
DT Article
DE Tumor microenvironment; Baicalein; Nanoparticles; Triple -negative
   breast cancer; Cancer -associated fibroblasts
ID DELIVERY; CELLS; PLGA; NANOPARTICLES; MYOFIBROBLAST; FIBROBLASTS;
   FIBROSIS; PH; DEGRADATION; PATHWAYS
AB Cancer-associated fibroblasts constitute a significant component in the tumor microenvironment, playing a pivotal role in tumor proliferation, invasion, migration, and metastasis. Consequently, therapy combining chemotherapeutic agents with tumor microenvironment (TME) modulators appears to be a promising avenue for cancer treatment. In this paper, a tumor microenvironment-based mPEG-PLGA nanoparticle loaded with bai-calein (PMs-Ba) was constructed for the purpose of improving the tumor microenvironment in cases of triple -negative breast cancer. The results demonstrate that, on the one hand, PMs-Ba was able to inhibit the trans-forming growth factor 13(TGF-13) signaling pathway to avoid the activation of cancer-associated fibroblasts (CAFs), thereby influencing the interstitial microenvironment of the tumor. On the other hand, the agent led to an increase in the infiltration of cytotoxic T cells, activating the tumor immune microenvironment. Meanwhile, in the murine breast cancer model, an intravenous injection of PMs-Ba combined with doxorubicin nanoparticles (PMs-ADM) significantly improved the antitumor effectiveness. These results suggest that baicalein encapsulated in nanoparticles may be a promising strategy for modulating the TME and for adjuvant chemotherapy, signifying a potential TME-remodeling nanoformulation that could enhance the antitumor efficacy of nanotherapeutics.
C1 [Zheng, Fang; Luo, Yujia; Liu, Yuanqi; Gao, Yuanyuan; Chen, Wenyu; Wei, Kun] South China Univ Technol, Sch Biosci & Bioengn, Guangzhou 510006, Peoples R China.
C3 South China University of Technology
RP Wei, K (corresponding author), South China Univ Technol, Sch Biosci & Bioengn, Guangzhou 510006, Peoples R China.
EM 201921047371@mail.scut.edu.cn; lyjparisny@163.com; yuanqi.l@foxmail.com;
   594871494@qq.com; dcwy11@163.com; weikun@scut.edu.cn
RI Chen, Wenyu/IQV-0732-2023; gao, yuanyuan/GSE-5627-2022
OI zheng, fang/0000-0002-5768-7806
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NR 69
TC 11
Z9 12
U1 7
U2 45
PU ELSEVIER
PI AMSTERDAM
PA RADARWEG 29, 1043 NX AMSTERDAM, NETHERLANDS
SN 0378-5173
EI 1873-3476
J9 INT J PHARMACEUT
JI Int. J. Pharm.
PD MAR 25
PY 2023
VL 635
AR 122778
DI 10.1016/j.ijpharm.2023.122778
EA FEB 2023
PG 11
WC Pharmacology & Pharmacy
WE Science Citation Index Expanded (SCI-EXPANDED)
SC Pharmacology & Pharmacy
GA 9X8AL
UT WOS:000949987600001
PM 36842519
DA 2025-03-13
ER

PT J
AU Wang, LY
   Hou, YX
   Sung, Y
   Zhao, LY
   Tang, X
   Hu, P
   Yang, JJ
   Zeng, ZY
   Yang, GL
   Cui, XJ
   Liu, MR
AF Wang, Liyang
   Hou, Yixuan
   Sung, Yan
   Zhao, Liuyang
   Tang, Xi
   Hu, Ping
   Yang, Jiajia
   Zeng, Zongyue
   Yang, Guanglun
   Cui, Xiaojiang
   Liu, Manran
TI c-Ski activates cancer-associated fibroblasts to regulate breast cancer
   cell invasion
SO MOLECULAR ONCOLOGY
LA English
DT Article
DE CAFs; c-Ski; P53; SDF-1; Tumor microenvironment
ID PROMOTES TUMOR-GROWTH; STROMAL FIBROBLASTS; TGF-BETA; EXPRESSION;
   REPRESSION; RECEPTOR; MYOFIBROBLASTS; OVEREXPRESSION; TUMORIGENESIS;
   PROGRESSION
AB Aberrant expression of c-Ski oncoprotein in some tumor cells has been shown to be associated with cancer development. However, the role of c-Ski in cancer-associated fibroblasts (CAFs) of tumor microenvironment has not been characterized. In the current study, we found that c-Ski is highly expressed in CAFs derived from breast carcinoma microenvironment and this CAF-associated c-Ski expression is associated with invasion and metastasis of human breast tumors. We showed that c-Ski overexpression in immortalized breast normal fibroblasts (NFs) induces conversion to breast CAFs by repressing p53 and thereby upregulating SDF-1 in NFs. SDF-1 treatment or p53 knockdown in NFs had similar effects on the activation of NFs as c-Ski overexpression. The c-Ski-activated CAFs show increased proliferation, migration, invasion and contraction compared with NFs. Furthermore, c-Ski-activated CAFs facilitated the migration and invasion of MDA-MB-231 breast cancer cells. Our data suggest that c-Ski is an important regulator in the activation of CAFs and may serve as a potential therapeutic target to block breast cancer progression. (C) 2013 Federation of European Biochemical Societies. Published by Elsevier B.V. All rights reserved.
C1 [Wang, Liyang; Hou, Yixuan; Sung, Yan; Zhao, Liuyang; Tang, Xi; Hu, Ping; Yang, Jiajia; Zeng, Zongyue; Liu, Manran] Chongqing Med Univ, Key Lab Lab Med Diagnost, Chinese Minist Educ, Chongqing 400016, Peoples R China.
   [Hou, Yixuan] Chongqing Med Univ, Experimental Teaching Ctr Basic Med Sci, Chongqing 400016, Peoples R China.
   [Yang, Guanglun] Chongqing Med Univ, Affiliated Hosp 1, Dept Endocrine & Breast Surg, Chongqing 400016, Peoples R China.
   [Cui, Xiaojiang] Cedars Sinai Med Ctr, Dept Surg, Samuel Oschin Comprehens Canc Inst, Womens Canc Program, Los Angeles, CA 91006 USA.
   [Cui, Xiaojiang] Cedars Sinai Med Ctr, Dept Obstet & Gynecol, Samuel Oschin Comprehens Canc Inst, Womens Canc Program, Los Angeles, CA 91006 USA.
C3 Chongqing Medical University; Chongqing Medical University; Chongqing
   Medical University; Cedars Sinai Medical Center; Cedars Sinai Medical
   Center
RP Liu, MR (corresponding author), Chongqing Med Univ, Key Lab Lab Med Diagnost, Chinese Minist Educ, 1 Yi Xue Yuan Rd, Chongqing 400016, Peoples R China.
EM mliu-hncq@hotmail.com
OI Zeng, Zongyue/0000-0002-4333-5412; Sun, Yan/0000-0003-2595-0961
FU National Natural Science Foundation of China [NSFC 81072147, NSFC
   30940096]; Natural Science Foundation of Chongqing Science & Technology
   Commission, China [CSTC2010BB5099]; Ministry of Education, China
   [20105503110001]; Scientific Research Foundation for the Returned
   Overseas Chinese Scholars, Ministry of Education, China [[2011]508];
   Major Program of Chongqing Medical University [XBZD201006]; Scientific
   Research Foundation for the Returned Overseas Scholars of Chongqing
   Medical University; National Institutes of Health [R01CA151610]; Avon
   Foundation [02-2010-068]
FX This work was supported in part by National Natural Science Foundation
   of China (NSFC 81072147, NSFC 30940096); Natural Science Foundation of
   Chongqing Science & Technology Commission, China (CSTC2010BB5099); the
   Doctoral Fund of Ministry of Education, China (20105503110001); the
   Scientific Research Foundation for the Returned Overseas Chinese
   Scholars, Ministry of Education, China ([2011]508); the Major Program of
   Chongqing Medical University XBZD201006; and the Scientific Research
   Foundation for the Returned Overseas Scholars of Chongqing Medical
   University; and supported from National Institutes of Health
   (R01CA151610) and Avon Foundation (02-2010-068) to Xiaojiang Cui.
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NR 45
TC 42
Z9 47
U1 0
U2 20
PU ELSEVIER SCI LTD
PI OXFORD
PA THE BOULEVARD, LANGFORD LANE, KIDLINGTON, OXFORD OX5 1GB, OXON, ENGLAND
SN 1574-7891
EI 1878-0261
J9 MOL ONCOL
JI Mol. Oncol.
PD DEC
PY 2013
VL 7
IS 6
BP 1116
EP 1128
DI 10.1016/j.molonc.2013.08.007
PG 13
WC Oncology
WE Science Citation Index Expanded (SCI-EXPANDED)
SC Oncology
GA 268NA
UT WOS:000328176400011
PM 24011664
OA Green Accepted, Green Published
DA 2025-03-13
ER

PT J
AU Li, Y
   Zhao, ZH
   Liu, W
   Li, X
AF Li, Yan
   Zhao, Zhenhui
   Liu, Wei
   Li, Xun
TI SNHG3 Functions as miRNA Sponge to Promote Breast Cancer Cells Growth
   Through the Metabolic Reprogramming
SO APPLIED BIOCHEMISTRY AND BIOTECHNOLOGY
LA English
DT Article
DE SNHG3; Cancer-associated; Fibroblasts; miR-330; Metabolism reprogram;
   Breast cancer
ID EMERGING ROLE; NONCODING RNAS; LNCRNA
AB Cancer-associated fibroblasts (CAFs) are important ingredient in tumor microenvironment. The dynamic interplay between CAFs and cancer cells plays essential roles during tumor development and progression. However, the mechanisms of intercellular communication between CAFs and cancer cells remain largely unknown. We characterized exosomes secreted from breast cancer patient-derived CAFs by transmission electron microscopy. The expression of SNHG3, miR-330-5p, and PKM (Pyruvate Kinase M1/M2) was examined by real-time QPCR and immunoblot. The function of SNHG3 on the growth and metabolism of tumor cells was used by CCK8 and mitochondrial oxygen consumption assays. The binding between SNHG3, miR-330-5p, and PKM was examined by dual luciferase reporter assays. Orthotopical xenograft of breast tumor experiments was performed to determine the function of SNHG3 in vivo. We demonstrated that exosomes secreted from CAFs reprogram the metabolic pathways after tumor cells uptake the exosomes. CAF-secreted exosomal lncRNA SNHG3 served as a molecular sponge for miR-330-5p in breast cancer cells. Moreover, PKM could be targeted by miR-330-5p and was controlled by SNHG3 in breast cancer cells. Mechanistically, SNHG3 knockdown in CAF-secreted exosomes suppressed glycolysis metabolism and cell proliferation by the increase of miR-330-5p and decrease of PKM expression in tumor cells. SNHG3 functions as a miR-330-5p sponge to positively regulate PKM expression, inhibit mitochondrial oxidative phosphorylation, increase glycolysis carboxylation, and enhance breast tumor cell proliferation. Overall, SNHG3 could play a major role in the development and progression of breast cancer and support the therapeutic potential of targeting communication between cancer cells and tumor microenvironment.
C1 [Li, Yan; Zhao, Zhenhui; Liu, Wei; Li, Xun] XinJiang Med Univ, Affiliated Teaching Hosp 3, Breast Internal Med Dept, Affiliated Canc Hosp, Urumqi 830011, Peoples R China.
C3 Xinjiang Medical University
RP Li, X (corresponding author), XinJiang Med Univ, Affiliated Teaching Hosp 3, Breast Internal Med Dept, Affiliated Canc Hosp, Urumqi 830011, Peoples R China.
EM francebyme112@aliyun.com; mickgotback@aliyun.com; q417955104@163.com;
   lxxjmu@163.com
FU Natural Science Foundation of Xinjiang Uygur Autonomous Region
   [2019D01C258]
FX This work was supported by The Natural Science Foundation of Xinjiang
   Uygur Autonomous Region (2019D01C258).
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NR 28
TC 106
Z9 111
U1 0
U2 15
PU SPRINGER
PI NEW YORK
PA ONE NEW YORK PLAZA, SUITE 4600, NEW YORK, NY, UNITED STATES
SN 0273-2289
EI 1559-0291
J9 APPL BIOCHEM BIOTECH
JI Appl. Biochem. Biotechnol.
PD JUL
PY 2020
VL 191
IS 3
BP 1084
EP 1099
DI 10.1007/s12010-020-03244-7
EA JAN 2020
PG 16
WC Biochemistry & Molecular Biology; Biotechnology & Applied Microbiology
WE Science Citation Index Expanded (SCI-EXPANDED)
SC Biochemistry & Molecular Biology; Biotechnology & Applied Microbiology
GA MC7EB
UT WOS:000507960700003
PM 31956955
OA hybrid, Green Published
DA 2025-03-13
ER

PT J
AU Chen, IX
   Chauhan, VP
   Posada, J
   Ng, MR
   Wu, MW
   Adstamongkonkul, P
   Huang, PG
   Lindeman, N
   Langer, R
   Jain, RK
AF Chen, Ivy X.
   Chauhan, Vikash P.
   Posada, Jessica
   Ng, Mei R.
   Wu, Michelle W.
   Adstamongkonkul, Pichet
   Huang, Peigen
   Lindeman, Neal
   Langer, Robert
   Jain, Rakesh K.
TI Blocking CXCR4 alleviates desmoplasia, increases T-lymphocyte
   infiltration, and improves immunotherapy in metastatic breast cancer
SO PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF
   AMERICA
LA English
DT Article
DE tumor microenvironment; metastatic breast cancer; immune checkpoint
   blockade; tumor desmoplasia; carcinoma-associated fibroblasts
ID MAMMARY CARCINOMAS; TUMOR-GROWTH; FIBROBLASTS; CELLS; BLOCKADE;
   SURVIVAL; STROMA; ANGIOGENESIS; RESISTANCE; ABROGATION
AB Metastatic breast cancers (mBCs) are largely resistant to immune checkpoint blockade, but the mechanisms remain unclear. Primary breast cancers are characterized by a dense fibrotic stroma, which is considered immunosuppressive in multiple malignancies, but the stromal composition of breast cancer metastases and its role in immunosuppression are largely unknown. Here we show that liver and lung metastases of human breast cancers tend to be highly fibrotic, and unlike primary breast tumors, they exclude cytotoxic T lymphocytes (CTLs). Unbiased analysis of the The Cancer Genome Atlas database of human breast tumors revealed a set of genes that are associated with stromal T-lymphocyte exclusion. Among these, we focused on CXCL12 as a relevant target based on its known roles in immunosuppression in other cancer types. We found that the CXCL12 receptor CXCR4 is highly expressed in both human primary tumors and metastases. To gain insight into the role of the CXCL12/CXCR4 axis, we inhibited CXCR4 signaling pharmacologically and found that plerixafor decreases fibrosis, alleviates solid stress, decompresses blood vessels, increases CTL infiltration, and decreases immunosuppression in murine mBC models. By deleting CXCR4 in alpha SMA(+) cells, we confirmed that these immunosuppressive effects are dependent on CXCR4 signaling in alpha SMA(+) cells, which include cancer-associated fibroblasts as well as other cells such as pericytes. Accordingly, CXCR4 inhibition more than doubles the response to immune checkpoint blockers in mice bearing mBCs. These findings demonstrate that CXCL12/CXCR4-mediated desmoplasia in mBC promotes immunosuppression and is a potential target for overcoming therapeutic resistance to immune checkpoint blockade in mBC patients.
C1 [Chen, Ivy X.; Chauhan, Vikash P.; Posada, Jessica; Ng, Mei R.; Wu, Michelle W.; Huang, Peigen; Jain, Rakesh K.] Massachusetts Gen Hosp, Dept Radiat Oncol, Edwin L Steele Labs, Boston, MA 02114 USA.
   [Chen, Ivy X.; Chauhan, Vikash P.; Posada, Jessica; Ng, Mei R.; Wu, Michelle W.; Huang, Peigen; Jain, Rakesh K.] Harvard Med Sch, Boston, MA 02114 USA.
   [Chen, Ivy X.; Chauhan, Vikash P.; Langer, Robert] MIT, Koch Inst Integrat Canc Res, 77 Massachusetts Ave, Cambridge, MA 02139 USA.
   [Chen, Ivy X.; Adstamongkonkul, Pichet] Harvard Univ, Harvard Sch Engn & Appl Sci, Cambridge, MA 02138 USA.
   [Posada, Jessica; Lindeman, Neal] Brigham & Womens Hosp, Dept Pathol, 75 Francis St, Boston, MA 02115 USA.
   [Langer, Robert] MIT, Dept Chem Engn, Cambridge, MA 02139 USA.
C3 Harvard University; Harvard University Medical Affiliates; Massachusetts
   General Hospital; Harvard University; Harvard Medical School;
   Massachusetts Institute of Technology (MIT); Harvard University; Harvard
   University; Harvard University Medical Affiliates; Brigham & Women's
   Hospital; Massachusetts Institute of Technology (MIT)
RP Jain, RK (corresponding author), Massachusetts Gen Hosp, Dept Radiat Oncol, Edwin L Steele Labs, Boston, MA 02114 USA.; Jain, RK (corresponding author), Harvard Med Sch, Boston, MA 02114 USA.
EM jain@steele.mgh.harvard.edu
RI Wu, Michelle/GRJ-2091-2022; Chen, Ivy/N-8231-2019; Jain,
   Rakesh/I-1384-2017; Chauhan, Vikash/H-8172-2013
OI Chauhan, Vikash/0000-0001-9126-2302; Adstamongkonkul,
   Pichet/0000-0002-6530-2398; Posada, Jessica/0000-0002-9056-0735; Wu,
   Michelle/0000-0002-1969-5792; Langer, Robert/0000-0003-4255-0492
FU National Foundation for Cancer Research; Ludwig Center at Harvard;
   Jane's Trust Foundation; National Cancer Institute (NCI) [P01-CA080124,
   R01-CA098706, R01-CA208205, U01-CA224348]; Department of Defense Breast
   Cancer Research Program Innovator Award [W81XWH-10-1-0016]; NCI
   [R35-CA197743]; Misrock Foundation; NIH [T32HL007627, F32-CA073479];
   Gates Graduate Fellowship; Department of Defense Breast Cancer Research
   Program Postdoctoral Fellowship [W81XWH-14-1-0034]; Simeon J. Fortin
   Charitable Foundation Postdoctoral Fellowship
FX We thank Julia Kahn, Sylvie Roberge, and Carolyn Smith for technical
   assistance and Drs. Meenal Datta, Dan G. Duda, Dai Fukumura, Takahiro
   Heishi, Louis Larrouquere, Hao Liu, John Martin, Ethel Pereira, and
   David Tuveson for their help. This research was supported by grants from
   the National Foundation for Cancer Research; the Ludwig Center at
   Harvard; the Jane's Trust Foundation; National Cancer Institute (NCI)
   Grants P01-CA080124, R01-CA098706; R01-CA208205 and U01-CA224348; and
   the Department of Defense Breast Cancer Research Program Innovator Award
   W81XWH-10-1-0016 (to R.K.J.). R.K.J. is a recipient of Outstanding
   Investigator Award R35-CA197743 from the NCI. V.P.C. is a Fellow of the
   Life Sciences Research Foundation and was supported by Ruth L.
   Kirschstein National Research Service Award Postdoctoral Fellowship
   F32-CA073479 from the NIH and by a Misrock Postdoctoral Fellowship from
   the Misrock Foundation through the S. Leslie Misrock (1949) Frontier
   Research Fund for Cancer Nanotechnology. J.P. was supported by NIH
   Training Grant T32HL007627. I.X.C. was supported by a Gates Graduate
   Fellowship. M.R.N. was supported by Department of Defense Breast Cancer
   Research Program Postdoctoral Fellowship W81XWH-14-1-0034 and by a
   Simeon J. Fortin Charitable Foundation Postdoctoral Fellowship.
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NR 55
TC 273
Z9 282
U1 6
U2 104
PU NATL ACAD SCIENCES
PI WASHINGTON
PA 2101 CONSTITUTION AVE NW, WASHINGTON, DC 20418 USA
SN 0027-8424
J9 P NATL ACAD SCI USA
JI Proc. Natl. Acad. Sci. U. S. A.
PD MAR 5
PY 2019
VL 116
IS 10
BP 4558
EP 4566
DI 10.1073/pnas.1815515116
PG 9
WC Multidisciplinary Sciences
WE Science Citation Index Expanded (SCI-EXPANDED)
SC Science & Technology - Other Topics
GA HN5RI
UT WOS:000460242100090
PM 30700545
OA Green Published
HC Y
HP N
DA 2025-03-13
ER

PT J
AU Kim, BG
   Sung, JS
   Jang, Y
   Cha, YJ
   Kang, S
   Han, HH
   Lee, JH
   Cho, NH
AF Kim, Baek Gil
   Sung, Jin Sol
   Jang, Yeonsue
   Cha, Yoon Jin
   Kang, Suki
   Han, Hyun Ho
   Lee, Joo Hyun
   Cho, Nam Hoon
TI Compression-induced expression of glycolysis genes in CAFs correlates
   with EMT and angiogenesis gene expression in breast cancer
SO COMMUNICATIONS BIOLOGY
LA English
DT Article
ID MECHANICAL COMPRESSION; INTERFACE ZONE; SOLID STRESS; CELLS; LACTATE;
   CHONDROCYTES; FIBROBLASTS; CARCINOMAS; ONTOLOGY; FIBROSIS
AB Tumor growth increases compressive stress within a tissue, which is associated with solid tumor progression. However, very little is known about how compressive stress contributes to tumor progression. Here, we show that compressive stress induces glycolysis in human breast cancer associated fibroblast (CAF) cells and thereby contributes to the expression of epithelial to mesenchymal (EMT)- and angiogenesis-related genes in breast cancer cells. Lactate production was increased in compressed CAF cells, in a manner dependent on the expression of metabolic genes ENO2, HK2, and PFKFB3. Conditioned medium from compressed CAFs promoted the proliferation of breast cancer cells and the expression of EMT and/or angiogenesis-related genes. In patient tissues with high compressive stress, the expression of compression-induced metabolic genes was significantly and positively correlated with EMT and/or angiogenesis-related gene expression and metastasis size. These findings illustrate a mechanotransduction pathway involving stromal glycolysis that may be relevant also for other solid tumours.
C1 [Kim, Baek Gil; Jang, Yeonsue; Cha, Yoon Jin; Kang, Suki; Cho, Nam Hoon] Yonsei Univ, Dept Pathol, Coll Med, Seoul, South Korea.
   [Kim, Baek Gil; Sung, Jin Sol; Han, Hyun Ho; Lee, Joo Hyun; Cho, Nam Hoon] Yonsei Univ, Brain Korea Plus Project Med Sci 21, Coll Med, Seoul, South Korea.
   [Kang, Suki; Cho, Nam Hoon] Yonsei Univ, SBSI, Coll Med, Seoul, South Korea.
   [Cho, Nam Hoon] Yonsei Univ, Global Syst Biol 5 5 10, Seoul, South Korea.
C3 Yonsei University; Yonsei University Health System; Yonsei University;
   Yonsei University Health System; Yonsei University; Yonsei University
   Health System; Yonsei University
RP Cho, NH (corresponding author), Yonsei Univ, Dept Pathol, Coll Med, Seoul, South Korea.; Cho, NH (corresponding author), Yonsei Univ, Brain Korea Plus Project Med Sci 21, Coll Med, Seoul, South Korea.; Cho, NH (corresponding author), Yonsei Univ, SBSI, Coll Med, Seoul, South Korea.; Cho, NH (corresponding author), Yonsei Univ, Global Syst Biol 5 5 10, Seoul, South Korea.
EM cho1988@yuhs.ac
RI KIM, BAEK GIL/KCL-0984-2024; jang, yeonsue/KCL-0916-2024
OI Han, Hyunho/0000-0002-6268-0860; Cha, Yoon Jin/0000-0002-5967-4064;
   KANG, SUKI/0000-0002-9957-3479; KIM, BAEK GIL/0000-0001-6270-1433; jo,
   namhun/0000-0002-0045-6441; Sung, Jin Sol/0000-0002-7899-8814
FU Mid-Career Researcher Program through a National Research Foundation of
   Korea grant [2019R1A2B5B01069934]; Basic Research in Science and
   Engineering through a National Research Foundation of Korea grant
   [2016R1D1A1B03932310]
FX This study was supported by the Mid-Career Researcher Program (No.
   2019R1A2B5B01069934; NHC) and Basic Research in Science and Engineering
   (No. 2016R1D1A1B03932310; BGK) through a National Research Foundation of
   Korea grant
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NR 53
TC 47
Z9 49
U1 1
U2 11
PU NATURE PUBLISHING GROUP
PI NEW YORK
PA 75 VARICK ST, 9TH FLR, NEW YORK, NY 10013-1917 USA
EI 2399-3642
J9 COMMUN BIOL
JI Commun. Biol.
PD AUG 14
PY 2019
VL 2
AR 313
DI 10.1038/s42003-019-0553-9
PG 15
WC Biology; Multidisciplinary Sciences
WE Science Citation Index Expanded (SCI-EXPANDED)
SC Life Sciences & Biomedicine - Other Topics; Science & Technology - Other
   Topics
GA IR5YB
UT WOS:000481514100002
OA gold, Green Published
DA 2025-03-13
ER

PT J
AU Lu, XX
   Gou, ZC
   Chen, H
   Li, L
   Chen, F
   Bao, CJ
   Bu, H
   Zhang, Z
AF Lu, Xunxi
   Gou, Zongchao
   Chen, Hong
   Li, Li
   Chen, Fei
   Bao, Chunjuan
   Bu, Hong
   Zhang, Zhang
TI Extracellular matrix cancer-associated fibroblasts promote stromal
   fibrosis and immune exclusion in triple-negative breast cancer
SO JOURNAL OF PATHOLOGY
LA English
DT Article
DE triple-negative breast cancer; tumor microenvironment; extracellular
   matrix; cancer-associated fibroblasts; macrophages; immunotherapy
ID SINGLE-CELL; SUPPRESSION; DECORIN; ATLAS
AB The impact of high heterogeneity of cancer-associated fibroblasts (CAFs) on triple-negative breast cancer (TNBC) immunotherapy response has not been fully elucidated, restricting progress in precision immuno-oncology. We integrated single-cell transcriptomic data from 18 TNBC patients and analyzed fibroblast subpopulations. Extracellular matrix CAFs (ecmCAFs) were identified as a fibroblast subpopulation with distinct ECM-associated characteristics. The ecmCAFs were significantly enriched in TNBC patients with residual disease after neoadjuvant immunotherapy and contributed to a fibrotic tumor microenvironment and T-cell exclusion. Secreted phosphoprotein 1 (SPP1) positive macrophages (SPP1+ M phi s) were closely localized to ecmCAFs and produced more transforming growth factor beta (TGFB1), interleukin 1 beta (IL1B), and SPP1 under hypoxic conditions. SPP1+ M phi s were found to facilitate the differentiation of normal breast fibroblasts to ecmCAFs, thus promoting ECM remodeling and stromal fibrosis. Our work revealed the critical role of ecmCAFs in generating a desmoplastic architecture and driving immunosuppression in TNBC. (c) 2025 The Pathological Society of Great Britain and Ireland.
C1 [Lu, Xunxi; Bu, Hong; Zhang, Zhang] Sichuan Univ, West China Hosp, Dept Pathol, 37 Guoxue Lane, Chengdu 610041, Peoples R China.
   [Lu, Xunxi; Bu, Hong; Zhang, Zhang] Sichuan Univ, West China Hosp, Lab Breast Pathol & Artificial Intelligence, Chengdu, Peoples R China.
   [Gou, Zongchao] Sichuan Univ, West China Hosp, Breast Ctr, Dept Gen Surg, Chengdu, Peoples R China.
   [Chen, Hong; Li, Li; Chen, Fei; Bao, Chunjuan] Sichuan Univ, West China Hosp, Inst Clin Pathol, Chengdu, Peoples R China.
C3 Sichuan University; Sichuan University; Sichuan University; Sichuan
   University
RP Zhang, Z (corresponding author), Sichuan Univ, West China Hosp, Dept Pathol, 37 Guoxue Lane, Chengdu 610041, Peoples R China.
EM zhangzhang714@163.com
RI Gou, Zongchao/M-6209-2018
OI Gou, Zongchao/0000-0002-9264-7586
FU National Natural Science Foundation of China [82404677]; National
   Natural Science Foundation of PR China [2021HXBH080]; West China
   Hospital, Sichuan University [2024YFFK0394]; Sichuan Science and
   Technology Program
FX This work was supported by the National Natural Science Foundation of PR
   China (82404677), Post-Doctor Research Project, West China Hospital,
   Sichuan University (2021HXBH080), Sichuan Science and Technology Program
   (No. 2024YFFK0394).
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NR 55
TC 0
Z9 0
U1 3
U2 3
PU WILEY
PI HOBOKEN
PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA
SN 0022-3417
EI 1096-9896
J9 J PATHOL
JI J. Pathol.
PD MAR
PY 2025
VL 265
IS 3
BP 385
EP 399
DI 10.1002/path.6395
EA JAN 2025
PG 15
WC Oncology; Pathology
WE Science Citation Index Expanded (SCI-EXPANDED)
SC Oncology; Pathology
GA U9B7N
UT WOS:001402451500001
PM 39846260
DA 2025-03-13
ER

PT J
AU Okazaki, H
   Mezawa, Y
   Shi, Y
   Sakimoto, M
   Wang, ZX
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   Koyama, Y
   Fukumura, Y
   Kajino, K
   Takano, A
   Yokose, T
   Yamashita, T
   Miyagi, Y
   Daigo, Y
   Katakura, A
   Yasukawa, T
   Orimo, A
AF Okazaki, Hiroya
   Mezawa, Yoshihiro
   Shi, Yang
   Sakimoto, Mizuki
   Wang, Zixu
   Ishizuka, Akane
   Yamashita, Kazunari
   Satoh, Asahi
   Koyama, Yu
   Fukumura, Yuki
   Kajino, Kazunori
   Takano, Atsushi
   Yokose, Tomoyuki
   Yamashita, Toshinari
   Miyagi, Yohei
   Daigo, Yataro
   Katakura, Akira
   Yasukawa, Takehiro
   Orimo, Akira
TI Expression of Lymphoid Enhancer-Binding Factor 1 in Cancer-Associated
   Fibroblasts Mediates Tumor Growth and Transdifferentiation Toward
   Squamous Cell Carcinoma in Human Breast Cancer
SO CANCER MEDICINE
LA English
DT Article
DE breast cancer; cancer biology; cancer-associated fibroblasts;
   microenvironment
ID BRAIN NATRIURETIC PEPTIDE; CARDIAC FIBROBLASTS; P40 DELTA-NP63;
   BIOMARKER; DISEASE; BETA; P63
AB BackgroundCancer-associated fibroblasts (CAFs) play a significant role in human breast cancer as a major stromal component. While their role in promoting cancer proliferation and malignancy through interaction with cancer cells in the tumor microenvironment is known, the exact mechanisms behind this interaction are not fully understood.ResultsOur study reveals that lymphoid enhancer-binding factor 1 (LEF1), a central transcription factor for Wnt/beta-catenin signaling, is expressed in experimentally generated tumor-promoting CAFs (exp-CAFs) as well as in CAFs from breast cancer patients, particularly those with a poor prognosis. Notably, LEF1-expressing CAFs are prevalent in the stroma of squamous cell carcinoma (SCC), an aggressive metaplastic breast cancer subtype with a limited understanding of its development. To investigate the functional importance of LEF1 expression in CAFs, we depleted LEF1 in the exp-CAFs and subcutaneously implanted them along with breast ductal carcinoma MCF10DCIS.com cells into immunodeficient mice. Depleting LEF1 resulted in reduced xenograft tumor growth, accompanied by decreased cancer-cell proliferation and angiogenesis in the tumors. Additionally, we observed a significant reduction in the expression of SCC markers p40 (Delta Np63) and cytokeratin 5/6 in the xenograft tumors when LEF1 was depleted in the exp-CAFs. Furthermore, we identified 13 genes, none of which are established downstream genes of the Wnt/beta-catenin pathway, that exhibit expression patterns similar to LFE1 in our cultured fibroblasts.ConclusionIn summary, our findings suggest that LEF1 expression contributes to the tumor-promoting abilities of breast CAFs and that LEF1-expressing CAFs may drive transdifferentiation toward SCC, possibly through a pathway independent of the canonical Wnt/beta-catenin signaling.
C1 [Okazaki, Hiroya; Koyama, Yu; Katakura, Akira] Tokyo Dent Coll, Dept Oral Pathobiol Sci & Surg, Tokyo, Japan.
   [Okazaki, Hiroya; Mezawa, Yoshihiro; Sakimoto, Mizuki; Yamashita, Kazunari; Koyama, Yu; Yasukawa, Takehiro; Orimo, Akira] Juntendo Univ, Fac Med, Dept Pathol & Oncol, Tokyo, Japan.
   [Shi, Yang; Wang, Zixu; Ishizuka, Akane; Satoh, Asahi; Yasukawa, Takehiro; Orimo, Akira] Juntendo Univ, Grad Sch Med, Dept Mol Pathogenesis, Tokyo, Japan.
   [Fukumura, Yuki; Kajino, Kazunori] Juntendo Univ, Dept Human Pathol, Fac Med, Tokyo, Japan.
   [Takano, Atsushi; Daigo, Yataro] Shiga Univ Med Sci, Dept Med Oncol Canc Ctr, Shiga, Japan.
   [Takano, Atsushi; Daigo, Yataro] Shiga Univ Med Sci, Ctr Adv Med Canc, Otsu, Shiga, Japan.
   [Takano, Atsushi; Daigo, Yataro] Univ Tokyo, Res Hosp, Inst Med Sci, Ctr Antibody & Vaccine Therapy, Tokyo, Japan.
   [Yokose, Tomoyuki] Kanagawa Canc Ctr, Dept Pathol, Kanagawa, Japan.
   [Yamashita, Toshinari] Kanagawa Canc Ctr, Dept Breast Surg, Yokohama, Kanagawa, Japan.
   [Miyagi, Yohei] Kanagawa Canc Ctr, Res Inst, Mol Pathol & Genet Div, Yokohama, Japan.
C3 Tokyo Dental College; Juntendo University; Juntendo University; Juntendo
   University; Shiga University of Medical Science; Shiga University of
   Medical Science; University of Tokyo; Kanagawa Prefectural Cancer
   Center; Kanagawa Prefectural Cancer Center; Kanagawa Prefectural Cancer
   Center
RP Yasukawa, T; Orimo, A (corresponding author), Juntendo Univ, Fac Med, Dept Pathol & Oncol, Tokyo, Japan.; Yasukawa, T; Orimo, A (corresponding author), Juntendo Univ, Grad Sch Med, Dept Mol Pathogenesis, Tokyo, Japan.
EM t.yasukawa.vb@juntendo.ac.jp; aorimo@juntendo.ac.jp
FU Japan Society for the Promotion of Science; Laboratory of Molecular and
   Biochemical Research, Biomedical Research Core Facilities at Juntendo
   University
FX We thank Mr. Masaaki Abe for technical and general assistance. We also
   thank the Laboratory of Molecular and Biochemical Research, Biomedical
   Research Core Facilities at Juntendo University.
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NR 52
TC 0
Z9 0
U1 3
U2 3
PU WILEY
PI HOBOKEN
PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA
SN 2045-7634
J9 CANCER MED-US
JI Cancer Med.
PD FEB
PY 2025
VL 14
IS 3
AR e70627
DI 10.1002/cam4.70627
PG 14
WC Oncology
WE Science Citation Index Expanded (SCI-EXPANDED)
SC Oncology
GA U2J4E
UT WOS:001410118100001
PM 39887653
OA gold
DA 2025-03-13
ER

PT J
AU Al-Kharashi, LA
   Tulbah, A
   Arafah, M
   Eldali, AM
   Al-Tweigeri, T
   Aboussekhra, A
AF Al-Kharashi, Layla A.
   Tulbah, Asma
   Arafah, Maria
   Eldali, Abdelmonneim M.
   Al-Tweigeri, Taher
   Aboussekhra, Abdelilah
TI High DNMT1 Expression in Stromal Fibroblasts Promotes Angiogenesis and
   Unfavorable Outcome in Locally Advanced Breast Cancer Patients
SO FRONTIERS IN ONCOLOGY
LA English
DT Article
DE DNMT-1; breast cancer; cancer-associated fibroblasts; VEGF-A; prognosis
ID DNA METHYLTRANSFERASE 1; OVEREXPRESSION; CHEMOTHERAPY; INHIBITOR;
   CARCINOMA; TARGET; HIF-1; 3B; 3A
AB BackgroundActive breast cancer-associated fibroblasts (CAFs) play a leading role in breast carcinogenesis through promoting angiogenesis and resistance to therapy. Consequently, these active stromal cells have significant influence on patient outcome. Therefore, we explored here the role of the DNA methyltransferase 1 (DNMT1) protein in CAF-dependent promotion of angiogenesis as well as the prognostic power of DNMT1 level in both cancer cells and their adjacent CAFs in locally advanced breast cancer patients. MethodsWe applied immunohistochemistry to evaluate the level of DNMT1 in breast cancer tissues and their adjacent normal counterparts. Quantitative RT-PCR and immunoblotting were performed to investigate the role of DNMT1 in regulating the expression of pro-angiogenic genes in active CAFs and also their response to the DNMT1 inhibitors decitabine (DAC) as well as eugenol. ResultsWe have shown that DNMT1 controls the pro-angiogenic potential of CAFs both in vitro and in vivo through positive regulation of the expression/secretion of 2 important pro-angiogenic factors VEGF-A and IL-8 as well as their upstream effectors mTOR and HIF-1 alpha. To confirm this, we have shown that these DNMT1-related pro-angiogenic effects were suppressed by 2 DNMT1 inhibitors decitabine and eugenol. Interestingly, in a cohort of 100 tumors from locally advanced breast cancer patients (LABC), we have shown that high expression of DNMT1 in tumor cells and their adjacent stromal fibroblasts is correlated with poor survival of these patients. ConclusionDNMT1 upregulation in breast stromal fibroblasts promotes angiogenesis via IL-8/VEGF-A upregulation, and correlates well with poor survival of LABC patients.
C1 [Al-Kharashi, Layla A.; Aboussekhra, Abdelilah] King Faisal Specialist Hosp & Res Ctr, Dept Mol Oncol, Riyadh, Saudi Arabia.
   [Al-Kharashi, Layla A.] King Saud Univ, Fac Pharm, Dept Pharmacol & Toxicol, Riyadh, Saudi Arabia.
   [Tulbah, Asma] King Faisal Specialist Hosp & Res Ctr, Dept Pathol, Riyadh, Saudi Arabia.
   [Arafah, Maria] King Saud Univ, Dept Pathol, Riyadh, Saudi Arabia.
   [Eldali, Abdelmonneim M.] King Faisal Specialist Hosp & Res Ctr, Dept Biostat Epidemiol & Sci Comp, Riyadh, Saudi Arabia.
   [Al-Tweigeri, Taher] King Faisal Specialist Hosp & Res Ctr, Dept Oncol, Riyadh, Saudi Arabia.
C3 King Faisal Specialist Hospital & Research Center; King Saud University;
   King Faisal Specialist Hospital & Research Center; King Saud University;
   King Faisal Specialist Hospital & Research Center; King Faisal
   Specialist Hospital & Research Center
RP Aboussekhra, A (corresponding author), King Faisal Specialist Hosp & Res Ctr, Dept Mol Oncol, Riyadh, Saudi Arabia.
EM aboussekhra@kfshrc.edu.sa
RI Arafah, Maria/ABH-3517-2020; Alkharashi, Layla/F-2598-2018; Aboussekhra,
   Abdelilah/JCD-8138-2023
FU King Faisal Specialist Hospital and Research Centre
FX This work was solely supported by the King Faisal Specialist Hospital
   and Research Centre.
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NR 42
TC 9
Z9 11
U1 4
U2 7
PU FRONTIERS MEDIA SA
PI LAUSANNE
PA AVENUE DU TRIBUNAL FEDERAL 34, LAUSANNE, CH-1015, SWITZERLAND
SN 2234-943X
J9 FRONT ONCOL
JI Front. Oncol.
PD JUN 2
PY 2022
VL 12
AR 877219
DI 10.3389/fonc.2022.877219
PG 12
WC Oncology
WE Science Citation Index Expanded (SCI-EXPANDED)
SC Oncology
GA 2E2GU
UT WOS:000812050600001
PM 35719957
OA gold, Green Published
DA 2025-03-13
ER

PT J
AU Cao, Y
   Cao, WJ
   Qiu, YM
   Zhou, YX
   Guo, QL
   Gao, Y
   Lu, N
AF Cao, Yue
   Cao, Wangjia
   Qiu, Yangmin
   Zhou, Yuxin
   Guo, Qinglong
   Gao, Yuan
   Lu, Na
TI Oroxylin A suppresses ACTN1 expression to inactivate cancer-associated
   fibroblasts and restrain breast cancer metastasis
SO PHARMACOLOGICAL RESEARCH
LA English
DT Article
DE CAFs; OA; ACTN1; STAT3; Cancer metastasis
ID CELL MOTILITY; ACTIVATION; ACTININ-4; ANGIOGENESIS; AUTOPHAGY; PATHWAY
AB Tumor initiation and progression are not only ascribed to the behavior of cancer cells, but also profoundly influenced by the tumor microenvironment. Inside, cancer-associated fibroblasts (CAFs) have become key factors to accelerate growth and metastasis for the abundance in most solid tumors. Our group previously reported that Oroxylin A (OA), a flavone from Scutellaria Baicalensis Georgi, possess the ability to suppress growth and invasion of several tumor cells. However, the regulatory effect of OA on stromal microenvironment is poorly understood. In this study, breast cancer-induced fibroblasts and primary breast CAFs from MMTV-PyMT mice were used to evaluate the influence of OA on the activation of fibroblasts. Results showed that OA could decrease the expression of alpha-SMA, fibronectin, vimentin and matrix metalloproteinases (MMPs). Thus, OA-deactivated CAFs did not further promote the proliferation and invasion in breast cancer cells. In vivo experiments, OA could also impede tumor metastasis through exhausting progressive CAFs. Mechanically, OA could specifically bind ACTN1 and significantly inhibit its expression to prevent CAF activation. As a consequence, OA could decrease the phosphorylation of FAK and STAT3, and reduce the secretion of CCL2 in CAFs. Altogether, OA could remodel stromal microenvironment and it is a potential therapeutic agent in breast cancer.
C1 [Cao, Yue; Cao, Wangjia; Qiu, Yangmin; Zhou, Yuxin; Guo, Qinglong; Lu, Na] China Pharmaceut Univ, Sch Basic Med & Clin Pharm, State Key Lab Nat Med, Jiangsu Key Lab Carcinogenesis & Intervent, 24 Tongjiaxiang, Nanjing 210009, Peoples R China.
   [Gao, Yuan] China Pharmaceut Univ, Pharmaceut Anim Expt Ctr, Sch Basic Med & Clin Pharm, 24 Tongjiaxiang, Nanjing 210009, Peoples R China.
C3 China Pharmaceutical University; China Pharmaceutical University
RP Lu, N (corresponding author), China Pharmaceut Univ, Sch Basic Med & Clin Pharm, State Key Lab Nat Med, Jiangsu Key Lab Carcinogenesis & Intervent, 24 Tongjiaxiang, Nanjing 210009, Peoples R China.; Gao, Y (corresponding author), China Pharmaceut Univ, Pharmaceut Anim Expt Ctr, Sch Basic Med & Clin Pharm, 24 Tongjiaxiang, Nanjing 210009, Peoples R China.
EM cpugaoyuan@163.com; nalu@cpu.edu.cn
OI Qiu, Yangmin/0000-0001-6039-7909
FU National Natural Science Foundation of China [81903625, 81872899];
   National Science & Technology Major Project [2017ZX09101003-005-023,
   2017ZX09301014, 2018ZX09711001-003-007]; Social Development Project of
   Jiangsu Provincial Science and Technology Department [BE2018711];
   Natural Science Foundation of Jiangsu Province [BK20190563]; "Double
   First-Class" University project [CPU2018GY17]
FX This work was supported by the National Natural Science Foundation of
   China (No. 81903625, 81872899), the National Science & Technology Major
   Project (No. 2017ZX09101003-005-023, 2017ZX09301014,
   2018ZX09711001-003-007), Social Development Project of Jiangsu
   Provincial Science and Technology Department (BE2018711), Natural
   Science Foundation of Jiangsu Province (BK20190563), and the "Double
   First-Class" University project (CPU2018GY17).
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NR 43
TC 33
Z9 34
U1 1
U2 35
PU ACADEMIC PRESS LTD- ELSEVIER SCIENCE LTD
PI LONDON
PA 24-28 OVAL RD, LONDON NW1 7DX, ENGLAND
SN 1043-6618
J9 PHARMACOL RES
JI Pharmacol. Res.
PD SEP
PY 2020
VL 159
AR 104981
DI 10.1016/j.phrs.2020.104981
PG 13
WC Pharmacology & Pharmacy
WE Science Citation Index Expanded (SCI-EXPANDED)
SC Pharmacology & Pharmacy
GA NK0MG
UT WOS:000566435200003
PM 32492489
DA 2025-03-13
ER

PT J
AU Luo, HJ
   Yang, GL
   Yu, TH
   Luo, SJ
   Wu, CY
   Sun, Y
   Liu, MR
   Tu, G
AF Luo, Haojun
   Yang, Guanglun
   Yu, Tenghua
   Luo, Shujuan
   Wu, Chengyi
   Sun, Yan
   Liu, Manran
   Tu, Gang
TI GPER-mediated proliferation and estradiol production in breast
   cancer-associated fibroblasts
SO ENDOCRINE-RELATED CANCER
LA English
DT Article
DE CAF; GPER; tamoxifen resistance; breast cancer
ID PROTEIN-COUPLED RECEPTOR; GROWTH-FACTOR RECEPTOR; ESTROGEN-RECEPTOR;
   GENE-EXPRESSION; GPR30; TUMOR; CELL; STROMA; TRANSACTIVATION; DISCOVERY
AB Cancer-associated fibroblasts (CAFs) are crucial co-mediators of breast cancer progression. Estrogen is the predominant driving force in the cyclic regulation of the mammary extracellular matrix, thus potentially affecting the tumor-associated stroma. Recently, a third estrogen receptor, estrogen (G-protein-coupled) receptor (GPER), has been reported to be expressed in breast CAFs. In this study, GPER was detected by immunohistochemical analysis in stromal fibroblasts of 41.8% (59/141) of the primary breast cancer samples. GPER expression in CAFs isolated from primary breast cancer tissues was confirmed by immunostaining and RT-PCR analyses. Tamoxifen (TAM) in addition to 17 beta-estradiol (E-2) and the GPER agonist G1 activated GPER, resulting in transient increases in cell index, intracellular calcium, and ERK 1/2 phosphorylation. Furthermore, TAM, E-2, and G1 promoted CAF proliferation and cell-cycle progression, both of which were blocked by GPER interference, the selective GPER antagonist G15, the epidermal growth factor receptor (EGFR) inhibitor AG1478, and the ERK1/2 inhibitor U0126. Importantly, TAM as well as G1 increased E-2 production in breast CAFs via GPER/EGFR/ERK signaling when the substrate of E-2, testosterone, was added to the medium. GPER-induced aromatase upregulation was probably responsible for this phenomenon, as TAM- and G1-induced CYP19A1 gene expression was reduced by GPER knockdown and G15, AG1478, and U0126 administration. Accordingly, GPER-mediated CAF-dependent estrogenic effects on the tumor-associated stroma are conceivable, and CAF is likely to contribute to breast cancer progression, especially TAM resistance, via a positive feedback loop involving GPER/EGFR/ERK signaling and E-2 production.
C1 [Luo, Haojun] Chongqing Med Univ, Affiliated Hosp 2, Dept Breast & Thyroid Surg, Chongqing 400010, Peoples R China.
   [Yang, Guanglun; Yu, Tenghua; Wu, Chengyi; Tu, Gang] Chongqing Med Univ, Affiliated Hosp 1, Dept Endocrine & Breast Surg, Chongqing 400016, Peoples R China.
   [Luo, Shujuan] Chongqing Hlth Ctr Women & Children, Dept Obstet & Gynecol, Chongqing 400010, Peoples R China.
   [Sun, Yan; Liu, Manran] Chongqing Med Univ, Key Lab Lab Med Diagnost, Chinese Minist Educ, Chongqing 400016, Peoples R China.
C3 Chongqing Medical University; Chongqing Medical University; Chongqing
   Medical University
RP Tu, G (corresponding author), Chongqing Med Univ, Affiliated Hosp 1, Dept Endocrine & Breast Surg, 1 You Yi Rd, Chongqing 400016, Peoples R China.
EM mliu-hncq@hotmail.com; tugang68@126.com
OI li, lu/0009-0009-8381-3093
FU National Natural Science Foundation of China [NSFC 81372398, NSFC
   81072149, NSFC 81072147]
FX This study was supported by the National Natural Science Foundation of
   China (NSFC 81372398, NSFC 81072149, and NSFC 81072147).
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NR 43
TC 75
Z9 91
U1 0
U2 30
PU BIOSCIENTIFICA LTD
PI BRISTOL
PA EURO HOUSE, 22 APEX COURT WOODLANDS, BRADLEY STOKE, BRISTOL BS32 4JT,
   ENGLAND
SN 1351-0088
EI 1479-6821
J9 ENDOCR-RELAT CANCER
JI Endocr.-Relat. Cancer
PD APR
PY 2014
VL 21
IS 2
BP 355
EP 369
DI 10.1530/ERC-13-0237
PG 15
WC Oncology; Endocrinology & Metabolism
WE Science Citation Index Expanded (SCI-EXPANDED)
SC Oncology; Endocrinology & Metabolism
GA AT2SY
UT WOS:000344787300023
PM 24481325
OA hybrid, Green Published, Green Submitted
DA 2025-03-13
ER

PT J
AU Becker, LM
   O'Connell, JT
   Vo, AP
   Cain, MP
   Tampe, D
   Bizarro, L
   Sugimoto, H
   McGow, AK
   Asara, JM
   Lovisa, S
   McAndrews, KM
   Zielinski, R
   Lorenzi, PL
   Zeisberg, M
   Raza, S
   LeBleu, VS
   Kalluri, R
AF Becker, Lisa M.
   O'Connell, Joyce T.
   Vo, Annie P.
   Cain, Margo P.
   Tampe, Desiree
   Bizarro, Lauren
   Sugimoto, Hikaru
   McGow, Anna K.
   Asara, John M.
   Lovisa, Sara
   McAndrews, Kathleen M.
   Zielinski, Rafal
   Lorenzi, Philip L.
   Zeisberg, Michael
   Raza, Sughra
   LeBleu, Valerie S.
   Kalluri, Raghu
TI Epigenetic Reprogramming of Cancer-Associated Fibroblasts Deregulates
   Glucose Metabolism and Facilitates Progression of Breast Cancer
SO CELL REPORTS
LA English
DT Article
ID CARCINOMA-ASSOCIATED FIBROBLASTS; TUMOR-STROMA RATIO; PYRUVATE-KINASE
   M2; LACTATE SHUTTLE; CELLS; HYPOXIA; ACTIVATION; SURVIVAL; GROWTH;
   IDENTIFICATION
AB The mechanistic contributions of cancer-associated fibroblasts (CAFs) in breast cancer progression remain to be fully understood. While altered glucose metabolism in CAFs could fuel cancer cells, how such metabolic reprogramming emerges and is sustained needs further investigation. Studying fibroblasts isolated from patients with benign breast tissues and breast cancer. in conjunction with multiple animal models, we demonstrate that CAFs exhibit a metabolic shift toward lactate and pyruvate production and fuel biosynthetic pathways of cancer cells. The depletion or suppression of the lactate production of CAFs alter the tumor metabolic profile and impede tumor growth. The glycolytic phenotype of the CAFs is in part sustained through epigenetic reprogramming of HIF-1 alpha and glycolytic enzymes. Hypoxia induces epigenetic reprogramming of normal fibroblasts, resulting in a pro-glycolytic, CAF-like transcriptome. Our findings suggest that the glucose metabolism of CAFs evolves during tumor progression, and their breast cancer-promoting phenotype is partly mediated by oxygen-dependent epigenetic modifications.
C1 [Becker, Lisa M.; Cain, Margo P.; Bizarro, Lauren; Sugimoto, Hikaru; Lovisa, Sara; McAndrews, Kathleen M.; LeBleu, Valerie S.; Kalluri, Raghu] Univ Texas MD Anderson Canc Ctr, Metastasis Res Ctr, Dept Canc Biol, Houston, TX 77054 USA.
   [O'Connell, Joyce T.; Vo, Annie P.; Bizarro, Lauren; Sugimoto, Hikaru; LeBleu, Valerie S.; Kalluri, Raghu] Beth Israel Deaconess Med Ctr, Dept Med, Div Matrix Biol, Boston, MA 02215 USA.
   [O'Connell, Joyce T.; Vo, Annie P.; Bizarro, Lauren; Sugimoto, Hikaru; LeBleu, Valerie S.; Kalluri, Raghu] Harvard Med Sch, Boston, MA 02215 USA.
   [Tampe, Desiree; Zeisberg, Michael] Georg August Univ, Gottingen Univ, Dept Nephrol & Rheumatol, Med Ctr, D-37075 Gottingen, Germany.
   [McGow, Anna K.; Raza, Sughra] Brigham & Womens Hosp, Dept Radiol, 75 Francis St, Boston, MA 02115 USA.
   [Asara, John M.] Beth Israel Deaconess Med Ctr, Div Signal Transduct, Boston, MA 02215 USA.
   [Asara, John M.] Harvard Med Sch, Dept Med, Boston, MA 02215 USA.
   [Zielinski, Rafal] Univ Texas MD Anderson Canc Ctr, Dept Expt Therapeut, Houston, TX 77054 USA.
   [Lorenzi, Philip L.] Univ Texas MD Anderson Canc Ctr, Dept Bioinformat & Computat Biol, Metabol Core Facil, Houston, TX 77030 USA.
   [LeBleu, Valerie S.] Northwestern Univ, Feinberg Sch Med, Chicago, IL 60611 USA.
   [Kalluri, Raghu] Rice Univ, Dept Bioengn, Houston, TX 77030 USA.
   [Kalluri, Raghu] Baylor Coll Med, Dept Mol & Cellular Biol, Houston, TX 77030 USA.
C3 University of Texas System; UTMD Anderson Cancer Center; Harvard
   University; Harvard University Medical Affiliates; Beth Israel Deaconess
   Medical Center; Harvard University; Harvard Medical School; University
   of Gottingen; Harvard University; Harvard University Medical Affiliates;
   Brigham & Women's Hospital; Harvard University; Harvard University
   Medical Affiliates; Beth Israel Deaconess Medical Center; Harvard
   University; Harvard Medical School; University of Texas System; UTMD
   Anderson Cancer Center; University of Texas System; UTMD Anderson Cancer
   Center; Northwestern University; Feinberg School of Medicine; Rice
   University; Baylor College of Medicine
RP LeBleu, VS; Kalluri, R (corresponding author), Univ Texas MD Anderson Canc Ctr, Metastasis Res Ctr, Dept Canc Biol, Houston, TX 77054 USA.; LeBleu, VS; Kalluri, R (corresponding author), Beth Israel Deaconess Med Ctr, Dept Med, Div Matrix Biol, Boston, MA 02215 USA.; LeBleu, VS; Kalluri, R (corresponding author), Harvard Med Sch, Boston, MA 02215 USA.; LeBleu, VS (corresponding author), Northwestern Univ, Feinberg Sch Med, Chicago, IL 60611 USA.; Kalluri, R (corresponding author), Rice Univ, Dept Bioengn, Houston, TX 77030 USA.; Kalluri, R (corresponding author), Baylor Coll Med, Dept Mol & Cellular Biol, Houston, TX 77030 USA.
EM valerie.lebleu@northwestern.edu; rkalluri@mdanderson.org
RI Asara, John/MGA-9345-2025; Zielinski, Rafal/AAU-5177-2021; LeBleu,
   Valerie/E-2991-2015; Kalluri, Raghu/E-2677-2015; Lovisa,
   Sara/AAB-1141-2020
OI Kalluri, Raghu/0000-0002-2190-547X; Tampe, Desiree/0000-0002-8724-4803;
   Becker, Lisa/0000-0003-1879-8789; McAndrews,
   Kathleen/0000-0002-4092-4991; Lovisa, Sara/0000-0001-7776-2896
FU National Cancer Institute (NCI) [CA125550, CA155370, CA15192]; Cancer
   Prevention and Research Institute of Texas (CPRIT); NCI
   [5P01CA120964-05, 5P30CA006516-46]; Harvard Clinical and Translational
   Science Center training grant; Department of Defense Breast Cancer
   Research Predoctoral Traineeship Award [W81XWH-09-1-0008]; NIH Research
   Training Grant in Gastroenterology [2T32DK007760-11]; Rosalie Hite
   Fellowship at the University of Texas MD Anderson Cancer Center (MDACC);
   CPRIT [RP130397]; NIH [S10OD012304-01, U01CA235510, P30CA016672]
FX The Kalluri laboratory was/is supported by the National Cancer Institute
   (NCI) (CA125550, CA155370, and CA15192) and the Cancer Prevention and
   Research Institute of Texas (CPRIT). Additional support includes
   5P01CA120964-05 and 5P30CA006516-46 from the NCI to J.M.A.; the Harvard
   Clinical and Translational Science Center training grant to A.P.V.; the
   Department of Defense Breast Cancer Research Predoctoral Traineeship
   Award (W81XWH-09-1-0008) to J.T.O.; the NIH Research Training Grant in
   Gastroenterology (2T32DK007760-11) to V.S.L.; and the Rosalie Hite
   Fellowship at the University of Texas MD Anderson Cancer Center (MDACC)
   to L.M.B. The Metabolomics Core Facility at MDACC is supported by CPRIT
   grant RP130397 and NIH grants S10OD012304-01, U01CA235510, and
   P30CA016672. We thank M. Esteller and J.F. Carmona Sanz for help with
   bisulfite sequencing, P. Phillips for help with immunohistochemistry, Y.
   Chen for advice on lymphatic immunolabeling, and F.L. Muller for helpful
   discussions regarding metabolic labeling studies.
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NR 69
TC 183
Z9 193
U1 4
U2 34
PU CELL PRESS
PI CAMBRIDGE
PA 50 HAMPSHIRE ST, FLOOR 5, CAMBRIDGE, MA 02139 USA
SN 2211-1247
J9 CELL REP
JI Cell Reports
PD JUN 2
PY 2020
VL 31
IS 9
AR 107701
DI 10.1016/j.celrep.2020.107701
PG 23
WC Cell Biology
WE Science Citation Index Expanded (SCI-EXPANDED)
SC Cell Biology
GA LV0XZ
UT WOS:000538168300005
PM 32492417
OA Green Accepted, gold
DA 2025-03-13
ER

PT J
AU Bochet, L
   Lehuédé, C
   Dauvillier, S
   Wang, YY
   Dirat, B
   Laurent, V
   Dray, C
   Guiet, R
   Maridonneau-Parini, I
   Le Gonidec, S
   Couderc, B
   Escourrou, G
   Valet, P
   Muller, C
AF Bochet, Ludivine
   Lehuede, Camille
   Dauvillier, Stephanie
   Wang, Yuan Yuan
   Dirat, Beatrice
   Laurent, Victor
   Dray, Cedric
   Guiet, Romain
   Maridonneau-Parini, Isabelle
   Le Gonidec, Sophie
   Couderc, Bettina
   Escourrou, Ghislaine
   Valet, Philippe
   Muller, Catherine
TI Adipocyte-Derived Fibroblasts Promote Tumor Progression and Contribute
   to the Desmoplastic Reaction in Breast Cancer
SO CANCER RESEARCH
LA English
DT Article
ID ADIPOSE-TISSUE; BETA-CATENIN; CELL-LINES; DIFFERENTIATION; ADIPOGENESIS;
   INVASION; MICROENVIRONMENT; EXPRESSION; SECRETION; EXHIBIT
AB Cancer-associated fibroblasts (CAF) comprise the majority of stromal cells in breast cancers, yet their precise origins and relative functional contributions to malignant progression remain uncertain. Local invasion leads to the proximity of cancer cells and adipocytes, which respond by phenotypical changes to generate fibroblast-like cells termed as adipocyte-derived fibroblasts (ADF) here. These cells exhibit enhanced secretion of fibronectin and collagen I, increased migratory/invasive abilities, and increased expression of the CAF marker FSP-1 but not alpha-SMA. Generation of the ADF phenotype depends on reactivation of the Wnt/beta-catenin pathway in response to Wnt3a secreted by tumor cells. Tumor cells cocultivated with ADFs in two-dimensional or spheroid culture display increased invasive capabilities. In clinical specimens of breast cancer, we confirmed the presence of this new stromal subpopulation. By defining a new stromal cell population, our results offer new opportunities for stroma-targeted therapies in breast cancer. (C) 2013 AACR.
C1 [Bochet, Ludivine; Lehuede, Camille; Dauvillier, Stephanie; Wang, Yuan Yuan; Dirat, Beatrice; Laurent, Victor; Dray, Cedric; Guiet, Romain; Maridonneau-Parini, Isabelle; Le Gonidec, Sophie; Valet, Philippe; Muller, Catherine] Univ Toulouse, UPS, Toulouse, France.
   [Bochet, Ludivine; Lehuede, Camille; Dauvillier, Stephanie; Wang, Yuan Yuan; Dirat, Beatrice; Laurent, Victor; Guiet, Romain; Maridonneau-Parini, Isabelle; Muller, Catherine] CNRS, Toulouse, France.
   [Bochet, Ludivine; Lehuede, Camille; Dauvillier, Stephanie; Wang, Yuan Yuan; Dirat, Beatrice; Laurent, Victor; Guiet, Romain; Maridonneau-Parini, Isabelle; Muller, Catherine] Inst Pharmacol & Biol Struct, F-31077 Toulouse, France.
   [Bochet, Ludivine; Lehuede, Camille; Wang, Yuan Yuan; Dirat, Beatrice; Dray, Cedric; Le Gonidec, Sophie; Valet, Philippe] Fac Med Toulouse, INSERM, U1048, F-31073 Toulouse, France.
   [Couderc, Bettina] Inst Claudius Regaud, EA3035, Toulouse, France.
   [Escourrou, Ghislaine] Hop Rangueil, Serv Anatomopathol, Toulouse, France.
C3 Universite de Toulouse; Universite Toulouse III - Paul Sabatier; Centre
   National de la Recherche Scientifique (CNRS); Universite de Toulouse;
   Universite Toulouse III - Paul Sabatier; Centre National de la Recherche
   Scientifique (CNRS); Universite de Toulouse; Universite Toulouse III -
   Paul Sabatier; Institut National de la Sante et de la Recherche Medicale
   (Inserm); UNICANCER; Institut Claudius Regaud; Universite de Toulouse;
   Universite Toulouse III - Paul Sabatier; CHU de Toulouse
RP Muller, C (corresponding author), Inst Pharmacol & Biol Struct, 205 Route Narbonne, F-31077 Toulouse, France.
EM muller@ipbs.fr
RI Maridonneau-Parini, Isabelle/F-1985-2011; Couderc, Bettina/P-1576-2014;
   MULLER, Catherine/M-2185-2018; dray, cedric/N-7440-2017; Valet,
   Philippe/N-7472-2017
OI DRAY, Cedric/0000-0002-4712-791X; Valet, Philippe/0000-0001-6520-7393;
   Maridonneau-Parini, Isabelle/0000-0003-0189-0976; DAUVILLIER,
   STEPHANIE/0000-0001-6689-4471; Le Gonidec, Sophie/0000-0002-8141-690X
FU French National Cancer Institute [INCA PL 2006-035, INCA PL 2010-214];
   'Ligue Regionale Midi-Pyrenees contre le Cancer' (Comite du Lot, de la
   Haute-Garonne et du Gers); Fondation de France; University of Toulouse;
   Fondation pour la Recherche Medicale, ANR [2010-120-1733]; Ligue
   Nationale Contre le Cancer
FX Studies conducted in our laboratories were supported by the French
   National Cancer Institute (INCA PL 2006-035 and INCA PL 2010-214; P.
   Valet, G. Escourrou, and C. Muller), the 'Ligue Regionale Midi-Pyrenees
   contre le Cancer' (Comite du Lot, de la Haute-Garonne et du Gers; C.
   Muller), the Fondation de France (P. Valet and C. Muller), and the
   University of Toulouse (AO CS 2009; C. Muller). In addition, the
   Fondation pour la Recherche Medicale, ANR Migre Flame 2010, and ARC
   #2010-120-1733 supported this work (R. Guiet and I. Maridonneau-Parini).
   C. Lehuede is a recipient of a PhD fellowship from the Ligue Nationale
   Contre le Cancer. The costs of publication of this article were defrayed
   in part by the payment of page charges. This article must therefore be
   hereby marked advertisement in accordance with 18 U.S.C. Section 1734
   solely to indicate this fact.
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NR 34
TC 382
Z9 418
U1 1
U2 46
PU AMER ASSOC CANCER RESEARCH
PI PHILADELPHIA
PA 615 CHESTNUT ST, 17TH FLOOR, PHILADELPHIA, PA 19106-4404 USA
SN 0008-5472
J9 CANCER RES
JI Cancer Res.
PD SEP 15
PY 2013
VL 73
IS 18
BP 5657
EP 5668
DI 10.1158/0008-5472.CAN-13-0530
PG 12
WC Oncology
WE Science Citation Index Expanded (SCI-EXPANDED)
SC Oncology
GA 223LK
UT WOS:000324806300007
PM 23903958
OA Green Submitted
DA 2025-03-13
ER

PT J
AU Vivacqua, A
   Sebastiani, A
   Miglietta, AM
   Rigiracciolo, DC
   Cirillo, F
   Galli, GR
   Talia, M
   Santolla, MF
   Lappano, R
   Giordano, F
   Panno, ML
   Maggiolini, M
AF Vivacqua, Adele
   Sebastiani, Anna
   Miglietta, Anna Maria
   Rigiracciolo, Damiano Cosimo
   Cirillo, Francesca
   Galli, Giulia Raffaella
   Talia, Marianna
   Santolla, Maria Francesca
   Lappano, Rosamaria
   Giordano, Francesca
   Panno, Maria Luisa
   Maggiolini, Marcello
TI miR-338-3p Is Regulated by Estrogens through GPER in Breast Cancer Cells
   and Cancer-Associated Fibroblasts (CAFs)
SO CELLS
LA English
DT Article
DE breast cancer; CAFs; estrogens; GPER; miR-338-3p; c-Fos; Cyclin D1
ID GROWTH-FACTOR-RECEPTOR; GENE-EXPRESSION; UP-REGULATION;
   17-BETA-ESTRADIOL; CARCINOMA; MICRORNAS; PROLIFERATION; MECHANISM;
   ACTIVATION; CONTRIBUTE
AB Estrogens acting through the classic estrogen receptors (ERs) and the G protein estrogen receptor (GPER) regulate the expression of diverse miRNAs, small sequences of non-coding RNA involved in several pathophysiological conditions, including breast cancer. In order to provide novel insights on miRNAs regulation by estrogens in breast tumor, we evaluated the expression of 754 miRNAs by TaqMan Array in ER-negative and GPER-positive SkBr3 breast cancer cells and cancer-associated fibroblasts (CAFs) upon 17 beta-estradiol (E2) treatment. Various miRNAs were regulated by E2 in a peculiar manner in SkBr3 cancer cells and CAFs, while miR-338-3p displayed a similar regulation in both cell types. By METABRIC database analysis we ascertained that miR-338-3p positively correlates with overall survival in breast cancer patients, according to previous studies showing that miR-338-3p may suppress the growth and invasion of different cancer cells. Well-fitting with these data, a miR-338-3p mimic sequence decreased and a miR-338-3p inhibitor sequence rescued the expression of genes and the proliferative effects induced by E2 through GPER in SkBr3 cancer cells and CAFs. Altogether, our results provide novel evidence on the molecular mechanisms by which E2 may regulate miR-338-3p toward breast cancer progression.
C1 [Vivacqua, Adele; Sebastiani, Anna; Rigiracciolo, Damiano Cosimo; Cirillo, Francesca; Galli, Giulia Raffaella; Talia, Marianna; Santolla, Maria Francesca; Lappano, Rosamaria; Giordano, Francesca; Panno, Maria Luisa; Maggiolini, Marcello] Univ Calabria, Dept Pharm Hlth & Nutr Sci, I-87036 Arcavacata Di Rende, Italy.
   [Miglietta, Anna Maria] Reg HospitalCosenza, I-87100 Cosenza, Italy.
C3 University of Calabria
RP Vivacqua, A; Maggiolini, M (corresponding author), Univ Calabria, Dept Pharm Hlth & Nutr Sci, I-87036 Arcavacata Di Rende, Italy.
EM adele.vivacqua@unical.it; annasebastiani86@gmail.com;
   annamariamiglietta@virgilio.it; damianorigiracciolo@yahoo.it;
   francesca89cirillo@libero.it; giulia.r.galli@gmail.com;
   mariannatalia11@gmail.com; m.f.s@hotmail.it; lappanorosamaria@yahoo.it;
   francesca.giordano@unical.it; mamissina@yahoo.it;
   marcellomaggiolini@yahoo.it
RI Rigiracciolo, Damiano Cosimo/GRS-9234-2022; Maggiolini,
   Marcello/Z-4729-2019; CIRILLO, FRANCESCA/K-2612-2018; Giordano,
   Francesca/E-4039-2017; Santolla, Maria/AAH-5481-2020; vivacqua,
   adele/I-2771-2015
OI Santolla, Maria Francesca/0000-0002-4838-5953; Talia,
   Marianna/0000-0002-3440-5618; vivacqua, adele/0000-0001-5333-8396;
   Maggiolini, Marcello/0000-0002-7485-854X
FU Italian Association for Cancer Research (AIRC); Fondazione Umberto
   Veronesi
FX This work has been supported by the Italian Association for Cancer
   Research (AIRC). MFS was supported by Fondazione Umberto Veronesi
   (Post-Doctoral Fellowship 2018).
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NR 72
TC 29
Z9 31
U1 0
U2 5
PU MDPI
PI BASEL
PA ST ALBAN-ANLAGE 66, CH-4052 BASEL, SWITZERLAND
EI 2073-4409
J9 CELLS-BASEL
JI Cells
PD NOV
PY 2018
VL 7
IS 11
AR 203
DI 10.3390/cells7110203
PG 19
WC Cell Biology
WE Science Citation Index Expanded (SCI-EXPANDED)
SC Cell Biology
GA HB8BD
UT WOS:000451308000022
PM 30423928
OA Green Published, Green Submitted, gold
DA 2025-03-13
ER

PT J
AU Dieters-Castator, D
   Dantonio, PM
   Piaseczny, M
   Zhang, GH
   Liu, JH
   Kuljanin, M
   Sherman, S
   Jewer, M
   Quesnel, K
   Kang, EY
   Köbel, M
   Siegers, GM
   Leask, A
   Hess, D
   Lajoie, G
   Postovit, LM
AF Dieters-Castator, Dylan
   Dantonio, Paola M.
   Piaseczny, Matt
   Zhang, Guihua
   Liu, Jiahui
   Kuljanin, Miljan
   Sherman, Stephen
   Jewer, Michael
   Quesnel, Katherine
   Kang, Eun Young
   Koebel, Martin
   Siegers, Gabrielle M.
   Leask, Andrew
   Hess, David
   Lajoie, Gilles
   Postovit, Lynne-Marie
TI Embryonic protein NODAL regulates the breast tumor microenvironment by
   reprogramming cancer-derived secretomes
SO NEOPLASIA
LA English
DT Article
DE Breast cancer; NODAL; Proteomics; Secretome; Mass spectrometry
ID MESENCHYMAL STEM-CELLS; STROMAL CELLS; TGF-BETA; MAPK PATHWAYS;
   COPY-NUMBER; FIBROBLASTS; MYOFIBROBLASTS; DIFFERENTIATION;
   CHEMORESISTANCE; IDENTIFICATION
AB The tumor microenvironment (TME) is an important mediator of breast cancer progression. Cancer-associated fibroblasts constitute a major component of the TME and may originate from tissue-associated fibroblasts or infiltrating mesenchymal stromal cells (MSCs). The mechanisms by which cancer cells activate fibroblasts and recruit MSCs to the TME are largely unknown, but likely include deposition of a pro-tumorigenic secretome. The secreted embryonic protein NODAL is clinically associated with breast cancer stage and promotes tumor growth, metastasis, and vascularization. Herein, we show that NODAL expression correlates with the presence of activated fibroblasts in human triple-negative breast cancers and that it directly induces Cancer-associated fibroblasts phenotypes. We further show that NODAL reprograms cancer cell secretomes by simultaneously altering levels of chemokines (e.g., CXCL1), cytokines (e.g., IL-6) and growth factors (e.g., PDGFRA), leading to alterations in MSC chemotaxis. We therefore demonstrate a hitherto unappreciated mechanism underlying the dynamic regulation of the TME.
C1 [Dieters-Castator, Dylan; Piaseczny, Matt; Jewer, Michael] Western Univ, Dept Anat & Cell Biol, London, ON, Canada.
   [Dantonio, Paola M.; Postovit, Lynne-Marie] Queens Univ, Dept Biomed & Mol Sci, Kingston, ON, Canada.
   [Zhang, Guihua; Liu, Jiahui; Jewer, Michael; Siegers, Gabrielle M.; Postovit, Lynne-Marie] Univ Alberta, Dept Oncol, Edmonton, AB, Canada.
   [Kuljanin, Miljan; Sherman, Stephen; Hess, David] Robarts Res Inst, London, ON, Canada.
   [Kuljanin, Miljan; Lajoie, Gilles] Western Univ, Dept Biochem, London, ON, Canada.
   [Sherman, Stephen; Quesnel, Katherine; Leask, Andrew; Hess, David] Western Univ, Dept Physiol & Pharmacol, London, ON, Canada.
   [Kang, Eun Young; Koebel, Martin] Univ Calgary, Dept Pathol & Lab Med, Calgary, AB, Canada.
C3 Western University (University of Western Ontario); Queens University -
   Canada; University of Alberta; Western University (University of Western
   Ontario); University Western Ontario Hospital; Western University
   (University of Western Ontario); Western University (University of
   Western Ontario); University of Calgary
RP Postovit, LM (corresponding author), Queens Univ, Dept Biomed & Mol Sci, Kingston, ON, Canada.; Postovit, LM (corresponding author), Univ Alberta, Dept Oncol, Edmonton, AB, Canada.
EM l.postovit@queensu.ca
RI Hess, David/M-2828-2013; Siegers, Gabrielle/M-2042-2017; Kang,
   Eun-Young/AAD-9016-2019; Köbel, Martin/A-7373-2011; zhang,
   guihua/GVU-4494-2022
OI Lajoie, Gilles/0009-0004-5424-1851; Kobel, Martin/0000-0002-6615-2037;
   Hess, David/0000-0003-2186-3166; Liu, Jiahui/0000-0003-2300-3848
FU Canadian Institutes of Health Research (CIHR) [PLS 95381, PLS 9538];
   Canadian Breast Cancer Foundation
FX The work was funded by operating grants from the Canadian Institutes of
   Health Research (CIHR) (PLS 9538 and PLS 95381) and the Canadian Breast
   Cancer Foundation awarded to LMP.
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NR 102
TC 4
Z9 5
U1 1
U2 4
PU ELSEVIER SCIENCE INC
PI NEW YORK
PA STE 800, 230 PARK AVE, NEW YORK, NY 10169 USA
SN 1476-5586
J9 NEOPLASIA
JI Neoplasia
PD APR
PY 2021
VL 23
IS 4
BP 375
EP 390
DI 10.1016/j.neo.2021.02.004
EA MAR 2021
PG 16
WC Oncology
WE Science Citation Index Expanded (SCI-EXPANDED)
SC Oncology
GA SD2TH
UT WOS:000651223900002
PM 33784590
OA Green Published, gold
DA 2025-03-13
ER

PT J
AU Elwakeel, E
   Weigert, A
AF Elwakeel, Eiman
   Weigert, Andreas
TI Breast Cancer CAFs: Spectrum of Phenotypes and Promising Targeting
   Avenues
SO INTERNATIONAL JOURNAL OF MOLECULAR SCIENCES
LA English
DT Review
DE cancer-associated fibroblasts; mammary carcinoma; cancer; tumor
   microenvironment; extracellular matrix; metastasis
ID CARCINOMA-ASSOCIATED FIBROBLASTS; EPITHELIAL-MESENCHYMAL TRANSITION;
   TIVANTINIB ARQ 197; TUMOR MICROENVIRONMENT; STROMAL CELLS; TGF-BETA;
   PROMOTES METASTASIS; MAMMARY-CARCINOMA; GENE-EXPRESSION; LUNG METASTASIS
AB Activation of the tumor-associated stroma to support tumor growth is a common feature observed in different cancer entities. This principle is exemplified by cancer-associated fibroblasts (CAFs), which are educated by the tumor to shape its development across all stages. CAFs can alter the extracellular matrix (ECM) and secrete a variety of different molecules. In that manner they have the capability to affect activation, survival, proliferation, and migration of other stromal cells and cancer cell themselves. Alteration of the ECM, desmoplasia, is a common feature of breast cancer, indicating a prominent role for CAFs in shaping tumor development in the mammary gland. In this review, we summarize the multiple roles CAFs play in mammary carcinoma. We discuss experimental and clinical strategies to interfere with CAFs function in breast cancer. Moreover, we highlight the issues arising from CAFs heterogeneity and the need for further research to identify CAFs subpopulation(s) that can be targeted to improve breast cancer therapy.
C1 [Elwakeel, Eiman; Weigert, Andreas] Goethe Univ Frankfurt, Fac Med, Inst Biochem 1, D-60590 Frankfurt, Germany.
   [Weigert, Andreas] Goethe Univ Frankfurt, Frankfurt Canc Inst, D-60596 Frankfurt, Germany.
   [Weigert, Andreas] German Canc Consortium DKTK, Partner Site Frankfurt, D-60590 Frankfurt, Germany.
C3 Goethe University Frankfurt; Goethe University Frankfurt; Helmholtz
   Association; German Cancer Research Center (DKFZ)
RP Elwakeel, E (corresponding author), Goethe Univ Frankfurt, Fac Med, Inst Biochem 1, D-60590 Frankfurt, Germany.
EM elwakeel@biochem.uni-frankfurt.de; weigert@biochem.uni-frankfurt.de
RI Weigert, Andreas/E-6540-2010
OI Weigert, Andreas/0000-0002-7529-1952
FU Wilhelm-Sander Foundation [2019.082.01]; Deutsche Krebshilfe [70114051];
   Deutsche Forschungsgemeinschaft [FOR 2438, SFB 1039, GRK 2336]; LOEWE
   Center Frankfurt Cancer Institute (FCI) - Hessen State Ministry for
   Higher Education, Research and the Arts [III L 5-519/03/03.001-(0015)];
   Goethe-Universitaet Frankfurt [71000644]
FX This work was supported by Wilhelm-Sander Foundation (2019.082.01),
   Deutsche Krebshilfe (70114051), Deutsche Forschungsgemeinschaft (FOR
   2438, TP8; SFB 1039, TPB06; GRK 2336, TP1), the LOEWE Center Frankfurt
   Cancer Institute (FCI) funded by the Hessen State Ministry for Higher
   Education, Research and the Arts [III L 5-519/03/03.001-(0015)], and
   Foerderung Nachwuchsforscher 2020 funded by Goethe-Universitaet
   Frankfurt (71000644).
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NR 174
TC 32
Z9 33
U1 0
U2 13
PU MDPI
PI BASEL
PA ST ALBAN-ANLAGE 66, CH-4052 BASEL, SWITZERLAND
SN 1661-6596
EI 1422-0067
J9 INT J MOL SCI
JI Int. J. Mol. Sci.
PD NOV
PY 2021
VL 22
IS 21
AR 11636
DI 10.3390/ijms222111636
PG 20
WC Biochemistry & Molecular Biology; Chemistry, Multidisciplinary
WE Science Citation Index Expanded (SCI-EXPANDED)
SC Biochemistry & Molecular Biology; Chemistry
GA XB2SJ
UT WOS:000721181600001
PM 34769066
OA Green Published, gold
DA 2025-03-13
ER

PT J
AU Sebastian, A
   Hum, NR
   Martin, KA
   Gilmore, SF
   Peran, I
   Byers, SW
   Wheeler, EK
   Coleman, MA
   Loots, GG
AF Sebastian, Aimy
   Hum, Nicholas R.
   Martin, Kelly A.
   Gilmore, Sean F.
   Peran, Ivana
   Byers, Stephen W.
   Wheeler, Elizabeth K.
   Coleman, Matthew A.
   Loots, Gabriela G.
TI Single-Cell Transcriptomic Analysis of Tumor-Derived Fibroblasts and
   Normal Tissue-Resident Fibroblasts Reveals Fibroblast Heterogeneity in
   Breast Cancer
SO CANCERS
LA English
DT Article
DE cancer-associated fibroblasts; breast cancer; mammary fat pad; gene
   expression profiling; scRNA-seq; CAF heterogeneity; normal fibroblasts;
   myofibroblasts; inflammatory fibroblasts; pancreatic cancer
ID EPITHELIAL-MESENCHYMAL TRANSITION; CARCINOMA-ASSOCIATED FIBROBLASTS;
   STROMAL FIBROBLASTS; GASTRIC-CANCER; GROWTH-FACTOR; EXPRESSION; IL-6;
   MICROENVIRONMENT; MYOFIBROBLAST; FIBRONECTIN
AB Cancer-associated fibroblasts (CAFs) are a prominent stromal cell type in solid tumors and molecules secreted by CAFs play an important role in tumor progression and metastasis. CAFs coexist as heterogeneous populations with potentially different biological functions. Although CAFs are a major component of the breast cancer stroma, molecular and phenotypic heterogeneity of CAFs in breast cancer is poorly understood. In this study, we investigated CAF heterogeneity in triple-negative breast cancer (TNBC) using a syngeneic mouse model, BALB/c-derived 4T1 mammary tumors. Using single-cell RNA sequencing (scRNA-seq), we identified six CAF subpopulations in 4T1 tumors including: 1) myofibroblastic CAFs, enriched for alpha -smooth muscle actin and several other contractile proteins; 2) 'inflammatory' CAFs with elevated expression of inflammatory cytokines; and 3) a CAF subpopulation expressing major histocompatibility complex (MHC) class II proteins that are generally expressed in antigen-presenting cells. Comparison of 4T1-derived CAFs to CAFs from pancreatic cancer revealed that these three CAF subpopulations exist in both tumor types. Interestingly, cells with inflammatory and MHC class II-expressing CAF profiles were also detected in normal breast/pancreas tissue, suggesting that these phenotypes are not tumor microenvironment-induced. This work enhances our understanding of CAF heterogeneity, and specifically targeting these CAF subpopulations could be an effective therapeutic approach for treating highly aggressive TNBCs.
C1 [Sebastian, Aimy; Hum, Nicholas R.; Martin, Kelly A.; Gilmore, Sean F.; Coleman, Matthew A.; Loots, Gabriela G.] Lawrence Livermore Natl Lab, Phys & Life Sci Directorate, Livermore, CA 94550 USA.
   [Hum, Nicholas R.; Loots, Gabriela G.] Univ Calif Merced, Sch Nat Sci, Merced, CA 95343 USA.
   [Peran, Ivana] Georgetown Univ, Med Ctr, Dept Oncol, Georgetown Lombardi Comprehens Canc Ctr, Washington, DC 20007 USA.
   [Wheeler, Elizabeth K.] Lawrence Livermore Natl Lab, Engn Directorate, Livermore, CA 94550 USA.
   [Loots, Gabriela G.] Univ Calif Davis, Dept Biochem & Mol Med, Sacramento, CA 95817 USA.
C3 United States Department of Energy (DOE); Lawrence Livermore National
   Laboratory; University of California System; University of California
   Merced; Georgetown University; United States Department of Energy (DOE);
   Lawrence Livermore National Laboratory; University of California System;
   University of California Davis
RP Loots, GG (corresponding author), Lawrence Livermore Natl Lab, Phys & Life Sci Directorate, Livermore, CA 94550 USA.; Loots, GG (corresponding author), Univ Calif Merced, Sch Nat Sci, Merced, CA 95343 USA.; Loots, GG (corresponding author), Univ Calif Davis, Dept Biochem & Mol Med, Sacramento, CA 95817 USA.
EM sebastian4@llnl.gov; hum3@llnl.gov; martin249@llnl.gov;
   gilmore24@llnl.gov; ip62@georgetown.edu; byerss@georgetown.edu;
   wheeler16@llnl.gov; coleman16@llnl.gov; loots1@llnl.gov
RI Peran, Ivana/AAL-7480-2020; Gilmore, Sean/AAX-1554-2020; Loots,
   Gabriela/AGA-4868-2022; Sebastian, Aimy/S-5230-2017
OI Hum, Nicholas/0000-0003-1605-3193; Martin, Kelly A./0000-0002-0025-994X;
   Coleman, Matthew/0000-0003-1389-4018; Loots,
   Gabriela/0000-0001-9546-5561; Sebastian, Aimy/0000-0002-7822-7040
FU LLNL internal grants LDRD [19-SI-003, 17-ER-121]; DOE; Comprehensive
   Cancer Center Support Grant (CCCSG) - National Cancer Institute [NCI
   P30CA093373]
FX The research was supported by LLNL internal grants LDRD grant number
   19-SI-003 and 17-ER-121. K.A.M. was supported by DOE-funded Livermore
   Graduate Scholar Program. G.G.L was also supported in part by a UC Davis
   Comprehensive Cancer Center Support Grant (CCCSG) awarded by the
   National Cancer Institute (NCI P30CA093373).
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NR 74
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U1 12
U2 64
PU MDPI
PI BASEL
PA ST ALBAN-ANLAGE 66, CH-4052 BASEL, SWITZERLAND
EI 2072-6694
J9 CANCERS
JI Cancers
PD MAY
PY 2020
VL 12
IS 5
AR 1307
DI 10.3390/cancers12051307
PG 22
WC Oncology
WE Science Citation Index Expanded (SCI-EXPANDED)
SC Oncology
GA LW6HT
UT WOS:000539246000248
PM 32455670
OA Green Published, gold
HC Y
HP N
DA 2025-03-13
ER

PT J
AU Suchanski, J
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AF Suchanski, Jaroslaw
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   Nowinska, Katarzyna
   Rys, Janusz
   Dziegiel, Piotr
   Kieda, Claudine
   Ugorski, Maciej
TI Podoplanin increases the migration of human fibroblasts and affects the
   endothelial cell network formation: A possible role for cancerassociated
   fibroblasts in breast cancer progression
SO PLOS ONE
LA English
DT Article
ID VEGF-C EXPRESSION; PLATELET-AGGREGATION; PA2.26 ANTIGEN;
   EPIDERMAL-KERATINOCYTES; MESENCHYMAL TRANSITION; POSITIVE FIBROBLASTS;
   LYMPHATIC SPREAD; POOR-PROGNOSIS; RHO; ENHANCE
AB In our previous studies we showed that in breast cancer podoplanin-positive cancer-associated fibroblasts correlated positively with tumor size, grade of malignancy, lymph node metastasis, lymphovascular invasion and poor patients' outcome. Therefore, the present study was undertaken to assess if podoplanin expressed by fibroblasts can affect malignancy-associated properties of breast cancer cells. Human fibroblastic cell lines (MSU1.1 and Hs 578Bst) overexpressing podoplanin and control fibroblasts were co-cultured with breast cancer MDA-MB-231 and MCF7 cells and the impact of podoplanin expressed by fibroblasts on migration and invasiveness of breast cancer cells were studied in vitro. Migratory and invasive properties of breast cancer cells were not affected by the presence of podoplanin on the surface of fibroblasts. However, ectopic expression of podoplanin highly increases the migration of MSU1.1 and Hs 578Bst fibroblasts. The present study also revealed for the first time, that podoplanin expression affects the formation of pseudo tubes by endothelial cells. When human HSkMEC cells were co-cultured with podoplanin-rich fibroblasts the endothelial cell capillary-like network was characterized by significantly lower numbers of nodes and meshes than in co-cultures of endothelial cells with podoplanin-negative fibroblasts. The question remains as to how our experimental data can be correlated with previous clinical data showing an association between the presence of podoplanin-positive cancer-associated fibroblasts and progression of breast cancer. Therefore, we propose that expression of podoplanin by fibroblasts facilitates their movement into the tumor stroma, which creates a favorable microenvironment for tumor progression by increasing the number of cancer-associated fibroblasts, which produce numerous factors affecting proliferation, survival and invasion of cancer cells. In accordance with this, the present study revealed for the first time, that such podoplanin-mediated effects can affect tube formation by endothelial cells and participate in their pathological properties in the tumor context. Our experimental data were supported by clinical studies. First, when IDC and DCIS were analyzed by immunohistochemistry according to the presence of podoplanin-expressing cells, the numbers of cancer-associated fibroblasts with high expression of this glycoprotein were significantly higher in IDC than in DCIS cases. Second, using immunofluorescence, the colocalization of PDPN-positive CAFs with blood vessels stained with antibody directed against CD34 was observed in tumor stroma of IDC samples.
C1 [Suchanski, Jaroslaw; Zacharski, Maciej; Ugorski, Maciej] Wroclaw Univ Environm & Life Sci, Fac Vet Med, Dept Biochem & Mol Biol, Wroclaw, Poland.
   [Tejchman, Anna; Ugorski, Maciej] Polish Acad Sci, Ludwik Hirszfeld Inst Immunol & Expt Therapy, Lab Glycobiol, Wroclaw, Poland.
   [Tejchman, Anna; Kieda, Claudine] CNRS, UPR4301, Ctr Mol Biophys Cell Recognit & Glycobiol, Orleans, France.
   [Piotrowska, Aleksandra; Grzegrzolka, Jedrzej; Nowinska, Katarzyna; Dziegiel, Piotr] Wroclaw Med Univ, Dept Histol & Embryol, Wroclaw, Poland.
   [Chodaczek, Grzegorz] EIT Wroclaw Res Ctr, Wroclaw, Poland.
   [Rys, Janusz] Maria Sklodowska Curie Mem Inst Oncol, Cracow Branch, Ctr Oncol, Dept Tumor Pathol, Krakow, Poland.
   [Dziegiel, Piotr] Wroclaw Univ, Sch Phys Educ, Dept Physiotherapy, Warsaw, Poland.
   [Kieda, Claudine] Mil Med Inst, Warsaw, Poland.
C3 Wroclaw University of Environmental & Life Sciences; Polish Academy of
   Sciences; Hirszfeld Institute of Immunology & Experimental Therapy of
   the Polish Academy of Sciences; Centre National de la Recherche
   Scientifique (CNRS); CNRS - Institute of Chemistry (INC); Wroclaw
   Medical University; Maria Sklodowska-Curie National Research Institute
   of Oncology; University of Wroclaw; Jozef Pilsudski University Physical
   Education in Warsaw; Military Medical Institute
RP Ugorski, M (corresponding author), Wroclaw Univ Environm & Life Sci, Fac Vet Med, Dept Biochem & Mol Biol, Wroclaw, Poland.; Ugorski, M (corresponding author), Polish Acad Sci, Ludwik Hirszfeld Inst Immunol & Expt Therapy, Lab Glycobiol, Wroclaw, Poland.; Kieda, C (corresponding author), CNRS, UPR4301, Ctr Mol Biophys Cell Recognit & Glycobiol, Orleans, France.; Kieda, C (corresponding author), Mil Med Inst, Warsaw, Poland.
EM claudine.keda@cnrs-orleans.fr; maciej.ugorski@upwr.edu.pl
RI Zacharski, Maciej/K-7138-2018; Chodaczek, Grzegorz/G-4073-2014; Ugorsku,
   Maciej/AAJ-1050-2020; Nowińska, Katarzyna/AAS-8363-2021; Kieda,
   Claudine/U-1361-2019
OI Suchanski, Jaroslaw/0000-0002-2672-1020; Zacharski,
   Maciej/0000-0002-9947-4980; Piotrowska, Aleksandra/0000-0003-4093-7386;
   Nowinska, Katarzyna/0000-0001-8316-8893; Grzegrzolka,
   Jedrzej/0000-0002-1548-279X; Ugorski, Maciej/0000-0003-0299-8372;
   Dziegiel, Piotr/0000-0002-8292-1385
FU National Science Center (Poland) [N N401 570340]; Wroclaw Centre of
   Biotechnology, programme the Leading National Research Centre (KNOW);
   French National league against cancer; CNRS PAN agreement IITD/CBM;
   Ministry of Polish Education and Research; French Ministry of Foreign
   Affairs; National Science Centre (Poland) [2014/15/B/NZ6/03502]
FX Grant support for this work was provided by the National Science Center
   (Poland): grant no. N N401 570340. Publication was supported by Wroclaw
   Centre of Biotechnology, programme the Leading National Research Centre
   (KNOW) for years 2014-2018, French National league against cancer (CK),
   CNRS PAN agreement IITD/CBM (CK). AT was a PhD student funded by the
   Ministry of Polish Education and Research and the French Ministry of
   Foreign Affairs. GC was supported by the National Science Centre
   (Poland) grant no. 2014/15/B/NZ6/03502.
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NR 53
TC 38
Z9 38
U1 0
U2 14
PU PUBLIC LIBRARY SCIENCE
PI SAN FRANCISCO
PA 1160 BATTERY STREET, STE 100, SAN FRANCISCO, CA 94111 USA
SN 1932-6203
J9 PLOS ONE
JI PLoS One
PD SEP 22
PY 2017
VL 12
IS 9
AR 0184970
DI 10.1371/journal.pone.0184970
PG 29
WC Multidisciplinary Sciences
WE Science Citation Index Expanded (SCI-EXPANDED)
SC Science & Technology - Other Topics
GA FH9IR
UT WOS:000411524700013
OA Green Published, gold, Green Submitted
DA 2025-03-13
ER

PT J
AU Zhang, GL
   He, YQ
   Liu, YW
   Du, Y
   Yang, CX
   Gao, F
AF Zhang, Guoliang
   He, Yiqing
   Liu, Yiwen
   Du, Yan
   Yang, Cuixia
   Gao, Feng
TI Reduced hyaluronan cross-linking induces breast cancer malignancy in a
   CAF-dependent manner
SO CELL DEATH & DISEASE
LA English
DT Article
ID INTER-ALPHA-INHIBITOR; HEAVY-CHAINS; TUMOR-GROWTH; FIBROBLASTS; TSG-6;
   OLIGOSACCHARIDES; EXPRESSION; PATHWAYS; STROMA; CD44
AB Hyaluronan (HA) cross-linking is a conformational state of HA, a covalent complex between HA and heavy chains (HCs) from inter-alpha-trypsin inhibitor (I-alpha-I) mediated by tumor necrosis factor-induced protein 6 (TSG6). Cross-linked HA has been identified as a protective factor in physiological and inflammatory conditions. However, the state of HA cross-linking in tumor microenvironment has not been fully elucidated. As a major constituent of the extracellular matrix (ECM), HA is mainly synthesized by cancer-associated fibroblasts (CAFs). Our study aimed to clarify the role of HA cross-linking in breast cancer malignancy. Compared to normal mammary gland tissues, cross-linked HA levels were significantly decreased in breast cancer and associated with tumor malignancy. When NFbs were activated into CAFs, the levels of cross-linked HA and TSG6 were both suppressed. Through upregulating TSG6, CAFs restored the high level of cross-linked HA and significantly inhibited breast cancer malignancy, whereas NFbs promoted the malignancy when the cross-linked HA level was reduced. Furthermore, the inhibitory role of HA cross-linking in tumor malignancy was directly verified using the synthesized HA-HC complex. Collectively, our study found that the deficiency of cross-linked HA induced breast cancer malignancy in a CAF-dependent manner, suggesting that recovering HA cross-linking may be a potential therapeutic strategy.
C1 [Zhang, Guoliang; He, Yiqing; Liu, Yiwen; Du, Yan; Yang, Cuixia; Gao, Feng] Shanghai Jiao Tong Univ Affiliated Peoples Hosp 6, Dept Mol Biol, 600 Yishan Rd, Shanghai 200233, Peoples R China.
   [Zhang, Guoliang; Yang, Cuixia; Gao, Feng] Shanghai Jiao Tong Univ Affiliated Peoples Hosp 6, Dept Clin Lab, 600 Yishan Rd, Shanghai 200233, Peoples R China.
C3 Shanghai Jiao Tong University; Shanghai Jiao Tong University
RP Yang, CX; Gao, F (corresponding author), Shanghai Jiao Tong Univ Affiliated Peoples Hosp 6, Dept Mol Biol, 600 Yishan Rd, Shanghai 200233, Peoples R China.; Yang, CX; Gao, F (corresponding author), Shanghai Jiao Tong Univ Affiliated Peoples Hosp 6, Dept Clin Lab, 600 Yishan Rd, Shanghai 200233, Peoples R China.
EM dr.steven@163.com; gao3507@126.com
RI He, Yiqing/LXA-1503-2024; Gao, Feng/HLX-4053-2023; zhang,
   guoliang/IYJ-8967-2023
OI Gao, Feng/0000-0002-4731-3886
FU National Natural Science Foundation of China [82073199, 81872357,
   81974446, 81974445, 81702852]; Shanghai Municipal Education
   Commission-Gaofeng Clinical Medicine Grant Support [20171924]; Shanghai
   Pujiang Program [2019PJD037]; Doctor Innovation Fund of Shanghai
   Jiaotong University School of Medicine [BXJ201944]; Shanghai "Rising
   Stars of Medical Talent" Youth Development Program [SHWRS2020_087]
FX This work was supported by the National Natural Science Foundation of
   China (82073199, 81872357, 81974446, 81974445, and 81702852), Shanghai
   Municipal Education Commission-Gaofeng Clinical Medicine Grant Support
   (20171924), Shanghai Pujiang Program (2019PJD037), Shanghai "Rising
   Stars of Medical Talent" Youth Development Program (SHWRS2020_087), and
   Doctor Innovation Fund of Shanghai Jiaotong University School of
   Medicine (BXJ201944).
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NR 48
TC 17
Z9 17
U1 0
U2 12
PU SPRINGERNATURE
PI LONDON
PA CAMPUS, 4 CRINAN ST, LONDON, N1 9XW, ENGLAND
SN 2041-4889
J9 CELL DEATH DIS
JI Cell Death Dis.
PD JUN 7
PY 2021
VL 12
IS 6
AR 586
DI 10.1038/s41419-021-03875-6
PG 14
WC Cell Biology
WE Science Citation Index Expanded (SCI-EXPANDED)
SC Cell Biology
GA UD6JN
UT WOS:000687311600004
PM 34099638
OA Green Published, gold
DA 2025-03-13
ER

PT J
AU Ahn, S
   Kwon, A
   Huh, YH
   Rhee, S
   Song, WK
AF Ahn, Suyeon
   Kwon, Ahreum
   Huh, Yun Hyun
   Rhee, Sangmyung
   Song, Woo Keun
TI Tumor-derived miR-130b-3p induces cancer-associated fibroblast
   activation by targeting SPIN90 in luminal A breast cancer
SO ONCOGENESIS
LA English
DT Article
ID MICRORNAS; CELLS; MICROENVIRONMENT; MYOFIBROBLASTS; PROGRESSION;
   DEPLETION; PROTEIN
AB Cancer-associated fibroblasts (CAFs) in the tumor microenvironment (TME) interact closely with cancer cells to promote tumor development. Downregulation of SPIN90 in CAFs has been reported to facilitate breast cancer progression, but the underlying mechanism has not been elucidated. Here, we demonstrate that miR-130b-3p directly downregulates SPIN90 in stromal fibroblasts, leading to their differentiation into CAFs. As the decrease of SPIN90 in CAFs was shown to be more prominent in estrogen receptor (ER)-positive breast tumors in this study, miR-130b-3p was selected by bioinformatics analysis of data from patients with ER-positive breast cancer. Ectopic expression of miR-130b-3p in fibroblasts accelerated their differentiation to CAFs that promote cancer cell motility; this was associated with SPIN90 downregulation. We also found that miR-130b-3p was generated in luminal A-type cancer cells and activated fibroblasts after being secreted via exosomes from cancer cells. Finally, miR-130b-3p increased in SPIN90-downregulated tumor stroma of luminal A breast cancer patients and MCF7 cell-xenograft model mice. Our data demonstrate that miR-130b-3p is a key modulator that downregulates SPIN90 in breast CAFs. The inverse correlation between miR-130b-3p and SPIN90 in tumor stroma suggests that the miR-130b-3p/SPIN90 axis is clinically significant for CAF activation during breast cancer progression.
C1 [Ahn, Suyeon; Kwon, Ahreum; Song, Woo Keun] Gwangju Inst Sci & Technol, Sch Life Sci, Cell Logist Res Ctr, Gwangju 61005, South Korea.
   [Huh, Yun Hyun] Gwangju Inst Sci & Technol, Sch Life Sci, Gwangju 61005, South Korea.
   [Rhee, Sangmyung] Chung Ang Univ, Dept Life Sci, Seoul 06974, South Korea.
C3 Gwangju Institute of Science & Technology (GIST); Gwangju Institute of
   Science & Technology (GIST); Chung Ang University
RP Song, WK (corresponding author), Gwangju Inst Sci & Technol, Sch Life Sci, Cell Logist Res Ctr, Gwangju 61005, South Korea.; Rhee, S (corresponding author), Chung Ang Univ, Dept Life Sci, Seoul 06974, South Korea.
EM Sangmyung.rhee@cau.ac.kr; wksong@gist.ac.kr
OI Kwon, Ahreum/0000-0002-2424-8372; Ahn, Suyeon/0000-0001-6992-3442
FU Cell Logistics Research center [NRF-2016R1A5A1007318]; National Research
   Foundation of Korea (NRF) [NRF-2020R1A2C2007389]; Korean government
   (MSIT); KBRI basic research program through the Korea Brain Research
   Institute - Ministry of Science and ICT [21-BR-03-05]
FX This research was supported by a grant from the Cell Logistics Research
   center (NRF-2016R1A5A1007318), the National Research Foundation of Korea
   (NRF) (NRF-2020R1A2C2007389, SR) funded by the Korean government (MSIT),
   and the KBRI basic research program through the Korea Brain Research
   Institute funded by the Ministry of Science and ICT (21-BR-03-05). We
   would also like to thank Dr. H. Kim (GIST Central Research Facility) for
   excellent technical support in imaging using the research slide scanner.
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NR 61
TC 13
Z9 16
U1 0
U2 3
PU SPRINGERNATURE
PI LONDON
PA CAMPUS, 4 CRINAN ST, LONDON, N1 9XW, ENGLAND
SN 2157-9024
J9 ONCOGENESIS
JI Oncogenesis
PD AUG 10
PY 2022
VL 11
IS 1
AR 47
DI 10.1038/s41389-022-00422-6
PG 13
WC Oncology
WE Science Citation Index Expanded (SCI-EXPANDED)
SC Oncology
GA 3R1JL
UT WOS:000838675400001
PM 35948548
OA Green Published, gold
DA 2025-03-13
ER

PT J
AU Lappano, R
   Talia, M
   Cirillo, F
   Rigiracciolo, DC
   Scordamaglia, D
   Guzzi, R
   Miglietta, AM
   De Francesco, EM
   Belfiore, A
   Sims, AH
   Maggiolini, M
AF Lappano, Rosamaria
   Talia, Marianna
   Cirillo, Francesca
   Rigiracciolo, Damiano Cosimo
   Scordamaglia, Domenica
   Guzzi, Rita
   Miglietta, Anna Maria
   De Francesco, Ernestina Marianna
   Belfiore, Antonino
   Sims, Andrew H.
   Maggiolini, Marcello
TI The IL1β-IL1R signaling is involved in the stimulatory effects triggered
   by hypoxia in breast cancer cells and cancer-associated fibroblasts
   (CAFs)
SO JOURNAL OF EXPERIMENTAL & CLINICAL CANCER RESEARCH
LA English
DT Article
DE Hypoxia; Hypoxia inducible factor-1 alpha (HIF-1 alpha); Interleukin-1
   beta (IL-beta); G protein estrogen receptor (GPER); Breast cancer;
   Cancer-associated fibroblasts (CAFs)
ID COMPREHENSIVE MOLECULAR PORTRAITS; INDUCIBLE FACTORS; UP-REGULATION;
   STEM-CELLS; INTERLEUKIN-1; INFLAMMATION; EXPRESSION; CYCLOOXYGENASE-2;
   GPR30; IDENTIFICATION
AB Background: Hypoxia plays a relevant role in tumor-related inflammation toward the metastatic spread and cancer aggressiveness. The pro-inflammatory cytokine interleukin-1 beta (IL-beta) and its cognate receptor IL1R1 contribute to the initiation and progression of breast cancer determining pro-tumorigenic inflammatory responses. The transcriptional target of the hypoxia inducible factor-1 alpha (HIF-1 alpha) namely the G protein estrogen receptor (GPER) mediates a feedforward loop coupling IL-1 beta induction by breast cancer-associated fibroblasts (CAFs) to IL1R1 expression by breast cancer cells toward the regulation of target genes and relevant biological responses.
   Methods: In order to ascertain the correlation of IL-beta with HIF-1 alpha and further hypoxia-related genes in triple-negative breast cancer (TNBC) patients, a bioinformatics analysis was performed using the information provided by The Invasive Breast Cancer Cohort of The Cancer Genome Atlas (TCGA) project and Molecular Taxonomy of Breast Cancer International Consortium (METABRIC) datasets. Gene expression correlation, statistical analysis and gene set enrichment analysis (GSEA) were carried out with R studio packages. Pathway enrichment analysis was evaluated with Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway. TNBC cells and primary CAFs were used as model system. The molecular mechanisms implicated in the regulation of IL-1 beta by hypoxia toward a metastatic gene expression profile and invasive properties were assessed performing gene and protein expression studies, PCR arrays, gene silencing and immunofluorescence analysis, co-immunoprecipitation and ChiP assays, ELISA, cell spreading, invasion and spheroid formation.
   Results: We first determined that IL-1 beta expression correlates with the levels of HIF-1 alpha as well as with a hypoxia-related gene signature in TNBC patients. Next, we demonstrated that hypoxia triggers a functional liaison among HIF-1 alpha, GPER and the IL-1 beta/IL1R1 signaling toward a metastatic gene signature and a feed-forward loop of IL-1 beta that leads to proliferative and invasive responses in TNBC cells. Furthermore, we found that the IL-1 beta released in the conditioned medium of TNBC cells exposed to hypoxic conditions promotes an invasive phenotype of CAFs.
   Conclusions: Our data shed new light on the role of hypoxia in the activation of the IL-1 beta/IL1R1 signaling, which in turn triggers aggressive features in both TNBC cells and CAFs. Hence, our findings provide novel evidence regarding the mechanisms through which the hypoxic tumor microenvironment may contribute to breast cancer progression and suggest further targets useful in more comprehensive therapeutic strategies.
C1 [Lappano, Rosamaria; Talia, Marianna; Cirillo, Francesca; Rigiracciolo, Damiano Cosimo; Scordamaglia, Domenica; Maggiolini, Marcello] Univ Calabria, Dept Pharm Hlth & Nutr Sci, I-87036 Arcavacata Di Rende, Italy.
   [Guzzi, Rita] Univ Calabria, Dept Phys, I-87036 Arcavacata Di Rende, Italy.
   [Miglietta, Anna Maria] Reg Hosp Cosenza, I-87100 Cosenza, Italy.
   [De Francesco, Ernestina Marianna; Belfiore, Antonino] Univ Catania, Garibaldi Nesima Hosp, Dept Clin & Expt Med, Endocrinol, I-95122 Catania, Italy.
   [Sims, Andrew H.] Univ Edinburgh, MRC Inst Genet & Mol Med, Edinburgh EH4 2XR, Midlothian, Scotland.
C3 University of Calabria; University of Calabria; Presidio Ospedaliero
   Garibaldi-Nesima; University of Catania; University of Edinburgh
RP Lappano, R; Maggiolini, M (corresponding author), Univ Calabria, Dept Pharm Hlth & Nutr Sci, I-87036 Arcavacata Di Rende, Italy.
EM rosamaria.lappano@unical.it; marcello.maggiolini@unical.it
RI Maggiolini, Marcello/Z-4729-2019; CIRILLO, FRANCESCA/K-2612-2018; Sims,
   Andrew/E-4819-2012; Rigiracciolo, Damiano Cosimo/GRS-9234-2022; De
   Francesco, Ernestina Marianna/LQK-4482-2024; Guzzi, Rita/M-7654-2015;
   BELFIORE, Antonino/B-4652-2011
OI De Francesco, Ernestina Marianna/0000-0002-2810-6128; Guzzi,
   Rita/0000-0001-6769-3399; BELFIORE, Antonino/0000-0002-6181-4193; Talia,
   Marianna/0000-0002-3440-5618
FU Fondazione AIRC [23369, 21322, 21651]; Italian Minister of University
   and Research [MIUR]]-PON R&I 2014-2020 'AIM Attrazione e Mobilita
   Internazionale' [3407/2018]
FX Fondazione AIRC supported AB (IG n. 23369), MM (IG n. 21322) and EMDF
   (Start-Up Grant 21651). DCR was supported by Italian Minister of
   University and Research [MIUR, D.D. n. 3407/2018]-PON R&I 2014-2020 'AIM
   Attrazione e Mobilita Internazionale'.
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NR 92
TC 56
Z9 60
U1 1
U2 17
PU BMC
PI LONDON
PA CAMPUS, 4 CRINAN ST, LONDON N1 9XW, ENGLAND
EI 1756-9966
J9 J EXP CLIN CANC RES
JI J. Exp. Clin. Cancer Res.
PD AUG 10
PY 2020
VL 39
IS 1
AR 153
DI 10.1186/s13046-020-01667-y
PG 22
WC Oncology
WE Science Citation Index Expanded (SCI-EXPANDED)
SC Oncology
GA NC5KR
UT WOS:000561254200001
PM 32778144
OA gold, Green Published
DA 2025-03-13
ER

PT J
AU Huang, JY
   Zhang, HY
   Ma, LS
   Ma, NH
   Luo, NC
   Jin, WY
   Shi, JB
   Xu, SJ
   Xiong, Y
AF Huang, Jingyi
   Zhang, Hongyan
   Ma, Lisha
   Ma, Ninghui
   Luo, Ningchao
   Jin, Wanyu
   Shi, Jingbin
   Xu, Shujun
   Xiong, Yang
TI Rhein and hesperidin nanoparticles remodel tumor immune microenvironment
   by reducing CAFs and CCL2 secreted by CAAs for efficient triple-negative
   breast cancer therapy
SO INTERNATIONAL IMMUNOPHARMACOLOGY
LA English
DT Article
DE Triple-negative breast cancer; Cancer-associated fibroblasts;
   Cancer-associated adipocytes; C-C Motif chemokine ligand 2; Tumor immune
   microenvironment
ID CELLS; FIBROBLASTS; ADIPOCYTES; BIOLOGY
AB In triple-negative breast cancer (TNBC), the tumor immune microenvironment (TIME) is a highly heterogeneous ecosystem that exerts indispensable roles in tumorigenesis and tumor progression. Cancer-associated fibroblasts (CAFs) and cancer-associated adipocytes (CAAs) are the main matrix components in the TIME of TNBC. CAFs mediate the edesmoplastic response, which is a major driver of the immunosuppressive microenvironment to promote tumor growth. In addition, CAAs, a type of tumor-educated adipocyte, participate in crosstalk with breast cancer and are capable of secreting various cytokines, adipokines and chemokines, especially C-C Motif Chemokine Ligand 2 (CCL2), resulting in changes of cancer cell phenotype and function. Therefore, how to treat tumors by regulating the CAFs and the secretion of CCL2 by CAAs in TIME is investigated here. Our research group previously found that rhein (Rhe) has been identified as effective against CAFs, while hesperidin (Hes) could effectively diminish CCL2 secretion by CAAs. Inspired by the above, we developed unique PLGA-based nanoparticles loaded with Rhe and Hes (RH-NP) using the emulsion solvent diffusion method. The RH-NP particles have an average size of 114.1 +/- 0.98 nm. RH-NP effectively reduces CAFs and inhibits CCL2 secretion by CAAs, promoting increased infiltration of cytotoxic T cells and reducing immunosuppressive cell presence within tumors. This innovative, safe, low-toxic, and highly effective anti-tumor strategy could be prospective in TNBC treatment.
C1 [Huang, Jingyi; Zhang, Hongyan; Ma, Lisha; Ma, Ninghui; Luo, Ningchao; Jin, Wanyu; Shi, Jingbin; Xu, Shujun; Xiong, Yang] Zhejiang Chinese Med Univ, Sch Pharmaceut Sci, Hangzhou 310053, Zhejiang, Peoples R China.
   [Huang, Jingyi; Zhang, Hongyan; Ma, Lisha; Ma, Ninghui; Luo, Ningchao; Jin, Wanyu; Shi, Jingbin; Xu, Shujun; Xiong, Yang] Zhejiang Chinese Med Univ, Acad Chinese Med Sci, Hangzhou 310053, Zhejiang, Peoples R China.
C3 Zhejiang Chinese Medical University; Zhejiang Chinese Medical University
RP Xiong, Y (corresponding author), Zhejiang Chinese Med Univ, Sch Pharmaceut Sci, Hangzhou 310053, Zhejiang, Peoples R China.; Xiong, Y (corresponding author), Zhejiang Chinese Med Univ, Acad Chinese Med Sci, Hangzhou 310053, Zhejiang, Peoples R China.
EM xiongyang@zcmu.edu.cn
RI Ma, Lisha/HMD-4095-2023; Huang, YJ/G-4624-2010
FU Public Plat-form of Medical Research Center, Academy of Chinese Medical
   Science, Zhejiang Chinese Medical University; National Natural Science
   Foundation of Zhejiang Province [LZ22H290001]; National Natural Science
   Foundation of China [82174095]; Zhejiang Province Traditional Chinese
   Medicine Science and Technology Project [2023ZL362]
FX We appreciate the great experimental support from the Public Plat-form
   of Medical Research Center, Academy of Chinese Medical Science, Zhejiang
   Chinese Medical University. The authors greatly appreciate the financial
   support of the National Natural Science Foundation of Zhejiang Province
   (LZ22H290001) , the National Natural Science Foundation of China
   (82174095) , and Zhejiang Province Traditional Chinese Medicine Science
   and Technology Project (2023ZL362) .
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NR 46
TC 3
Z9 3
U1 11
U2 12
PU ELSEVIER
PI AMSTERDAM
PA RADARWEG 29, 1043 NX AMSTERDAM, NETHERLANDS
SN 1567-5769
EI 1878-1705
J9 INT IMMUNOPHARMACOL
JI Int. Immunopharmacol.
PD NOV 15
PY 2024
VL 141
AR 113001
DI 10.1016/j.intimp.2024.113001
EA AUG 2024
PG 9
WC Immunology; Pharmacology & Pharmacy
WE Science Citation Index Expanded (SCI-EXPANDED)
SC Immunology; Pharmacology & Pharmacy
GA E3D0Y
UT WOS:001301827900001
PM 39186835
DA 2025-03-13
ER

PT J
AU Wu, RR
   Roy, AM
   Tokumaru, Y
   Gandhi, S
   Asaoka, M
   Oshi, M
   Yan, L
   Ishikawa, T
   Takabe, K
AF Wu, Rongrong
   Roy, Arya Mariam
   Tokumaru, Yoshihisa
   Gandhi, Shipra
   Asaoka, Mariko
   Oshi, Masanori
   Yan, Li
   Ishikawa, Takashi
   Takabe, Kazuaki
TI NR2F1, a Tumor Dormancy Marker, Is Expressed Predominantly in
   Cancer-Associated Fibroblasts and Is Associated with Suppressed Breast
   Cancer Cell Proliferation
SO CANCERS
LA English
DT Article
DE breast cancer; cancer associated fibroblasts; dormancy; single cell
   sequence; TGF beta
ID NEOADJUVANT CHEMOTHERAPY; EARLY DISSEMINATION; T-CELLS; METASTASIS;
   MICROENVIRONMENT; HETEROGENEITY; INFILTRATION; BIOMARKERS; PATTERNS;
   SURVIVAL
AB Simple Summary Tumor dormancy is a state in which some cancer cells are dormant by less cell proliferation, and are resistant to treatments, thus leading to late recurrence. As nuclear receptor subfamily 2 group F member 1 (NR2F1) is a biomarker of dormancy shown in experimental settings, we studied its clinical relevance by analyzing comprehensive gene expression profiles of approximately 7000 breast cancer patients using computational biological approaches. NR2F1 gene expression of bulk tumors correlated with the suppression of cell proliferation and metastasis-related pathways, but not with metastasis or survival. Using single-cell sequence cohorts, we found that NR2F1 was predominantly expressed in cancer-associated fibroblasts, particularly in inflammatory type, rather than in cancer cells. Further, NR2F1 expression in breast cancer cells did not consistently correlate with stem cell-like traits. Our findings suggest that the NR2F1 gene expression signal from a patient's bulk tumor is not from the cancer cells. Background: Tumor dormancy is a crucial mechanism responsible for the late recurrence of breast cancer. Thus, we investigated the clinical relevance of the expression of NR2F1, a known dormancy biomarker. Methods: A total of 6758 transcriptomes of bulk tumors from multiple breast cancer patient cohorts and two single-cell sequence cohorts were analyzed. Results: Breast cancer (BC) with high NR2F1 expression enriched TGF beta signaling, multiple metastases, and stem cell-related pathways. Cell proliferation-related gene sets were suppressed, and MKi67 expression was lower in high NR2F1 BC. In tumors with high Nottingham grade, NR2F1 expression was found to be lower. There was no consistent relationship between NR2F1 expression and metastasis or survival. Cancer mutation rates, immune responses, and immune cell infiltrations were lower in high NR2F1 tumors, whereas the infiltration of stromal cells including cancer-associated fibroblasts (CAFs) was higher. NR2F1 was predominantly expressed in CAFs, particularly inflammatory CAFs, rather than in cancer cells, consistently in the two single-cell sequence cohorts. Conclusions: NR2F1 expression in breast cancer is associated with tumor dormancy traits, and it is predominantly expressed in CAFs in the tumor microenvironment.
C1 [Wu, Rongrong; Takabe, Kazuaki] Roswell Pk Comprehens Canc Ctr, Dept Surg Oncol, Buffalo, NY 14263 USA.
   [Wu, Rongrong; Asaoka, Mariko; Ishikawa, Takashi; Takabe, Kazuaki] Tokyo Med Univ, Dept Breast Surg & Oncol, Tokyo 1608402, Japan.
   [Roy, Arya Mariam; Gandhi, Shipra] Roswell Pk Comprehens Canc Ctr, Dept Med, Buffalo, NY 14263 USA.
   [Tokumaru, Yoshihisa] Gifu Univ, Grad Sch Med, Dept Surg Oncol, Gifu 5011193, Japan.
   [Oshi, Masanori] Yokohama City Univ, Grad Sch Med, Dept Gastroenterol Surg, Yokohama, Kanagawa 2360004, Japan.
   [Yan, Li] Roswell Pk Comprehens Canc Ctr, Dept Biostat & Bioinformat, Buffalo, NY 14263 USA.
   [Takabe, Kazuaki] Univ Buffalo, Jacobs Sch Med & Biomed Sci, Dept Surg, Buffalo, NY 14263 USA.
   [Takabe, Kazuaki] Niigata Univ, Grad Sch Med & Dent Sci, Dept Surg, Niigata 9518510, Japan.
   [Takabe, Kazuaki] Fukushima Med Univ, Dept Breast Surg, Fukushima 9601295, Japan.
C3 Roswell Park Comprehensive Cancer Center; Tokyo Medical University;
   Roswell Park Comprehensive Cancer Center; Gifu University; Yokohama City
   University; Roswell Park Comprehensive Cancer Center; State University
   of New York (SUNY) System; University at Buffalo, SUNY; Niigata
   University; Fukushima Medical University
RP Takabe, K (corresponding author), Roswell Pk Comprehens Canc Ctr, Dept Surg Oncol, Buffalo, NY 14263 USA.; Takabe, K (corresponding author), Tokyo Med Univ, Dept Breast Surg & Oncol, Tokyo 1608402, Japan.; Takabe, K (corresponding author), Univ Buffalo, Jacobs Sch Med & Biomed Sci, Dept Surg, Buffalo, NY 14263 USA.; Takabe, K (corresponding author), Niigata Univ, Grad Sch Med & Dent Sci, Dept Surg, Niigata 9518510, Japan.; Takabe, K (corresponding author), Fukushima Med Univ, Dept Breast Surg, Fukushima 9601295, Japan.
EM rongrong.wu@roswellpark.org; arya.roy@roswellpark.org;
   yt1090@gifu-u.ac.jp; shipra.gandhi@roswellpark.org;
   Masaoka@tokyo-med.ac.jp; oshi.mas.wc@yokohama-cu.ac.jp;
   li.yan@roswellpark.org; tishik@tokyo-med.ac.jp;
   kazuaki.takabe@roswellpark.org
RI Gandhi, Sanyam/AFA-4740-2022; Roy, Arya/AAW-2378-2020; Tokumaru,
   Yoshihisa/AAG-2387-2020
OI Wu, Rongrong/0000-0003-1230-2391; Takabe, Kazuaki/0000-0002-6435-4241;
   Tokumaru, Yoshihisa/0000-0003-2481-7739; Gandhi,
   Sanyam/0000-0001-9394-1210; Oshi, Masanori/0000-0002-1404-1570; Asaoka,
   Mariko/0000-0002-4573-4572; GANDHI, SHIPRA/0000-0003-3506-0284
FU National Institutes of Health, USA [R37CA248 -018, R01CA250412,
   R01CA251545, R01EB029596]; US Department of Defense BCRP
   [W81XWH-19-1-0674, W81XWH-19-1-0111]; National Institute of Health TO
   Roswell Park grant [P30CA016056]; National Cancer Institute
   [R37CA248018] Funding Source: NIH RePORTER
FX This research was supported by National Institutes of Health, USA grant
   number R37CA248 -018, R01CA250412, R01CA251545, R01EB029596, as well as
   US Department of Defense BCRP, grant number W81XWH-19-1-0674 and
   W81XWH-19-1-0111, and National Institute of Health TO Roswell Park grant
   number P30CA016056 to K.T.
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NR 67
TC 20
Z9 20
U1 6
U2 17
PU MDPI
PI BASEL
PA ST ALBAN-ANLAGE 66, CH-4052 BASEL, SWITZERLAND
EI 2072-6694
J9 CANCERS
JI Cancers
PD JUN
PY 2022
VL 14
IS 12
AR 2962
DI 10.3390/cancers14122962
PG 16
WC Oncology
WE Science Citation Index Expanded (SCI-EXPANDED)
SC Oncology
GA 2K4IP
UT WOS:000816302000001
PM 35740627
OA gold, Green Published
DA 2025-03-13
ER

PT J
AU Gao, H
   Tian, Q
   Zhu, LZ
   Feng, JT
   Zhou, Y
   Yang, J
AF Gao, Huan
   Tian, Qi
   Zhu, Lizhe
   Feng, Jinteng
   Zhou, Yan
   Yang, Jin
TI 3D Extracellular Matrix Regulates the Activity of T Cells and Cancer
   Associated Fibroblasts in Breast Cancer
SO FRONTIERS IN ONCOLOGY
LA English
DT Article
DE extracellular matrix (ECM); cancer associated fibroblast (CAF); T cell
   activation; tumor microenvironment; breast cancer
ID HALLMARKS; RESPONSES; COLLAGEN; TUMOR
AB BackgroundBreast cancer progression has been gradually recognized as a bidirectional interaction between cancer cells and tumor microenvironment including stroma cells, immune cells, and the dynamically altered ECM. However, there still lacks direct experimental evidences about how ECM properties modulate the activities of stroma and immune cells. MethodThe transcriptomic data and corresponding clinical information of breast cancer pawere obtained from TCGA. Patients were divided into ECM-high, ECM-median and ECM-low groups based on ssGSEA scores of C-ECM genes. The prognostic value of ECM was confirmed by univariate/multivariate Cox regression and survival analyses. GO and KEGG analyses were performed between ECM-high and -low groups. Then associations between ECM characteristics and clinical stages were verified by Masson's trichrome and Sirius red/Fast Green staining of clinical breast cancer tissues. To evaluate the effects of ECM on CAF induction and T cell activation, the MRC-5, NIH/3T-3, primary T cells and Jurkat T cells were encapsulated in 3D collagen with different densities and organizations, and the expression levels of CAF biomarkers and secretion levels of IL-2 were assessed. ResultsECM scores showed broad variation across paracancerous and cancer samples as well as breast cancer molecular subtypes, and patients with different ECM groups showed distinct prognosis. Immunological activity and ECM associated biology processes were identified by GO and KEGG analyses across ECM-high and -low groups. According to MCP-counter algorithm, the infiltration of T cells was significantly lower in the ECM-high group, while CAF abundance was significantly higher. It is furtherly confirmed by clinical samples that collagen density and organization were associate with breast cancer progression. Finally, in vitro 3D-cultured fibroblasts and T cells validated that the density and organization of collagen showed significant effects on CAF induction and T cell activation. ConclusionOur study revealed a new mechanism of T cell immunosuppression and CAF induction, which could be of central importance for the breast cancer invasion and may constitute novel therapeutic targets to improve breast cancer outcomes.
C1 [Gao, Huan; Tian, Qi; Feng, Jinteng; Zhou, Yan; Yang, Jin] Xi An Jiao Tong Univ, Affiliated Hosp 1, Dept Med Oncol, Xian, Peoples R China.
   [Zhu, Lizhe] Xi An Jiao Tong Univ, Affiliated Hosp 1, Dept Breast Surg, Xian, Peoples R China.
C3 Xi'an Jiaotong University; Xi'an Jiaotong University
RP Yang, J (corresponding author), Xi An Jiao Tong Univ, Affiliated Hosp 1, Dept Med Oncol, Xian, Peoples R China.
EM yangjin@xjtu.edu.cn
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NR 35
TC 9
Z9 10
U1 3
U2 20
PU FRONTIERS MEDIA SA
PI LAUSANNE
PA AVENUE DU TRIBUNAL FEDERAL 34, LAUSANNE, CH-1015, SWITZERLAND
SN 2234-943X
J9 FRONT ONCOL
JI Front. Oncol.
PD DEC 9
PY 2021
VL 11
AR 764204
DI 10.3389/fonc.2021.764204
PG 14
WC Oncology
WE Science Citation Index Expanded (SCI-EXPANDED)
SC Oncology
GA YA4ZD
UT WOS:000738342200001
PM 34956886
OA gold, Green Published
DA 2025-03-13
ER

PT J
AU Dou, DW
   Ren, XY
   Han, ML
   Xu, XD
   Ge, X
   Gu, YT
   Wang, XX
AF Dou, Dongwei
   Ren, Xiaoyang
   Han, Mingli
   Xu, Xiaodong
   Ge, Xin
   Gu, Yuanting
   Wang, Xinxing
TI Cancer-Associated Fibroblasts-Derived Exosomes Suppress Immune Cell
   Function in Breast Cancer via the miR-92/PD-L1 Pathway
SO FRONTIERS IN IMMUNOLOGY
LA English
DT Article
DE YAP1; miR-92; PD-L1; CAF; breast cancer
ID IMMUNOTHERAPY; EXPRESSION; INVASION; MICRORNA
AB Cancer-associated fibroblasts (CAFs) are an essential component in the tumor microenvironment and have been reported to contribute to tumor progression through many mechanisms; however, the detailed mechanism underlying the immune-suppression effect of CAFs is not clearly defined. In this study, human breast cancer-derived CAFs were cultured, and CAF-derived exosomes in a culture medium were isolated. Using a miRNA profiles assay, we identify a significantly higher level of microRNA-92 isolated in CAFs exosomes. After treatment by CAF-derived exosomes, breast cancer cells express higher programmed cell death receptor ligand 1 (PD-L1), accompanied with increased miR-92 expression. Increased PD-L1 expression, which was induced by CAF-derived exosomes, significantly promotes apoptosis and impaired proliferation of T cells. The underlying mechanism of this effect was studied, proliferation and migration of breast cancer cells were increased after the transfection of miR-92, LATS2 was recognized as a target gene of miR-92, and further confirmed by a luciferase assay. Immunoprecipitation showed that LATS2 can interact with YAP1, chromatin immunoprecipitation confirmed that after nuclear translocation YAP1 could bind to the enhancer region of PD-L1 to promotes transcription activity. Furthermore, the animal study confirmed that CAFs significantly promoted tumor progression and impaired the function of tumor-infiltrated immune cells in vivo. Our data revealed a novel mechanism that can induce immune suppression in the tumor microenvironment.
C1 [Dou, Dongwei; Han, Mingli; Xu, Xiaodong; Ge, Xin; Gu, Yuanting; Wang, Xinxing] Zhengzhou Univ, Affiliated Hosp 1, Dept Breast Surg, Zhengzhou, Peoples R China.
   [Ren, Xiaoyang] Zhengzhou Univ, Affiliated Hosp 1, Dept Informat, Zhengzhou, Peoples R China.
C3 Zhengzhou University; Zhengzhou University
RP Wang, XX (corresponding author), Zhengzhou Univ, Affiliated Hosp 1, Dept Breast Surg, Zhengzhou, Peoples R China.
EM xx_wang86@163.com
RI Wang, Xinxing/AEU-6408-2022
OI Ge, Xin/0000-0001-8438-802X
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NR 32
TC 154
Z9 159
U1 1
U2 34
PU FRONTIERS MEDIA SA
PI LAUSANNE
PA AVENUE DU TRIBUNAL FEDERAL 34, LAUSANNE, CH-1015, SWITZERLAND
SN 1664-3224
J9 FRONT IMMUNOL
JI Front. Immunol.
PD OCT 9
PY 2020
VL 11
AR 2026
DI 10.3389/fimmu.2020.02026
PG 12
WC Immunology
WE Science Citation Index Expanded (SCI-EXPANDED)
SC Immunology
GA OH2DG
UT WOS:000582379400001
PM 33162971
OA Green Published, gold
DA 2025-03-13
ER

PT J
AU Zhang, J
   Zuo, TT
   Yang, J
   Hu, ZW
   Wang, ZH
   Xu, R
   Ma, SY
   Wei, YW
   Shen, Q
AF Zhang, Jun
   Zuo, Tiantian
   Yang, Jie
   Hu, Zongwei
   Wang, Zhihua
   Xu, Rui
   Ma, Siyu
   Wei, Yawen
   Shen, Qi
TI Hierarchically Releasing Bio-Responsive Nanoparticles for Complete Tumor
   Microenvironment Modulation via TGF-β Pathway Inhibition and TAF
   Reduction
SO ACS APPLIED MATERIALS & INTERFACES
LA English
DT Article
DE tumor microenvironment; nanoparticles; TAFs; TGF-beta; anti-metastasis
ID CANCER-ASSOCIATED FIBROBLASTS; IN-VITRO; STROMAL CELLS; ACTIVATION;
   IMMUNITY; DELIVERY; GROWTH; PROGRESSION; METASTASIS; MECHANISM
AB The aggressive progression of breast cancer is impacted significantly by the tumor microenvironment (TME). The current chemotherapy normally causes cytotoxicity to tumor cells, while does not effectively modulate the TME. Thus, the chemotherapy effect of breast cancer is usually dissatisfactory. In this study, a kind of hierarchically releasing bio-responsive nanoparticles (R(D)/H(S) NPs), constructed by beta-cyclodextrin-grafted heparin and pH-sensitive pseudorotaxane, were investigated to enhance the breast cancer chemotherapeutic efficacy through TME modulation. Doxorubicin (DOX) and transforming growth factor-beta (TGF-beta) receptor inhibitor (SB431542) loaded onto R(D)/H(S) NPs were released rapidly for the respective response to low pH in endosomes/lysosomes and heparanase (HPSE) in TME. Our results showed that R(D)/H(S) NPs effectively inhibited the formation of tumor-associated fibroblasts (TAFs) and reduced TGF-beta and collagen I secretion. Besides, the immunosuppressive microenvironment was effectively reversed into immunogenic, characterized by increased CDS+ and CD4(+) T cell infiltration, which distinctly inhibited breast cancer metastasis. Therefore, R(D)/H(S) NPs remodeled the TME by downregulating TAFs, TGF-beta, and collagen I; activating the immune microenvironment; and then amplifying the chemotherapeutic efficacy of DOX.
C1 [Zhang, Jun; Zuo, Tiantian; Yang, Jie; Hu, Zongwei; Wang, Zhihua; Xu, Rui; Ma, Siyu; Wei, Yawen; Shen, Qi] Shanghai Jiao Tong Univ, Sch Pharm, Shanghai 200240, Peoples R China.
C3 Shanghai Jiao Tong University
RP Shen, Q (corresponding author), Shanghai Jiao Tong Univ, Sch Pharm, Shanghai 200240, Peoples R China.
EM qshen@sjtu.edu.cn
RI xu, rui/GRX-5734-2022; yang, jie/IXN-9789-2023
FU National Natural Science Foundation of China [81972812]; Shanghai Jiao
   Tong University "Starting Program for Young New Teachers" [20X100040060]
FX Q.S. received funding from the National Natural Science Foundation of
   China [grant no. 81972812]. J.Z. received funding from Shanghai Jiao
   Tong University "Starting Program for Young New Teachers", project no.:
   20X100040060.
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NR 65
TC 12
Z9 13
U1 5
U2 47
PU AMER CHEMICAL SOC
PI WASHINGTON
PA 1155 16TH ST, NW, WASHINGTON, DC 20036 USA
SN 1944-8244
EI 1944-8252
J9 ACS APPL MATER INTER
JI ACS Appl. Mater. Interfaces
PD JAN 20
PY 2021
VL 13
IS 2
BP 2256
EP 2268
DI 10.1021/acsami.0c18545
EA JAN 2021
PG 13
WC Nanoscience & Nanotechnology; Materials Science, Multidisciplinary
WE Science Citation Index Expanded (SCI-EXPANDED)
SC Science & Technology - Other Topics; Materials Science
GA PZ2DX
UT WOS:000612551400011
PM 33423468
DA 2025-03-13
ER

PT J
AU Penkert, J
   Ripperger, T
   Schieck, M
   Schlegelberger, B
   Steinemann, D
   Illig, T
AF Penkert, Judith
   Ripperger, Tim
   Schieck, Maximilian
   Schlegelberger, Brigitte
   Steinemann, Doris
   Illig, Thomas
TI On metabolic reprogramming and tumor biology: A comprehensive survey of
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SO ONCOTARGET
LA English
DT Review
DE cancer metabolism; breast cancer; metabolomics; cancer microenvironment;
   tumor heterogeneity
ID OXIDATIVE STRESS; GROWTH-FACTOR; C-MYC; ESTROGEN-RECEPTOR;
   GENE-EXPRESSION; STEM-CELLS; HISTOPATHOLOGICAL ALTERATIONS;
   ALPHA-KETOGLUTARATE; AEROBIC GLYCOLYSIS; MITOCHONDRIAL MASS
AB Altered metabolism in tumor cells has been a focus of cancer research for as long as a century but has remained controversial and vague due to an inhomogeneous overall picture. Accumulating genomic, metabolomic, and lastly panomic data as well as bioenergetics studies of the past few years enable a more comprehensive, systemsbiologic approach promoting deeper insight into tumor biology and challenging hitherto existing models of cancer bioenergetics. Presenting a compendium on breast cancer-specific metabolome analyses performed thus far, we review and compile currently known aspects of breast cancer biology into a comprehensive network, elucidating previously dissonant issues of cancer metabolism. As such, some of the aspects critically discussed in this review include the dynamic interplay or metabolic coupling between cancer (stem) cells and cancer-associated fibroblasts, the intratumoral and intertumoral heterogeneity and plasticity of cancer cell metabolism, the existence of distinct metabolic tumor compartments in need of separate yet simultaneous therapeutic targeting, the reliance of cancer cells on oxidative metabolism and mitochondrial power, and the role of pro-inflammatory, pro-tumorigenic stromal conditioning. Comprising complex breast cancer signaling networks as well as combined metabolomic and genomic data, we address metabolic consequences of mutations in tumor suppressor genes and evaluate their contribution to breast cancer predisposition in a germline setting, reasoning for distinct personalized preventive and therapeutic measures. The review closes with a discussion on central root mechanisms of tumor cell metabolism and rate-limiting steps thereof, introducing essential strategies for therapeutic targeting.
C1 [Penkert, Judith; Ripperger, Tim; Schieck, Maximilian; Schlegelberger, Brigitte; Steinemann, Doris; Illig, Thomas] Hannover Med Sch, Inst Human Genet, Hannover, Germany.
   [Illig, Thomas] Hannover Med Sch, Hannover Unified Biobank, Hannover, Germany.
C3 Hannover Medical School; Hannover Medical School
RP Illig, T (corresponding author), Hannover Med Sch, Inst Human Genet, Hannover, Germany.; Illig, T (corresponding author), Hannover Med Sch, Hannover Unified Biobank, Hannover, Germany.
EM Illig.Thomas@mh-hannover.de
RI Schieck, Maximilian/D-4121-2013
OI Schieck, Maximilian/0000-0001-5878-0546; Ripperger,
   Tim/0000-0001-6470-8612
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NR 178
TC 47
Z9 52
U1 0
U2 30
PU IMPACT JOURNALS LLC
PI ORCHARD PARK
PA 6666 E QUAKER ST, STE 1, ORCHARD PARK, NY 14127 USA
EI 1949-2553
J9 ONCOTARGET
JI Oncotarget
PD OCT 11
PY 2016
VL 7
IS 41
BP 67626
EP 67649
DI 10.18632/oncotarget.11759
PG 24
WC Oncology; Cell Biology
WE Science Citation Index Expanded (SCI-EXPANDED)
SC Oncology; Cell Biology
GA EB5UO
UT WOS:000387446200100
PM 27590516
OA Green Published, Green Submitted, gold
DA 2025-03-13
ER

PT J
AU Kim, HM
   Jung, WH
   Koo, JS
AF Kim, Hye Min
   Jung, Woo Hee
   Koo, Ja Seung
TI Expression of cancer-associated fibroblast related proteins in
   metastatic breast cancer: an immunohistochemical analysis
SO JOURNAL OF TRANSLATIONAL MEDICINE
LA English
DT Article
DE Breast cancer; Cancer-associated fibroblast; Molecular subtype; Stroma
ID ACTIVATION PROTEIN; BRAIN METASTASES; HIGH-RISK; CARCINOMA; GROWTH;
   CELLS; IDENTIFICATION; RECEPTORS; PHENOTYPE
AB Background: Cancer-associated fibroblast (CAF) is the most studied element of the tumor microenvironment, although no relationship has been identified between expression of their related proteins and the metastasis site. The purpose of this study was to investigate the expression of CAF related proteins and their implications according to the metastasis site in metastatic breast cancer.
   Methods: Immunohistochemical staining was used to evaluate the expression of CAF related proteins (podoplanin, prolyl 4-hydroxylase, FAP alpha, S100A4, PDGFR alpha, PDGFR beta, and NG2) in tissue microarrays from 132 cases of metastatic breast cancer (bone metastasis: 32 cases, brain metastasis: 38 cases, liver metastasis: 10 cases, and lung metastasis: 52 cases). Breast cancer subtypes were classified as luminal A, luminal B, HER-2, and triple negative breast cancer, according to the immunohistochemical staining results for estrogen and progesterone receptors, HER-2, and Ki-67 and FISH results for HER-2. Tumors were classified as desmoplastic, sclerotic, normal-like, and inflammatory type, according to the histologic findings from the tumor stroma.
   Results: Various CAF related protein expression profiles were observed, according to the metastasis site. For bone metastasis, the expression of stromal podoplanin, S100A4, and PDGFR alpha was significantly high. For lung metastasis, the expression of stromal PDGFR beta was significantly elevated (p < 0.001). For liver metastasis, significantly reduced expression of stromal S100A4 (p = 0.002) and PDGFR alpha (p = 0.011) was observed. Expression of CAF related proteins also differed according to the stromal phenotype. Desmoplastic stroma exhibited significantly elevated expression of stromal podoplanin (p < 0.001), S100A4 (p < 0.001), PDGFR alpha (p = 0.010), and PDGFR beta (p = 0.021). Inflammatory stroma exhibited significantly elevated expression of stromal FAP alpha (p = 0.044) and significantly reduced stromal S100A4 expression (p < 0.001). Sclerotic stroma exhibited significantly elevated tumoral FAP alpha (p = 0.005) expression. For lung metastasis, shorter overall survival was significantly related to tumoral podoplanin expression (p = 0.006), stromal podoplanin expression (p = 0.018), tumoral prolyl 4-hydroxylase negativity (p = 0.016), and tumoral PDGFR alpha expression (p = 0.001).
   Conclusion: For metastatic breast cancer, significant differences were observed in the expression of CAF related proteins, according to the metastasis site and stromal histologic phenotype.
C1 [Kim, Hye Min; Jung, Woo Hee; Koo, Ja Seung] Yonsei Univ, Coll Med, Dept Pathol, Severance Hosp, Seoul 120752, South Korea.
C3 Yonsei University; Yonsei University Health System
RP Koo, JS (corresponding author), Yonsei Univ, Coll Med, Dept Pathol, Severance Hosp, 50 Yonsei Ro, Seoul 120752, South Korea.
EM kjs1976@yuhs.ac
RI Kim, Sun Jung/AAM-7334-2020; Kim, Hyo-Won/M-9932-2019
OI Kim, Hye Min/0000-0002-2899-9480; koo, ja seung/0000-0003-4546-4709
FU Basic Science Research Program through the National Research Foundation
   of Korea (NRF) - Ministry of Science, ICT and Future Planning
   [2015R1A1A1A05001209]; Yonsei University College of Medicine
   [6-2014-0131]
FX This research was supported by Basic Science Research Program through
   the National Research Foundation of Korea (NRF) funded by the Ministry
   of Science, ICT and Future Planning (2015R1A1A1A05001209). This study
   was supported by a faculty research grant from Yonsei University College
   of Medicine for 2014 (6-2014-0131).
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NR 38
TC 46
Z9 48
U1 1
U2 17
PU BMC
PI LONDON
PA CAMPUS, 4 CRINAN ST, LONDON N1 9XW, ENGLAND
EI 1479-5876
J9 J TRANSL MED
JI J. Transl. Med.
PD JUL 11
PY 2015
VL 13
AR 222
DI 10.1186/s12967-015-0587-9
PG 11
WC Medicine, Research & Experimental
WE Science Citation Index Expanded (SCI-EXPANDED)
SC Research & Experimental Medicine
GA CM5FV
UT WOS:000357713100003
PM 26163388
OA Green Published, gold
DA 2025-03-13
ER

PT J
AU Bonuccelli, G
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   Pavlides, S
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   Lisanti, MP
AF Bonuccelli, Gloria
   Whitaker-Menezes, Diana
   Castello-Cros, Remedios
   Pavlides, Stephanos
   Pestell, Richard G.
   Fatatis, Alessandro
   Witkiewicz, Agnieszka K.
   Vander Heiden, Matthew G.
   Migneco, Gemma
   Chiavarina, Barbara
   Frank, Philippe G.
   Capozza, Franco
   Flomenberg, Neal
   Martinez-Outschoorn, Ubaldo E.
   Sotgia, Federica
   Lisanti, Michael P.
TI The reverse Warburg effect Glycolysis inhibitors prevent the tumor
   promoting effects of caveolin-1 deficient cancer associated fibroblasts
SO CELL CYCLE
LA English
DT Article
DE caveolin-1; tumor stroma; myofibroblast; cancer associated fibroblast;
   aerobic glycolysis; M2-isoform of pyruvate kinase; lactate
   dehydrogenase; Warburg effect
ID BREAST-CANCER; MITOCHONDRIAL STAT3; STROMAL CAVEOLIN-1; EXPRESSION;
   TUMORIGENESIS; CELLS; INVASIVENESS; HYPERPLASIA; PROGRESSION; THERAPY
AB We and others have previously identified a loss of stromal caveolin-1 (Cav-1) in cancer-associated fibroblasts (CAFs) as a powerful single independent predictor of breast cancer patient tumor recurrence, metastasis, tamoxifen-resistance and poor clinical outcome. However, it remains unknown how loss of stromal Cav-1 mediates these effects clinically. To mechanistically address this issue, we have now generated a novel human tumor xenograft model. In this two-component system, nude mice are co-injected with (i) human breast cancer cells (MDA-MB-231), and (ii) stromal fibroblasts (wild-type (WT) versus Cav-1 (-/-) deficient). This allowed us to directly evaluate the effects of a Cav-1 deficiency solely in the tumor stromal compartment. Here, we show that Cav-1-deficient stromal fibroblasts are sufficient to promote both tumor growth and angiogenesis, and to recruit Cav-1 (+) micro-vascular cells. Proteomic analysis of Cav-1-deficient stromal fibroblasts indicates that these cells upregulate the expression of glycolytic enzymes, a hallmark of aerobic glycolysis (the Warburg effect). Thus, Cav-1-deficient stromal fibroblasts may contribute towards tumor growth and angiogenesis, by providing energy-rich metabolites in a paracrine fashion. We have previously termed this new idea the "Reverse Warburg Effect". In direct support of this notion, treatment of this xenograft model with glycolysis inhibitors functionally blocks the positive effects of Cav-1-deficient stromal fibroblasts on breast cancer tumor growth. Thus, pharmacologically-induced metabolic restriction (via treatment with glycolysis inhibitors) may be a promising new therapeutic strategy for breast cancer patients that lack stromal Cav-1 expression. We also identify the stromal expression of PKM2 and LDH-B as new candidate biomarkers for the "Reverse Warburg Effect" or "Stromal-Epithelial Metabolic Coupling" in human breast cancers.
C1 [Bonuccelli, Gloria; Whitaker-Menezes, Diana; Castello-Cros, Remedios; Pavlides, Stephanos; Pestell, Richard G.; Migneco, Gemma; Chiavarina, Barbara; Frank, Philippe G.; Capozza, Franco; Martinez-Outschoorn, Ubaldo E.; Sotgia, Federica; Lisanti, Michael P.] Thomas Jefferson Univ, Dept Stem Cell Biol & Regenerat Med, Philadelphia, PA 19107 USA.
   [Bonuccelli, Gloria; Whitaker-Menezes, Diana; Castello-Cros, Remedios; Pavlides, Stephanos; Pestell, Richard G.; Migneco, Gemma; Chiavarina, Barbara; Frank, Philippe G.; Capozza, Franco; Martinez-Outschoorn, Ubaldo E.; Sotgia, Federica; Lisanti, Michael P.] Thomas Jefferson Univ, Dept Canc Biol, Philadelphia, PA 19107 USA.
   [Bonuccelli, Gloria; Whitaker-Menezes, Diana; Castello-Cros, Remedios; Pavlides, Stephanos; Pestell, Richard G.; Migneco, Gemma; Chiavarina, Barbara; Frank, Philippe G.; Capozza, Franco; Martinez-Outschoorn, Ubaldo E.; Sotgia, Federica; Lisanti, Michael P.] Thomas Jefferson Univ, Jefferson Stem Cell Biol & Regenerat Med Ctr, Philadelphia, PA 19107 USA.
   [Witkiewicz, Agnieszka K.] Thomas Jefferson Univ, Dept Pathol, Philadelphia, PA 19107 USA.
   [Witkiewicz, Agnieszka K.] Thomas Jefferson Univ, Dept Anat & Cell Biol, Philadelphia, PA 19107 USA.
   [Flomenberg, Neal; Martinez-Outschoorn, Ubaldo E.; Lisanti, Michael P.] Thomas Jefferson Univ, Dept Med Oncol, Kimmel Canc Ctr, Philadelphia, PA 19107 USA.
   [Fatatis, Alessandro] Drexel Univ, Coll Med, Dept Physiol & Pharmacol, Philadelphia, PA 19104 USA.
   [Fatatis, Alessandro] Drexel Univ, Coll Med, Dept Pathol & Lab Med, Philadelphia, PA 19104 USA.
   [Vander Heiden, Matthew G.] MIT, Koch Inst Integrat Canc Res, Cambridge, MA 02139 USA.
C3 Thomas Jefferson University; Thomas Jefferson University; Thomas
   Jefferson University; Thomas Jefferson University; Thomas Jefferson
   University; Thomas Jefferson University; Drexel University; Drexel
   University; Massachusetts Institute of Technology (MIT)
RP Sotgia, F (corresponding author), Thomas Jefferson Univ, Dept Stem Cell Biol & Regenerat Med, Philadelphia, PA 19107 USA.
EM federica.sotgia@jefferson.edu; michael.lisanti@kimmelcancercenter.org
RI Lisanti, Michael/C-6866-2013; Martinet, Wim/I-7375-2015; Pavlides,
   Stephanos/F-9673-2011; Pestell, Richard/JQW-3484-2023; Capozza,
   Franco/H-6086-2012; Frank, Philippe/A-3463-2011
OI Capozza, Franco/0000-0002-4235-0610; Sotgia,
   Federica/0000-0003-2826-4529; Martinez-Outschoorn,
   Ubaldo/0000-0003-1483-4551; Bonuccelli, Gloria/0000-0001-7576-5508;
   Frank, Philippe/0000-0003-4857-5279
FU NIH/NCI [R01-CA-080250, R01-CA-098779, R01-CA-120876, R01-AR-055660,
   R01-CA-70896, R01-CA-75503, R01-CA-86072, R01-CA-107382]; Susan G. Komen
   Breast Cancer Foundation; Breast Cancer Alliance, Inc.; Susan G. Komen
   Career Catalyst Grant; W.W. Smith Charitable Trust; American Cancer
   Society (ACS); Dr. Ralph and Marian C. Falk Medical Research Trust;
   NIH/NCI Cancer Center [P30-CA-56036]; Margaret Q. Landenberger Research
   Foundation; Pennsylvania Department of Health
FX M. P. L. and his laboratory were supported by grants from the NIH/NCI
   (R01-CA-080250; R01-CA-098779; R01-CA-120876; R01-AR-055660), and the
   Susan G. Komen Breast Cancer Foundation. A. K. W. was supported by a
   Young Investigator Award from Breast Cancer Alliance, Inc., and a Susan
   G. Komen Career Catalyst Grant. F. S. was supported by grants from the
   W.W. Smith Charitable Trust, the Breast Cancer Alliance (BCA), and a
   Research Scholar Grant from the American Cancer Society (ACS). P. G. F.
   was supported by a grant from the W.W. Smith Charitable Trust, and a
   Career Catalyst Award from the Susan G. Komen Breast Cancer Foundation.
   R. G. P. was supported by grants from the NIH/NCI (R01-CA-70896,
   R01-CA-75503, R01-CA-86072 and R01-CA-107382) and the Dr. Ralph and
   Marian C. Falk Medical Research Trust. The Kimmel Cancer Center was
   supported by the NIH/NCI Cancer Center Core grant P30-CA-56036 (to R. G.
   P.). Funds were also contributed by the Margaret Q. Landenberger
   Research Foundation (to M. P. L.).This project is funded, in part, under
   a grant with the Pennsylvania Department of Health (to M. P. L.). The
   Department specifically disclaims responsibility for any analyses,
   interpretations or conclusions. We also thank Dr. Gabriela Dontu (U. K.)
   for her critical suggestions.
CR DANG CV, 2010, MOL CELL BIOL
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NR 25
TC 190
Z9 225
U1 0
U2 35
PU TAYLOR & FRANCIS INC
PI PHILADELPHIA
PA 530 WALNUT STREET, STE 850, PHILADELPHIA, PA 19106 USA
SN 1538-4101
EI 1551-4005
J9 CELL CYCLE
JI Cell Cycle
PD MAY 15
PY 2010
VL 9
IS 10
BP 1960
EP 1971
DI 10.4161/cc.9.10.11601
PG 12
WC Cell Biology
WE Science Citation Index Expanded (SCI-EXPANDED)
SC Cell Biology
GA 600VB
UT WOS:000278015900024
PM 20495363
OA Bronze
DA 2025-03-13
ER

PT J
AU Houthuijzen, JM
   de Bruijn, R
   van der Burg, E
   Drenth, AP
   Wientjens, E
   Filipovic, T
   Bullock, E
   Brambillasca, CS
   Pulver, EM
   Nieuwland, M
   de Rink, I
   van Diepen, F
   Klarenbeek, S
   Kerkhoven, R
   Brunton, VG
   Scheele, CLGJ
   Boelens, MC
   Jonkers, J
AF Houthuijzen, Julia M.
   de Bruijn, Roebi
   van der Burg, Eline
   Drenth, Anne Paulien
   Wientjens, Ellen
   Filipovic, Tamara
   Bullock, Esme
   Brambillasca, Chiara S.
   Pulver, Emilia M.
   Nieuwland, Marja
   de Rink, Iris
   van Diepen, Frank
   Klarenbeek, Sjoerd
   Kerkhoven, Ron
   Brunton, Valerie G.
   Scheele, Colinda L. G. J.
   Boelens, Mirjam C.
   Jonkers, Jos
TI CD26-negative and CD26-positive tissue-resident fibroblasts contribute
   to functionally distinct CAF subpopulations in breast cancer
SO NATURE COMMUNICATIONS
LA English
DT Article
ID MAMMARY EPITHELIAL-CELLS; MESENCHYMAL STEM-CELLS; STROMAL FIBROBLASTS;
   TUMOR; MYOFIBROBLASTS; HETEROGENEITY; DIFFERENTIATION; TRANSPLANTATION;
   ENVIRONMENT; CARCINOMAS
AB Cancer-associated fibroblasts (CAFs) are abundantly present in the microenvironment of virtually all tumors and strongly impact tumor progression. Despite increasing insight into their function and heterogeneity, little is known regarding the origin of CAFs. Understanding the origin of CAF heterogeneity is needed to develop successful CAF-based targeted therapies. Through various transplantation studies in mice, we show that CAFs in both invasive lobular breast cancer and triple-negative breast cancer originate from mammary tissue-resident normal fibroblasts (NFs). Single-cell transcriptomics, in vivo and in vitro studies reveal the transition of CD26+ and CD26- NF populations into inflammatory CAFs (iCAFs) and myofibroblastic CAFs (myCAFs), respectively. Functional co-culture experiments show that CD26+ NFs transition into pro-tumorigenic iCAFs which recruit myeloid cells in a CXCL12-dependent manner and enhance tumor cell invasion via matrix-metalloproteinase (MMP) activity. Together, our data suggest that CD26+ and CD26- NFs transform into distinct CAF subpopulations in mouse models of breast cancer.
   The origin of cancer-associated fibroblasts (CAFs) in cancer remains to be identified. Here, single-cell transcriptomics, in vivo and in vitro studies suggest that CD26+ and CD26- normal fibroblasts transform into distinct CAF subpopulations in mouse models of breast cancer.
C1 [Houthuijzen, Julia M.; de Bruijn, Roebi; van der Burg, Eline; Drenth, Anne Paulien; Wientjens, Ellen; Filipovic, Tamara; Brambillasca, Chiara S.; Pulver, Emilia M.; Boelens, Mirjam C.; Jonkers, Jos] Netherlands Canc Inst, Oncode Inst, Div Mol Pathol, Amsterdam, Netherlands.
   [de Bruijn, Roebi] Netherlands Canc Inst, Div Mol Carcinogenesis, Amsterdam, Netherlands.
   [Bullock, Esme; Brunton, Valerie G.] Univ Edinburgh, Inst Genet & Canc, Canc Res UK Edinburgh Ctr, Edinburgh, Scotland.
   [Nieuwland, Marja; de Rink, Iris; Kerkhoven, Ron] Netherlands Canc Inst, Genom Core Facil, Amsterdam, Netherlands.
   [van Diepen, Frank] Netherlands Canc Inst, Flow Cytometry Facil, Amsterdam, Netherlands.
   [Klarenbeek, Sjoerd] Netherlands Canc Inst, Expt Anim Pathol Facil, Amsterdam, Netherlands.
   [Scheele, Colinda L. G. J.] Katholieke Univ Leuven, VIB Ctr Canc Biol, Lab Intravital Imaging & Dynam Tumor Progress, Leuven, Belgium.
   [Scheele, Colinda L. G. J.] Katholieke Univ Leuven, Dept Oncol, Leuven, Belgium.
C3 Netherlands Cancer Institute; Netherlands Cancer Institute; University
   of Edinburgh; Netherlands Cancer Institute; Netherlands Cancer
   Institute; Netherlands Cancer Institute; Flanders Institute for
   Biotechnology (VIB); KU Leuven; KU Leuven
RP Houthuijzen, JM; Jonkers, J (corresponding author), Netherlands Canc Inst, Oncode Inst, Div Mol Pathol, Amsterdam, Netherlands.
EM j.houthuijzen@nki.nl; j.jonkers@nki.nl
RI Jonkers, Jos/AAG-3246-2019; Scheele, Colinda/AAZ-9118-2021
OI Pulver, Emilia/0000-0001-5748-1835; Houthuijzen,
   Julia/0000-0003-0404-1961; Scheele, Colinda/0000-0001-8999-5451
FU Oncode Institute; Dutch Research Council (NWO, Veni grant)
   [016.196.120]; Dutch Cancer Society (KWF) [NKI 2015-7589, NKI
   2021-13751]
FX This research was funded by Oncode Institute (J.J.), the Dutch Research
   Council (NWO, Veni grant 016.196.120, J.M.H.) and the Dutch Cancer
   Society (KWF, grants NKI 2015-7589 (M.C.B.) and NKI 2021-13751, J.M.H.).
   We would like to thank the people at the Genomics Core Facility of the
   Netherlands Cancer Institute, especially Wim Brugman, for all the RNA
   isolations, RNA library preps and sequence runs presented in this study.
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NR 69
TC 38
Z9 38
U1 1
U2 25
PU NATURE PORTFOLIO
PI BERLIN
PA HEIDELBERGER PLATZ 3, BERLIN, 14197, GERMANY
EI 2041-1723
J9 NAT COMMUN
JI Nat. Commun.
PD JAN 12
PY 2023
VL 14
IS 1
AR 183
DI 10.1038/s41467-023-35793-w
PG 21
WC Multidisciplinary Sciences
WE Science Citation Index Expanded (SCI-EXPANDED)
SC Science & Technology - Other Topics
GA A5SV7
UT WOS:000955726400006
PM 36635273
OA Green Published, gold, Green Submitted
DA 2025-03-13
ER

PT J
AU Wang, SH
   Su, XD
   Xu, MQ
   Xiao, X
   Li, XX
   Li, HL
   Keating, A
   Zhao, RC
AF Wang, Shihua
   Su, Xiaodong
   Xu, Meiqian
   Xiao, Xian
   Li, Xiaoxia
   Li, Hongling
   Keating, Armand
   Zhao, Robert Chunhua
TI Exosomes secreted by mesenchymal stromal/stem cell-derived adipocytes
   promote breast cancer cell growth via activation of Hippo signaling
   pathway
SO STEM CELL RESEARCH & THERAPY
LA English
DT Article
DE Exosomes; Adipocyte; Mesenchymal stromal/stem cell; Breast cancer; Hippo
   signaling pathway
ID ANGIOGENESIS; BIOLOGY; OBESITY
AB Objective: Although adipocytes are the most abundant stromal cell component in breast cancer tissues, their interaction with breast cancer cells has been less investigated compared to cancer-associated fibroblasts or macrophages. Exosomes are a novel way of cell-cell communication and have been demonstrated to play an important role in various biological processes. However, to our knowledge, only a few studies have reported the effects of adipocyte exosomes on tumor development. Here, utilizing exosomes isolated from in vitro mesenchymal stromal/stem cell (MSC)-differentiated adipocytes, we systematically investigated this issue in a breast cancer model.
   Material and methods: Exosomes were isolated from MSC-differentiated adipocytes and added to breast cancer cells MCF7. Cell proliferation was detected by MTS, and migration was analyzed by wound healing and transwell assay. An in vivo mouse xenograft model was used to evaluate MSC-differentiated adipocyte exosomes' contribution to tumor growth. Signaling pathway activation was evaluated by western blot and immunofluorescence staining.
   Results: We found MSC-differentiated adipocyte-derived exosomes are actively incorporated by breast cancer cell MCF7 and subsequently promote MCF7 proliferation and migration as well as protect MCF7 from serum derivation or chemotherapeutic drug-induced apoptosis in vitro. In the in vivo mouse xenograft model, depletion of exosomes reduces tumor-promoting effects of adipocytes. Transcriptomic analysis of MSC-differentiated adipocyte exosome-treated MCF7 identified several activated signaling pathways, among which we confirm the Hippo signaling pathway and found a blockade of this pathway leads to a reduced growth-promoting effect of adipocyte exosomes.
   Conclusion: Taken together, our findings provide new insights into the role of adipocyte exosomes in the tumor microenvironment.
C1 [Wang, Shihua; Su, Xiaodong; Xu, Meiqian; Xiao, Xian; Li, Hongling; Zhao, Robert Chunhua] Chinese Acad Med Sci, Ctr Excellence Tissue Engn, Peking Union Med Coll, Sch Basic Med,Inst Basic Med Sci, Beijing 100005, Peoples R China.
   [Su, Xiaodong] Capital Med Univ, Beijing Tiantan Hosp, Beijing Neurosurg Inst, Brain Tumor Res Ctr, Tiantan Xili 6, Beijing 100050, Peoples R China.
   [Li, Xiaoxia] Qingdao Univ, Basic Med Coll, Dept Genet & Cell Biol, 308 Ningxia Rd, Qingdao 266071, Shandong, Peoples R China.
   [Keating, Armand] Princess Margaret Hosp, Cell Therapy Program, Toronto, ON M5G 2M9, Canada.
   [Keating, Armand] Univ Toronto, Inst Biomat & Biomed Engn, Toronto, ON M5G 2M9, Canada.
   [Keating, Armand] Univ Toronto, Inst Med Sci, Toronto, ON M5G 2M9, Canada.
C3 Chinese Academy of Medical Sciences - Peking Union Medical College;
   Peking Union Medical College; Beijing Neurosurgical Institute; Capital
   Medical University; Qingdao University; University of Toronto;
   University Health Network Toronto; Princess Margaret Cancer Centre;
   University of Toronto; University of Toronto
RP Li, HL; Zhao, RC (corresponding author), Chinese Acad Med Sci, Ctr Excellence Tissue Engn, Peking Union Med Coll, Sch Basic Med,Inst Basic Med Sci, Beijing 100005, Peoples R China.; Keating, A (corresponding author), Princess Margaret Hosp, Cell Therapy Program, Toronto, ON M5G 2M9, Canada.; Keating, A (corresponding author), Univ Toronto, Inst Biomat & Biomed Engn, Toronto, ON M5G 2M9, Canada.; Keating, A (corresponding author), Univ Toronto, Inst Med Sci, Toronto, ON M5G 2M9, Canada.
EM lihongling@ibms.pumc.edu.cn; armand.keating@uhn.ca;
   zhaochunhua@ibms.pumc.edu.cn
OI wang, shihua/0000-0003-1853-5399; Keating, Armand/0000-0002-7676-6059
FU CAMS Innovation Fund for Medical Sciences [2017-I2M-3-007]; National Key
   Research and Development Program of China [2016YFA0101000,
   2016YFA0101003]; Beijing Key Laboratory of New Drug Development and
   Clinical Trial of Stem Cell Therapy [BZ0381]
FX This study was supported by CAMS Innovation Fund for Medical Sciences
   (2017-I2M-3-007), The National Key Research and Development Program of
   China (2016YFA0101000, 2016YFA0101003), Beijing Key Laboratory of New
   Drug Development and Clinical Trial of Stem Cell Therapy (BZ0381).
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NR 37
TC 126
Z9 135
U1 5
U2 39
PU BMC
PI LONDON
PA CAMPUS, 4 CRINAN ST, LONDON N1 9XW, ENGLAND
EI 1757-6512
J9 STEM CELL RES THER
JI Stem Cell Res. Ther.
PD APR 11
PY 2019
VL 10
AR 117
DI 10.1186/s13287-019-1220-2
PG 12
WC Cell & Tissue Engineering; Cell Biology; Medicine, Research &
   Experimental
WE Science Citation Index Expanded (SCI-EXPANDED)
SC Cell Biology; Research & Experimental Medicine
GA HT7JU
UT WOS:000464741800001
PM 30971292
OA Green Published, gold
DA 2025-03-13
ER

PT J
AU Liu, YL
   Hua, FL
   Zhan, YX
   Yang, YF
   Xie, JF
   Cheng, YF
   Li, F
AF Liu, Yonglei
   Hua, Fanli
   Zhan, Yanxia
   Yang, Yanfei
   Xie, Jianfang
   Cheng, Yunfeng
   Li, Feng
TI Carcinoma associated fibroblasts small extracellular vesicles with low
   miR-7641 promotes breast cancer stemness and glycolysis by HIF-1α
SO CELL DEATH DISCOVERY
LA English
DT Article
ID COLORECTAL-CANCER; HYPOXIA; METABOLISM; EXPRESSION; EXOSOME
AB Fibroblasts play an important role in cancer development and progression. Small extracellular vesicles (sEVs) are one type of extracellular vesicles, which mediate the interaction between cancer-associated fibroblasts and cancer cells by transferring their contents. However, the roles of sEVs from cancer-associated fibroblasts on breast cancer stem cell properties are largely unraveled. The purpose of this study was to explore the roles of sEVs from cancer-associated fibroblasts on breast cancer progression. The miRNA array data showed a different miRNA profile between CAFs sEVs and normal fibroblasts sEVs. By verification using real-time RT-PCR, the data analysis indicated that miR-7641 levels were lower in sEVs from CAFs compared with NFs. The cellular functions were assayed and the results indicated that CAFs derived sEVs with low miR-7641 levels suppressed breast cancer cell survival, glycolysis, and stem cell properties via the HIF-1 alpha pathway. Collectively, these findings indicated that sEVs from CAFs promoted breast cancer stem cell properties and glycolysis via miR-7641/HIF-1 alpha, which was a possible new way for targeting breast cancer.
C1 [Liu, Yonglei; Yang, Yanfei; Xie, Jianfang] Fudan Univ, Zhongshan Hosp, Qingpu Branch, Res Ctr, Shanghai, Peoples R China.
   [Hua, Fanli; Cheng, Yunfeng; Li, Feng] Fudan Univ, Zhongshan Hosp, Qingpu Branch, Dept Hematol, Shanghai, Peoples R China.
   [Zhan, Yanxia; Cheng, Yunfeng] Fudan Univ, Zhongshan Hosp, Res Ctr, Shanghai, Peoples R China.
   [Zhan, Yanxia; Cheng, Yunfeng; Li, Feng] Fudan Univ, Zhongshan Hosp, Dept Hematol, Shanghai, Peoples R China.
C3 Fudan University; Fudan University; Fudan University; Fudan University
RP Cheng, YF; Li, F (corresponding author), Fudan Univ, Zhongshan Hosp, Qingpu Branch, Dept Hematol, Shanghai, Peoples R China.; Cheng, YF (corresponding author), Fudan Univ, Zhongshan Hosp, Res Ctr, Shanghai, Peoples R China.; Cheng, YF; Li, F (corresponding author), Fudan Univ, Zhongshan Hosp, Dept Hematol, Shanghai, Peoples R China.
EM yfcheng@fudan.edu.cn; li.feng@zs-hospital.sh.cn
RI Cheng, Yunfeng/ISS-0527-2023; Xu, Meng/HJY-7139-2023
FU National Natural Science Foundation of China [81502571]; Shanghai
   Science and Technology Committee [19140901000]; Natural Science
   Foundation of Shanghai [19ZR1410000]
FX This work was supported by grands from National Natural Science
   Foundation of China (No. 81502571), Shanghai Science and Technology
   Committee (No. 19140901000) and Natural Science Foundation of Shanghai
   (19ZR1410000).
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NR 30
TC 27
Z9 30
U1 2
U2 25
PU SPRINGERNATURE
PI LONDON
PA CAMPUS, 4 CRINAN ST, LONDON, N1 9XW, ENGLAND
EI 2058-7716
J9 CELL DEATH DISCOV
JI Cell Death Discov.
PD JUL 8
PY 2021
VL 7
IS 1
AR 176
DI 10.1038/s41420-021-00524-x
PG 11
WC Cell Biology
WE Science Citation Index Expanded (SCI-EXPANDED)
SC Cell Biology
GA TI3GC
UT WOS:000672681300001
PM 34238918
OA Green Published, gold
DA 2025-03-13
ER

PT J
AU Gokyavuz, B
   Gunaydin, G
   Gedik, ME
   Kosemehmetoglu, K
   Karakoc, D
   Ozgur, F
   Guc, D
AF Gokyavuz, Betul
   Gunaydin, Gurcan
   Gedik, M. Emre
   Kosemehmetoglu, Kemal
   Karakoc, Derya
   Ozgur, Figen
   Guc, Dicle
TI Cancer associated fibroblasts sculpt tumour microenvironment by
   recruiting monocytes and inducing immunosuppressive PD-1<SUP>+</SUP>
   TAMs
SO SCIENTIFIC REPORTS
LA English
DT Article
ID BREAST-CANCER; MACROPHAGE ACTIVATION; STROMAL FIBROBLASTS; PROGRESSION;
   GROWTH; CELLS; INFLAMMATION; ANGIOGENESIS; PARACRINE; RECEPTOR
AB Fibroblasts turn into cancer associated fibroblasts (CAFs) in the tumour microenvironment. CAFs have recently attracted attention for their function as a regulator of immune cell recruitment and function in addition to their tumour-promoting roles. In this study, we aimed to determine the role of CAFs on monocyte recruitment and macrophage polarization in breast cancer. CAFs, which were alpha-SMA expressing fibroblasts in contrast to normal fibroblasts (NFs), effectively recruited monocytes. Recruitment of monocytes by CAFs might be mediated by monocyte chemotactic protein-1 (MCP-1) as well as stromal cell-derived factor-1 (SDF-1) cytokines. CAFs differentiated the recruited monocytes into M2-like macrophages which are capable of exerting their immunosuppressive roles via the PD-1 axis. CAF-educated monocytes exhibited strong immune suppression unlike NF-educated monocytes and enhanced the motility/invasion of breast cancer cells in addition to increasing the expressions of epithelial-mesenchymal transition (EMT)-related genes and vimentin protein in cancer cells. CAF-educated M1 macrophages displayed increased expression of M2 markers and production of anti-inflammatory cytokine IL-10 in contrast to decreased production of pro-inflammatory cytokine IL-12 compared with control M1 macrophages; suggesting that CAFs were also able to induce the trans-differentiation of M1 macrophages to M2 macrophages. We then investigated the relationship between the infiltration of CAFs and tumour associated macrophages (TAMs) using tissue samples obtained from breast cancer patients. High grade of CAFs significantly correlated with the number of TAMs in human breast cancer tissue samples. It was also associated with higher Ki-67 proliferation index, and higher tumour volume. This result is in line with our finding of increased breast cancer cell proliferation due to the effects of CAF-educated monocytes in vitro. Our results concluded that CAFs play pivotal roles in sculpturing the tumour microenvironment in breast cancer, and therapeutic strategies to reverse the CAF-mediated immunosuppressive microenvironment should be taken into consideration.
C1 [Gokyavuz, Betul; Gunaydin, Gurcan; Gedik, M. Emre; Guc, Dicle] Hacettepe Univ, Canc Inst, Dept Basic Oncol, TR-06100 Ankara, Turkey.
   [Kosemehmetoglu, Kemal] Hacettepe Univ, Sch Med, Dept Pathol, TR-06100 Ankara, Turkey.
   [Karakoc, Derya] Hacettepe Univ, Sch Med, Dept Gen Surg, TR-06100 Ankara, Turkey.
   [Ozgur, Figen] Hacettepe Univ, Sch Med, Dept Plast Reconstruct & Aesthet Surg, TR-06100 Ankara, Turkey.
C3 Hacettepe University; Hacettepe University; Hacettepe University;
   Hacettepe University
RP Gunaydin, G (corresponding author), Hacettepe Univ, Canc Inst, Dept Basic Oncol, TR-06100 Ankara, Turkey.
EM gurcangunaydin@hacettepe.edu.tr
RI Kosemehmetoglu, Kemal/A-2423-2016; Gok Yavuz, Betul/AAY-4098-2021;
   Gunaydin, Gurcan/F-8343-2019; Gedik, M. Emre/KVB-4144-2024
OI Gok Yavuz, Betul/0000-0003-3786-1456; OZGUR, FATMA
   FIGEN/0000-0002-4922-6348
FU Hacettepe University Scientific Research Projects Coordination Unit
FX This study was supported by Hacettepe University Scientific Research
   Projects Coordination Unit.
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NR 54
TC 204
Z9 212
U1 3
U2 32
PU NATURE PORTFOLIO
PI BERLIN
PA HEIDELBERGER PLATZ 3, BERLIN, 14197, GERMANY
SN 2045-2322
J9 SCI REP-UK
JI Sci Rep
PD FEB 28
PY 2019
VL 9
AR 3172
DI 10.1038/s41598-019-39553-z
PG 15
WC Multidisciplinary Sciences
WE Science Citation Index Expanded (SCI-EXPANDED)
SC Science & Technology - Other Topics
GA HN0SB
UT WOS:000459897600106
PM 30816272
OA Green Published, gold
HC Y
HP N
DA 2025-03-13
ER

PT J
AU Sotgia, F
   Del Galdo, F
   Casimiro, MC
   Bonuccelli, G
   Mercier, I
   Whitaker-Menezes, D
   Daumer, KM
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   Wang, CG
   Katiyar, S
   Xu, H
   Bosco, E
   Quong, AA
   Aronow, B
   Witkiewicz, AK
   Minetti, C
   Frank, PG
   Jimenez, SA
   Knudsen, ES
   Pestell, RG
   Lisanti, MP
AF Sotgia, Federica
   Del Galdo, Francesco
   Casimiro, Mathew C.
   Bonuccelli, Gloria
   Mercier, Isabelle
   Whitaker-Menezes, Diana
   Daumer, Kristin M.
   Zhou, Jie
   Wang, Chenguang
   Katiyar, Sanjay
   Xu, Huan
   Bosco, Emily
   Quong, Andrew A.
   Aronow, Bruce
   Witkiewicz, Agnieszka K.
   Minetti, Carlo
   Frank, Philippe G.
   Jimenez, Sergio A.
   Knudsen, Erik S.
   Pestell, Richard G.
   Lisanti, Michael P.
TI Caveolin-1<SUP>-/-</SUP> Null Mammary Stromal Fibroblasts Share
   Characteristics with Human Breast Cancer-Associated Fibroblasts
SO AMERICAN JOURNAL OF PATHOLOGY
LA English
DT Article
ID GENE-EXPRESSION SIGNATURE; GROWTH-FACTOR; ENDOSIALIN TEM1; STEM-CELLS;
   IN-VITRO; RESPONSIVENESS INVITRO; MESENCHYMAL TRANSITION; HORMONE
   RECEPTORS; EPITHELIAL-CELLS; TUMOR STROMA
AB Recently, we reported that human breast cancer-associated fibroblasts show functional inactivation of the retinoblastoma (RB) tumor suppressor and down-regulation of caveolin-1 (Cav-1) protein expression. However, it remains unknown whether loss of Cav-1 is sufficient to confer functional RB inactivation in mammary fibroblasts. To establish a direct cause-and-effect relationship, mammary stromal fibroblasts (MSFs) were prepared from Cav-1(-/-) null mice and subjected to phenotypic analysis. Here, we provide evidence that Cav-1(-/-) MSFs share many characteristics with human cancer-associated fibroblasts. The Cav-1(-/-) MSF transcriptome significantly overlaps with human cancer-associated fibroblasts; both show a nearly identical profile of RB/E2F-regulated genes that are up-regulated, which is consistent with RB inactivation. This Cav-1(-/-)MSF gene signature is predictive of poor clinical outcome in breast cancer patients treated with tamoxifen. Consistent with these findings, Cav-1(-/-) MSFs show RB hyperphosphorylation and the up-regulation of estrogen receptor co-activator genes. We also evaluated the paracrine effects of "conditioned media" prepared from Cav-1(-/-) MSFs on wild-type mammary epithelia. Our
C1 [Sotgia, Federica; Casimiro, Mathew C.; Bonuccelli, Gloria; Mercier, Isabelle; Whitaker-Menezes, Diana; Daumer, Kristin M.; Zhou, Jie; Wang, Chenguang; Katiyar, Sanjay; Quong, Andrew A.; Frank, Philippe G.; Knudsen, Erik S.; Pestell, Richard G.; Lisanti, Michael P.] Thomas Jefferson Univ, Kimmel Canc Ctr, Dept Canc Biol & Med Oncol, Philadelphia, PA 19107 USA.
   [Del Galdo, Francesco; Jimenez, Sergio A.] Thomas Jefferson Univ, Kimmel Canc Ctr, Dept Dermatol, Philadelphia, PA 19107 USA.
   [Sotgia, Federica; Casimiro, Mathew C.; Bonuccelli, Gloria; Mercier, Isabelle; Whitaker-Menezes, Diana; Daumer, Kristin M.; Zhou, Jie; Wang, Chenguang; Katiyar, Sanjay; Quong, Andrew A.; Frank, Philippe G.; Knudsen, Erik S.; Pestell, Richard G.; Lisanti, Michael P.] Thomas Jefferson Univ, Stem Cell Biol & Regenerat Med Ctr, Philadelphia, PA 19107 USA.
   [Witkiewicz, Agnieszka K.] Thomas Jefferson Univ, Dept Pathol Anat & Cell Biol, Philadelphia, PA 19107 USA.
   [Sotgia, Federica; Minetti, Carlo; Lisanti, Michael P.] Univ Genoa, Muscular & Neurodegenerat Dis Unit, Genoa, Italy.
   G Gaslini Pediat Inst, Genoa, Italy.
   [Xu, Huan; Bosco, Emily; Aronow, Bruce] Cincinnati Childrens Hosp & Med Ctr, Cincinnati, OH USA.
C3 Thomas Jefferson University; Thomas Jefferson University; Thomas
   Jefferson University; Thomas Jefferson University; University of Genoa;
   Cincinnati Children's Hospital Medical Center
RP Sotgia, F (corresponding author), Thomas Jefferson Univ, Kimmel Canc Ctr, Dept Canc Biol, 233 S 10th St, Philadelphia, PA 19107 USA.
EM michael.lisanti@kimmelcancercenter.org
RI Aronow, Bruce/F-8438-2012; Jimenez-Perez, Salvio/H-5824-2015; Mercier,
   Isabelle/C-5775-2011; Del+Galdo, Francesco/ABD-9872-2021; Pestell,
   Richard/JQW-3484-2023; Lisanti, Michael/C-6866-2013; MINETTI,
   Carlo/K-4666-2018; Frank, Philippe/A-3463-2011
OI MINETTI, Carlo/0000-0002-0640-1804; Sotgia,
   Federica/0000-0003-2826-4529; Katiyar, Sanjay/0000-0003-1622-5661; Del
   Galdo, Francesco/0000-0002-8528-2283; Frank,
   Philippe/0000-0003-4857-5279; Jimenez, Sergio/0000-0001-5213-1203;
   Bonuccelli, Gloria/0000-0001-7576-5508
FU NCI NIH HHS [R01-CA-107382, T32 CA117846, P30-CA-56036, R01-CA-80250,
   R01-CA-86072, R01-CA-70896, R01 CA120876, R01-CA-120876, P30 CA056036,
   R01 CA107382, R01 CA086072, R01-CA-098779, R01 CA070896, R01 CA098779,
   R01 CA080250, R01-CA-75503, R01 CA075503] Funding Source: Medline; NIAMS
   NIH HHS [R01 AR055660, R01 AR055660-03] Funding Source: Medline
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NR 42
TC 110
Z9 124
U1 0
U2 6
PU ELSEVIER SCIENCE INC
PI NEW YORK
PA 360 PARK AVE SOUTH, NEW YORK, NY 10010-1710 USA
SN 0002-9440
EI 1525-2191
J9 AM J PATHOL
JI Am. J. Pathol.
PD MAR
PY 2009
VL 174
IS 3
BP 746
EP 761
DI 10.2353/ajpath.2009.080658
PG 16
WC Pathology
WE Science Citation Index Expanded (SCI-EXPANDED)
SC Pathology
GA 410XW
UT WOS:000263612600005
PM 19234134
OA Bronze, Green Published
DA 2025-03-13
ER

PT J
AU Avagliano, A
   Fiume, G
   Ruocco, MR
   Martucci, N
   Vecchio, E
   Insabato, L
   Russo, D
   Accurso, A
   Masone, S
   Montagnani, S
   Arcucci, A
AF Avagliano, Angelica
   Fiume, Giuseppe
   Ruocco, Maria Rosaria
   Martucci, Nunzia
   Vecchio, Eleonora
   Insabato, Luigi
   Russo, Daniela
   Accurso, Antonello
   Masone, Stefania
   Montagnani, Stefania
   Arcucci, Alessandro
TI Influence of Fibroblasts on Mammary Gland Development, Breast Cancer
   Microenvironment Remodeling, and Cancer Cell Dissemination
SO CANCERS
LA English
DT Review
DE fibroblasts; breast cancer associated fibroblasts (BCAFs); mammary
   gland; breast cancer microenvironment; ECM remodeling; metastasis
ID EPITHELIAL-MESENCHYMAL TRANSITION; NONSTEROIDAL ANTIINFLAMMATORY DRUGS;
   CARCINOMA-ASSOCIATED FIBROBLASTS; CHEMOKINE RECEPTOR CXCR4; LYMPH-NODE
   METASTASES; TERMINAL END BUDS; STROMAL FIBROBLASTS;
   EXTRACELLULAR-MATRIX; LYSYL OXIDASE; TGF-BETA
AB The stromal microenvironment regulates mammary gland development and tumorigenesis. In normal mammary glands, the stromal microenvironment encompasses the ducts and contains fibroblasts, the main regulators of branching morphogenesis. Understanding the way fibroblast signaling pathways regulate mammary gland development may offer insights into the mechanisms of breast cancer (BC) biology. In fact, the unregulated mammary fibroblast signaling pathways, associated with alterations in extracellular matrix (ECM) remodeling and branching morphogenesis, drive breast cancer microenvironment (BCM) remodeling and cancer growth. The BCM comprises a very heterogeneous tissue containing non-cancer stromal cells, namely, breast cancer-associated fibroblasts (BCAFs), which represent most of the tumor mass. Moreover, the different components of the BCM highly interact with cancer cells, thereby generating a tightly intertwined network. In particular, BC cells activate recruited normal fibroblasts in BCAFs, which, in turn, promote BCM remodeling and metastasis. Thus, comparing the roles of normal fibroblasts and BCAFs in the physiological and metastatic processes, could provide a deeper understanding of the signaling pathways regulating BC dissemination. Here, we review the latest literature describing the structure of the mammary gland and the BCM and summarize the influence of epithelial-mesenchymal transition (EpMT) and autophagy in BC dissemination. Finally, we discuss the roles of fibroblasts and BCAFs in mammary gland development and BCM remodeling, respectively.
C1 [Avagliano, Angelica; Martucci, Nunzia; Montagnani, Stefania; Arcucci, Alessandro] Univ Naples Federico II, Dept Publ Hlth, I-80131 Naples, Italy.
   [Fiume, Giuseppe; Vecchio, Eleonora] Magna Graecia Univ Catanzaro, Dept Expt & Clin Med, I-88100 Catanzaro, Italy.
   [Ruocco, Maria Rosaria] Univ Naples Federico II, Dept Mol Med & Med Biotechnol, I-80131 Naples, Italy.
   [Insabato, Luigi; Russo, Daniela] Univ Naples Federico II, Sch Med, Dept Adv Biomed Sci, Anat Pathol Unit, I-80131 Naples, Italy.
   [Accurso, Antonello] Univ Naples Federico II, Dept Gen Oncol Bariatr & Endocrine Metab Surg, I-80131 Naples, Italy.
   [Masone, Stefania] Univ Naples Federico II, Dept Clin Med & Surg, I-80131 Naples, Italy.
C3 University of Naples Federico II; Magna Graecia University of Catanzaro;
   University of Naples Federico II; University of Naples Federico II;
   University of Naples Federico II; University of Naples Federico II
RP Avagliano, A; Arcucci, A (corresponding author), Univ Naples Federico II, Dept Publ Hlth, I-80131 Naples, Italy.
EM angelica.avagliano@unina.it; fiume@unicz.it;
   mariarosaria.ruocco2@unina.it; nu.martucci@studenti.unina.it;
   eleonoravecchio@unicz.it; insabato@unina.it; daniela.russo@unina.it;
   antonello.accurso@unina.it; stefania.masone@unina.it; montagna@unina.it;
   alessandro.arcucci2@unina.it
RI vecchio, eleonora/AAT-4287-2020; masone, stefania/I-5077-2012;
   Avagliano, Angelica/ABI-2247-2020; Arcucci, Alessandro/AAV-7902-2020
OI FIUME, Giuseppe/0000-0002-5414-6190; Russo, Daniela/0000-0002-6961-3695;
   vecchio, eleonora/0000-0001-8422-2679
FU Italian Ministry of Education, Universities and Research
   [PRIN-20177TTP3S]; Regione Campania "SATIN" grant 2018-2020
FX This study was funded by the Italian Ministry of Education, Universities
   and Research through the grant: "Integrated mechanobiology approaches
   for a precise medicine in cancer treatment" (award number:
   PRIN-20177TTP3S) and by the Regione Campania "SATIN" grant 2018-2020.
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NR 285
TC 31
Z9 36
U1 0
U2 16
PU MDPI
PI BASEL
PA ST ALBAN-ANLAGE 66, CH-4052 BASEL, SWITZERLAND
EI 2072-6694
J9 CANCERS
JI Cancers
PD JUN
PY 2020
VL 12
IS 6
AR 1697
DI 10.3390/cancers12061697
PG 35
WC Oncology
WE Science Citation Index Expanded (SCI-EXPANDED)
SC Oncology
GA ML0YT
UT WOS:000549203300001
PM 32604738
OA Green Published, Green Submitted, gold
DA 2025-03-13
ER

PT J
AU Sharon, Y
   Raz, Y
   Cohen, N
   Ben-Shmuel, A
   Schwartz, H
   Geiger, T
   Erez, N
AF Sharon, Yoray
   Raz, Yael
   Cohen, Noam
   Ben-Shmuel, Amir
   Schwartz, Hila
   Geiger, Tamar
   Erez, Neta
TI Tumor-Derived Osteopontin Reprograms Normal Mammary Fibroblasts to
   Promote Inflammation and Tumor Growth in Breast Cancer
SO CANCER RESEARCH
LA English
DT Article
ID TGF-BETA; STROMAL FIBROBLASTS; EXPRESSION PROFILES; COLORECTAL-CANCER;
   CELLS; METASTASIS; PROGRESSION; PHENOTYPE; CARCINOMA; INTEGRIN
AB Breast tumors are characterized by an extensive desmoplastic stroma, abundantly populated by fibroblasts. Cancer-associated fibroblasts (CAF) support tumorigenesis by stimulating angiogenesis, cancer cell proliferation, and invasion. CAF also orchestrate tumor-promoting inflammation in multiple tumor types, including breast cancer. However, the mechanisms through which normal tissue fibroblasts are reprogrammed to tumor-promoting CAFs are mainly obscure. Here, we show that mammary fibroblasts can be educated by breast cancer cells to become activated to a proinflammatory state that supports malignant progression. Proteomic analysis of breast cancer cell-secreted factors identified the secreted proinflammatory mediator osteopontin, which has been implicated in inflammation, tumor progression, and metastasis. Osteopontin was highly secreted by mouse and human breast cancer cells, and tumor cell-secreted osteopontin activated a CAF phenotypes in normal mammary fibroblasts in vitro and in vivo. Osteopontin was sufficient to induce fibroblast reprogramming and neutralizing antibodies against osteopontin-blocked fibroblast activation induced by tumor cells. The ability of secreted osteopontin to activate mammary fibroblasts relied upon its known receptors CD44 and alpha(V)beta(3) integrin. Strikingly, osteopontin silencing in tumor cells in vivo attenuated stromal activation and inhibited tumor growth. Our findings establish a critical functional role for paracrine signaling by tumor-derived osteopontin in reprograming normal fibroblasts into tumor-promoting CAFs. (C)2015 AACR.
C1 [Sharon, Yoray; Raz, Yael; Cohen, Noam; Ben-Shmuel, Amir; Schwartz, Hila; Erez, Neta] Tel Aviv Univ, Sackler Sch Med, Dept Pathol, IL-69978 Tel Aviv, Israel.
   [Raz, Yael] Tel Aviv Univ, Tel Aviv Sourasky Med Ctr, Dept Obstet & Gynecol, LIS Matern Hosp, IL-69978 Tel Aviv, Israel.
   [Geiger, Tamar] Tel Aviv Univ, Sackler Sch Med, Dept Human Mol Genet & Biochem, IL-69978 Tel Aviv, Israel.
C3 Tel Aviv University; Sackler Faculty of Medicine; Tel Aviv University;
   Sackler Faculty of Medicine; Tel Aviv Sourasky Medical Center; Tel Aviv
   University; Sackler Faculty of Medicine
RP Erez, N (corresponding author), Tel Aviv Univ, Levanon St, IL-69978 Tel Aviv, Israel.
EM netaerez@post.tau.ac.il
RI Geiger, Tamar/C-2349-2014; Yana, Yael/S-7100-2019; Erez,
   Neta/G-8584-2012
OI Doron, Hila/0000-0001-9704-7240; Geiger, Tamar/0000-0002-9526-197X;
   Erez, Neta/0000-0001-6506-9074; Cohen, Noam/0009-0003-7047-8843
FU Israel Science Foundation [813/12, 1617/12]; Israel Cancer Association
   [20110078]; Israel Cancer Research Fund (Research Career Development
   Award); Israel Center of Research Excellence program (I-CORE, Gene
   Regulation in Complex Human Disease Center) [41/11]; European Union
   Seventh Framework Program (FP7) [276890]
FX This research was supported by grants to N. Erez from the Israel Science
   Foundation (#813/12), the Israel Cancer Association (#20110078), The
   Israel Cancer Research Fund (Research Career Development Award), and
   from the European Union Seventh Framework Program (FP7/2007-2013) under
   grant agreement number (276890). T. Geiger acknowledges support from The
   Israel Science Foundation (grant 1617/12) and Israel Center of Research
   Excellence program (I-CORE, Gene Regulation in Complex Human Disease
   Center no. 41/11).
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NR 50
TC 129
Z9 136
U1 0
U2 16
PU AMER ASSOC CANCER RESEARCH
PI PHILADELPHIA
PA 615 CHESTNUT ST, 17TH FLOOR, PHILADELPHIA, PA 19106-4404 USA
SN 0008-5472
EI 1538-7445
J9 CANCER RES
JI Cancer Res.
PD MAR 15
PY 2015
VL 75
IS 6
BP 963
EP 973
DI 10.1158/0008-5472.CAN-14-1990
PG 11
WC Oncology
WE Science Citation Index Expanded (SCI-EXPANDED)
SC Oncology
GA CE6IZ
UT WOS:000351941400008
PM 25600648
OA Green Submitted
DA 2025-03-13
ER

PT J
AU Allaoui, R
   Bergenfelz, C
   Mohlin, S
   Hagerling, C
   Salari, K
   Werb, Z
   Anderson, RL
   Ethier, SP
   Jirström, K
   Påhlman, S
   Bexell, D
   Tahin, B
   Johansson, ME
   Larsson, C
   Leandersson, K
AF Allaoui, Roni
   Bergenfelz, Caroline
   Mohlin, Sofie
   Hagerling, Catharina
   Salari, Kiarash
   Werb, Zena
   Anderson, Robin L.
   Ethier, Stephen P.
   Jirstrom, Karin
   Pahlman, Sven
   Bexell, Daniel
   Tahin, Balazs
   Johansson, Martin E.
   Larsson, Christer
   Leandersson, Karin
TI Cancer-associated fibroblast-secreted CXCL16 attracts monocytes to
   promote stroma activation in triple-negative breast cancers
SO NATURE COMMUNICATIONS
LA English
DT Article
ID SUPPRESSOR-CELLS; TUMOR-STROMA; VI COLLAGEN; MACROPHAGES; METASTASIS;
   FIBROSIS; GROWTH; ACCUMULATION; EXPRESSION; S100A9
AB Triple-negative (TN) breast cancers (ER (-) PR (-) HER2 (-)) are highly metastatic and associated with poor prognosis. Within this subtype, invasive, stroma-rich tumours with infiltration of inflammatory cells are even more aggressive. The effect of myeloid cells on reactive stroma formation in TN breast cancer is largely unknown. Here, we show that primary human monocytes have a survival advantage, proliferate in vivo and develop into immunosuppressive myeloid cells expressing the myeloid-derived suppressor cell marker S100A9 only in a TN breast cancer environment. This results in activation of cancer-associated fibroblasts and expression of CXCL16, which we show to be a monocyte chemoattractant. We propose that this migratory feedback loop amplifies the formation of a reactive stroma, contributing to the aggressive phenotype of TN breast tumours. These insights could help select more suitable therapies targeting the stromal component of these tumours, and could aid prediction of drug resistance.
C1 [Allaoui, Roni; Bergenfelz, Caroline; Hagerling, Catharina; Johansson, Martin E.; Leandersson, Karin] Lund Univ, Canc Immunol, Dept Translat Med, S-20502 Malmo, Sweden.
   [Mohlin, Sofie; Pahlman, Sven; Bexell, Daniel; Larsson, Christer] Lund Univ, Translat Canc Res, Dept Lab Med, S-22363 Lund, Sweden.
   [Hagerling, Catharina; Salari, Kiarash; Werb, Zena] Univ Calif San Francisco, Dept Anat, San Francisco, CA 94143 USA.
   [Hagerling, Catharina; Salari, Kiarash; Werb, Zena] Univ Calif San Francisco, Helen Diller Family Comprehens Canc Ctr, San Francisco, CA 94143 USA.
   [Anderson, Robin L.] Univ Melbourne, Peter MacCallum Canc Ctr, Sir Peter MacCallum Dept Oncol, Melbourne, Vic 8006, Australia.
   [Ethier, Stephen P.] Med Univ South Carolina, Hollings Canc Ctr, Dept Pathol & Lab Med, Charleston, SC 29425 USA.
   [Jirstrom, Karin] Lund Univ, Dept Clin Sci Lund Oncol & Pathol, S-22185 Lund, Sweden.
   [Tahin, Balazs; Johansson, Martin E.] Skanes Univ Sjukhus, Dept Translat Med, Clin Pathol, S-20502 Malmo, Sweden.
C3 Lund University; Lund University; University of California System;
   University of California San Francisco; University of California System;
   University of California San Francisco; UCSF Medical Center; UCSF Helen
   Diller Family Comprehensive Cancer Center; University of Melbourne;
   Peter Maccallum Cancer Center; Medical University of South Carolina;
   Lund University
RP Leandersson, K (corresponding author), Lund Univ, Canc Immunol, Dept Translat Med, S-20502 Malmo, Sweden.
EM Karin.Leandersson@med.lu.se
RI Bergenfelz, Caroline/AAQ-2660-2020; Anderson, Robin/S-1005-2017
OI Bergenfelz, Caroline/0000-0001-9337-7285; Jirstrom,
   Karin/0000-0003-2257-5000; Hagerling, Catharina/0000-0001-5631-7988;
   Mohlin, Sofie/0000-0002-2458-3963; Anderson, Robin/0000-0002-6841-7422;
   Allaoui Fredriksson, Roni/0009-0005-9662-8357
FU Swedish Research Council; Swedish Cancer Society; Kocks Foundation;
   Osterlunds Foundation; Gunnar Nilsson Cancer Foundation; MAS Cancer
   Foundation; Ake Wibergs Foundation; National Cancer Institute, USA [R01
   CA180039, U01 CA199315]; SCAN-B project; Mrs Berta Kamprad foundation
FX The results are in part based upon data generated by the TCGA Research
   Network: http://cancergenome.nih.gov/. We thank Ms Elise Nilsson and Mrs
   Kristina Ekstrom-Holka for professional technical skills in preparation
   of IHC. We also thank Drs Susan Evans Axelsson, Kristofer Ahlqvist and
   Giacomo Canesin for extra help in the animal house. This work was
   generously supported by grants from the Swedish Research Council, The
   Swedish Cancer Society, Kocks Foundation, Osterlunds Foundation, Gunnar
   Nilsson Cancer Foundation, MAS Cancer Foundation, Ake Wibergs
   Foundation, The National Cancer Institute, USA (R01 CA180039 and U01
   CA199315 to Z.W.) and finally the SCAN-B project
   (http://www.med.lu.se/scan_b) and the Mrs Berta Kamprad foundation.
   Elevate Scientific, www.elevatescientific.com, Lund, Sweden, was used
   for linguistic corrections and improvements.
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NR 55
TC 139
Z9 151
U1 0
U2 27
PU NATURE PUBLISHING GROUP
PI LONDON
PA MACMILLAN BUILDING, 4 CRINAN ST, LONDON N1 9XW, ENGLAND
SN 2041-1723
J9 NAT COMMUN
JI Nat. Commun.
PD OCT 11
PY 2016
VL 7
AR 13050
DI 10.1038/ncomms13050
PG 14
WC Multidisciplinary Sciences
WE Science Citation Index Expanded (SCI-EXPANDED)
SC Science & Technology - Other Topics
GA DZ0SM
UT WOS:000385550000001
PM 27725631
OA gold, Green Published
DA 2025-03-13
ER

PT J
AU Hu, MR
   Cheng, N
   Wang, SW
   Li, RQ
   Liu, Y
   Wang, L
   Chen, WD
   Chen, YN
AF Hu, Mengru
   Cheng, Nuo
   Wang, Siwei
   Li, Ruoqing
   Liu, Yu
   Wang, Lei
   Chen, Weidong
   Chen, Yunna
TI Salvianolic acid B-loaded polydopamine-modified hollow mesoporous
   organic silica nanoparticles for treatment of breast cancer metastasis
   via suppressing cancer-associated fibroblasts
SO EUROPEAN JOURNAL OF PHARMACEUTICAL SCIENCES
LA English
DT Article
DE Organic-inorganic hybrid hollow mesoporous; organic silica
   nanoparticles; Cancer-associated fibroblasts; Epithelial -Mesenchymal
   Transition; Salvianolic acid B; Breast cancer lung metastases
ID MICROENVIRONMENT
AB Objective: Drug Delivery System was constructed using dopamine-coated organic-inorganic hybrid hollow mesoporous organic silica nanoparticles (HMON-PDA) as drug carriers and salvianolic acid B (SAB) as a model drug. Then, we further investigated whether it can inhibit lung metastasis of breast cancer by inhibiting cancerassociated fibroblasts (CAFs). Methods: The organic-inorganic hybrid hollow mesoporous organic silica nanoparticles (HMON) were prepared. The particle size, zeta potential, and polydispersion coefficient were characterized. High-performance liquid chromatography was used to determine the effect of different feed ratios of HMON and SAB on drug loading rate. Then, SAB-loaded HMON were modified by polydopamine, which is called SAB@HMON-PDA. Cell viability was detected by MTT assay. The migration of 4T1 cells was investigated by wound healing experiment, and the invasion of 4T1 cells was detected by the transwell method. Finally, the mouse breast cancer lung metastasis models were used to explore whether SAB@HMON-PDA can inhibit lung metastasis of breast cancer by inhibiting CAFs. Results: The obtained nanoparticles have hollow spherical structure. The average particle sizes of HMON, SAB@HMON, and SAB@HMON-PDA were 143.5 +/- 0.03, 138.3 +/- 0.02, and 172.3 +/- 0.18 nm, respectively. The zeta potentials were -44.33 +/- 0.15, -41.4 +/- 1.30, and -24.13 +/- 0.47 mV, respectively. When the ratio of HMON to SAB was 2:1, the drug loading rate reached (18.37 +/- 0.04)%. In addition, the prepared SAB@HMON-PDA responded to release SAB under acidic and GSH conditions. The prepared SAB@HMON-PDA could inhibit the migration and invasion of 4T1 cells. The results showed that SAB@HMON-PDA and SAB could inhibit lung metastasis of breast cancer in mice, and SAB@HMON-PDA had a more significant inhibitory effect than SAB. Conclusion: We successfully prepared SAB@HMON-PDA with the dual response of pH and GSH. SAB@HMONPDA can inhibit the migration and invasion of 4T1 cells, and the effect is more significant than free SAB. This inhibitory effect may be related to the inhibition of CAFs. In vivo experiments demonstrated that SAB@HMONPDA can inhibit lung metastasis of breast cancer by inhibiting CAFs, and its effect was more significant than that of free SAB.
C1 [Hu, Mengru; Cheng, Nuo; Wang, Siwei; Li, Ruoqing; Liu, Yu; Wang, Lei; Chen, Weidong; Chen, Yunna] Anhui Univ Chinese Med, Coll Pharm, Hefei 230012, Anhui, Peoples R China.
   [Cheng, Nuo; Chen, Yunna] Anhui Univ Chinese Med, Key Lab Mol Biol Brain Dis, Hefei 230012, Anhui, Peoples R China.
   [Hu, Mengru; Wang, Siwei; Li, Ruoqing; Wang, Lei; Chen, Weidong] MOE Anhui Joint Collaborat Innovat Ctr Qual Impro, Hefei 230012, Anhui, Peoples R China.
   [Hu, Mengru; Wang, Siwei; Li, Ruoqing; Wang, Lei; Chen, Weidong] Anhui Prov Key Lab Chinese Med Formula, Hefei 230012, Anhui, Peoples R China.
   [Wang, Lei; Chen, Weidong; Chen, Yunna] Anhui Univ Chinese Med, Hefei 230012, Peoples R China.
C3 Anhui University of Chinese Medicine; Anhui University of Chinese
   Medicine; Anhui University of Chinese Medicine
RP Wang, L; Chen, WD; Chen, YN (corresponding author), Anhui Univ Chinese Med, Hefei 230012, Peoples R China.
EM wanglei@ahtcm.edu.cn; wdchen@ahtcm.edu.cn; ynchen@ahtcm.edu.cn
FU National Natural Science Foundation of China [81773988]; University
   Natural Science Research Project of Anhui Province [KJ2021A0586,
   2022AH050533]; Anhui University of Traditional Chinese Medicine Youth
   Science and Technology Talent Cultivation Project [2021qnyc02]; Anhui
   University of Traditional Chinese Medicine Talent Support Program
   [2022rczd004]; Domestic and foreign research and study programs for
   outstanding young back-bone talents in colleges and universities
   [gxgwfx2021026]
FX This work was supported by the National Natural Science Foundation of
   China (81773988) , University Natural Science Research Project of Anhui
   Province (KJ2021A0586, 2022AH050533) , Anhui University of Traditional
   Chinese Medicine Youth Science and Technology Talent Cultivation Project
   (2021qnyc02) , and Anhui University of Traditional Chinese Medicine
   Talent Support Program (2022rczd004) , Domestic and foreign research and
   study programs for outstanding young back-bone talents in colleges and
   universities (gxgwfx2021026) .
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NR 28
TC 5
Z9 5
U1 4
U2 14
PU ELSEVIER
PI AMSTERDAM
PA RADARWEG 29, 1043 NX AMSTERDAM, NETHERLANDS
SN 0928-0987
EI 1879-0720
J9 EUR J PHARM SCI
JI Eur. J. Pharm. Sci.
PD JAN 1
PY 2024
VL 192
AR 106641
DI 10.1016/j.ejps.2023.106641
EA NOV 2023
PG 12
WC Pharmacology & Pharmacy
WE Science Citation Index Expanded (SCI-EXPANDED)
SC Pharmacology & Pharmacy
GA AU0T4
UT WOS:001120857200001
PM 37972905
OA gold
DA 2025-03-13
ER

PT J
AU Luo, HJ
   Tu, G
   Liu, ZM
   Liu, MR
AF Luo, Haojun
   Tu, Gang
   Liu, Zhimin
   Liu, Manran
TI Cancer-associated fibroblasts: A multifaceted driver of breast cancer
   progression
SO CANCER LETTERS
LA English
DT Review
DE Cancer-associated fibroblasts (CAFs); Breast carcinoma; Progression;
   Tumor microenvironment
ID EPITHELIAL-MESENCHYMAL TRANSITION; STROMAL CAVEOLIN-1 EXPRESSION;
   INVASIVE DUCTAL CARCINOMA; HEPATOCYTE GROWTH-FACTOR; EARLY TUMOR
   RECURRENCE; EXTRACELLULAR-MATRIX; PROGNOSTIC VALUE; PODOPLANIN
   EXPRESSION; OXIDATIVE STRESS; TGF-BETA
AB Cancerous tissue is a complex mix of tumor cells, stromal cells and extracellular matrix (ECM), all of which make up a disordered and aggressive niche in comparison with organized and homeostatic normal tissue. It is well accepted that the tumor microenvironment plays an indispensable role in cancer development, and thus can be recognized as an additional cancer hallmark alongside those that are well established. In breast cancer, cancer associated fibroblasts (CAFs) are the predominant cellular components and play a centric role in the tumor microenvironment since they not only promote cancer initiation, growth, invasion, metastasis and therapeutic resistance but are also involved in microenvironmental events including angiogenesis/lymphangiogenesis, ECM remodeling, cancer-associated inflammation and metabolism reprogramming, all of which are known to have pre-malignancy potency. At the molecular level, there is a sophisticated network underlying the interactions between CAFs and epithelial cells as well as other stromal components. Accordingly, targeting CAFs provides a novel strategy in cancer. therapy. Herein, we summarize the current understanding of the role of CAFs in breast cancer. (C) 2015 Elsevier Ireland Ltd. All rights reserved.
C1 [Luo, Haojun] Chongqing Med Univ, Affiliated Hosp 2, Dept Thyroid & Breast Surg, Chongqing 400010, Peoples R China.
   [Tu, Gang] Chongqing Med Univ, Affiliated Hosp 1, Dept Endocrine & Breast Surg, Chongqing 400016, Peoples R China.
   [Liu, Zhimin] Chongqing Med Univ, Dept Biochem & Mol Biol, Chongqing 400016, Peoples R China.
   [Liu, Manran] Chongqing Med Univ, Chinese Minist Educ, Key Lab Lab Med Diagnost, Chongqing 400016, Peoples R China.
C3 Chongqing Medical University; Chongqing Medical University; Chongqing
   Medical University; Chongqing Medical University
RP Liu, MR (corresponding author), Chongqing Med Univ, Chinese Minist Educ, Key Lab Lab Med Diagnost, Chongqing 400016, Peoples R China.
EM mliu-hncq@hotmail.com
OI li, lu/0009-0009-8381-3093
FU National Natural Science Foundation of China [NSFC 81372389, NSFC
   81472476]
FX This work was supported by National Natural Science Foundation of China
   (NSFC 81372389, and NSFC 81472476).
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NR 154
TC 168
Z9 195
U1 1
U2 99
PU ELSEVIER IRELAND LTD
PI CLARE
PA ELSEVIER HOUSE, BROOKVALE PLAZA, EAST PARK SHANNON, CO, CLARE, 00000,
   IRELAND
SN 0304-3835
EI 1872-7980
J9 CANCER LETT
JI Cancer Lett.
PD JUN 1
PY 2015
VL 361
IS 1
BP 155
EP 163
DI 10.1016/j.canlet.2015.02.018
PG 9
WC Oncology
WE Science Citation Index Expanded (SCI-EXPANDED)
SC Oncology
GA CG6QO
UT WOS:000353427300001
PM 25700776
DA 2025-03-13
ER

PT J
AU Busch, S
   Acar, A
   Magnusson, Y
   Gregersson, P
   Rydén, L
   Landberg, G
AF Busch, S.
   Acar, A.
   Magnusson, Y.
   Gregersson, P.
   Ryden, L.
   Landberg, G.
TI TGF-beta receptor type-2 expression in cancer-associated fibroblasts
   regulates breast cancer cell growth and survival and is a prognostic
   marker in pre-menopausal breast cancer
SO ONCOGENE
LA English
DT Article
DE TGF-beta; tumour stroma; cancer-associated fibroblast; breast cancer;
   clonogenic survival
ID STROMAL FIBROBLASTS; CARCINOMA; MYOFIBROBLASTS; HETEROGENEITY; TAMOXIFEN
AB Transforming growth factor-beta (TGF-beta) is a pleiotropic cytokine with the capability to act as tumour suppressor or tumour promoter depending on the cellular context. TGF-beta receptor type-2 (TGFBR2) is the ligand-binding receptor for all members of the TGF-beta family. Data from mouse model experiments demonstrated that loss of Tgfbr2 expression in mammary fibroblasts was linked to tumour initiation and metastasis. Using a randomised tamoxifen trial cohort including in total 564 invasive breast carcinomas, we examined TGFBR2 expression (n = 252) and phosphorylation level of downstream target SMAD2 (pSMAD2) (n = 319) in cancer-associated fibroblasts (CAFs) and assessed links to clinicopathological markers, prognostic and treatment-predictive values. The study revealed that CAF-specific TGFBR2 expression correlated with improved recurrence-free survival. Multivariate analysis confirmed CAF-TGFBR2 to be an independent prognostic marker (multivariate Cox regression, hazard ratio: 0.534, 95% (Cl): 0.360-0.793, P = 0.002). CAF-specific pSMAD2 levels, however, did not associate with survival outcome. Experimentally, TGF-beta signalling in fibroblasts was modulated using a TGF-beta ligand and inhibitor or through lentiviral short hairpin RNA-mediated TGFBR2-specific knockdown. To determine the role of fibroblastic TGF-beta pathway on breast cancer cells, we used cell contact-dependent cell growth and clonogenicity assays, which showed that knockdown of TGFBR2 in CAFs resulted in increased cell growth, proliferation and clonogenic survival. Further, in a mouse model transfected CAFs were co-injected with MCF7 and tumour weight and proportion was monitored. We found that mouse xenograft tumours comprising TGFBR2 knockdown fibroblasts were slightly bigger and displayed increased tumour cell capacity. Overall, our data demonstrate that fibroblast-related biomarkers possess clinically relevant information and that fibroblasts confer effects on breast cancer cell growth and survival. Regulation of tumour-stromal cross-talk through fibroblastic TGF-beta pathway may depend on fibroblast phenotype, emphasising the importance to characterise tumour microenvironment subtypes.
C1 [Busch, S.; Magnusson, Y.; Gregersson, P.; Landberg, G.] Gothenburg Univ, Sahlgrenska Canc Ctr, Dept Pathol, S-40530 Gothenburg, Sweden.
   [Acar, A.] Univ Manchester, Fac Life Sci, Wellcome Trust Ctr Cell Matrix Res, Manchester, Lancs, England.
   [Ryden, L.] Univ Lund Hosp, Inst Clin Sci, Dept Surg, S-22185 Lund, Sweden.
   [Landberg, G.] Univ Manchester, Paterson Inst Canc Res, Inst Canc Sci, Breakthrough Breast Canc Res Unit,Mol Pathol Grp, Manchester, Lancs, England.
C3 University of Gothenburg; University of Manchester; Lund University;
   Skane University Hospital; Paterson Institute for Cancer Research;
   University of Manchester
RP Landberg, G (corresponding author), Gothenburg Univ, Sahlgrenska Canc Ctr, Dept Pathol, Medicinaregatan 1F, S-40530 Gothenburg, Sweden.
EM Goran.landberg@gu.se
RI ; Acar, Ahmet/ABI-3298-2020
OI Ryden, Lisa/0000-0001-7515-3130; Acar, Ahmet/0000-0002-2478-8029
FU Swedish Cancer Society; Breakthrough Breast Cancer UK; BioCARE-a
   National Strategic Research Program at University of Gothenburg
FX We thank Elise Nilsson for excellent technical assistance, the MCRC
   Biobank for providing us with patient material and Dr Akira Orimo for
   the kind gift of fibroblast model cell lines and lentiviral plasmids. We
   would further thank Eamon Hughes for his assistance with the animal
   work. This study was supported by the Swedish Cancer Society and
   Breakthrough Breast Cancer UK. The project was further supported by
   BioCARE-a National Strategic Research Program at University of
   Gothenburg.
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NR 29
TC 92
Z9 100
U1 0
U2 29
PU NATURE PUBLISHING GROUP
PI LONDON
PA MACMILLAN BUILDING, 4 CRINAN ST, LONDON N1 9XW, ENGLAND
SN 0950-9232
EI 1476-5594
J9 ONCOGENE
JI Oncogene
PD JAN 2
PY 2015
VL 34
IS 1
BP 27
EP 38
DI 10.1038/onc.2013.527
PG 12
WC Biochemistry & Molecular Biology; Oncology; Cell Biology; Genetics &
   Heredity
WE Science Citation Index Expanded (SCI-EXPANDED)
SC Biochemistry & Molecular Biology; Oncology; Cell Biology; Genetics &
   Heredity
GA CB6MC
UT WOS:000349740100003
PM 24336330
DA 2025-03-13
ER

PT J
AU Hu, DD
   Zhuo, WY
   Gong, PR
   Ji, FY
   Zhang, X
   Chen, YX
   Mao, MS
   Ju, SW
   Pan, YH
   Shen, J
AF Hu, Dengdi
   Zhuo, Wenying
   Gong, Peirong
   Ji, Feiyang
   Zhang, Xun
   Chen, Yongxia
   Mao, Misha
   Ju, Siwei
   Pan, Yuehong
   Shen, Jun
TI Biological differences between normal and cancer-associated fibroblasts
   in breast cancer
SO HELIYON
LA English
DT Article
DE Breast cancer; Cancer-associated fibroblasts; Normal fibroblasts;
   Biological profile; microRNA
ID TO-MESENCHYMAL TRANSITION; GENE-EXPRESSION; IN-SITU
AB Background: Cancer-associated fibroblasts (CAFs) constitute the primary constituents of the tumor microenvironment (TME) and exert significant influences on cancer progression. However, adequate comprehension of CAF profiles in breast cancer, as well as the precise mechanisms underlying their promotion of cancer, remains lacking. Objectives: To discerns the biological differences between normal fibroblasts (NFs) and CAFs in breast cancer and explore the underlying mechanism. Methods: Three pairs of CAFs and NFs were isolated from breast cancer patients of diverse subtypes who had not undergone prior radiotherapy or chemotherapy. Morphological characteristics of CAFs and NFs were assessed through optical and electron microscopy, their biological attributes were examined using cell counting kits and transwell assays, and their impact on breast cancer cells was simulated using a coculture system. Furthermore, the miRNA profiles of CAFs and NFs were sequenced via an Illumina HiSeq 2500 platform. Results: CAFs exhibited higher growth rate and motility than NFs and a stronger potential to promote the malignancy of breast cancer cells. RNA sequencing of both NFs and CAFs revealed differentially expressed miRNAs with notable variability among distinct patients within their NFs and CAFs, while the enrichment of the target genes of differentially expressed miRNAs within both GO terms and KEGG pathways demonstrated significant similarity across patients with different profiles. Conclusion: CAFs have greater malignancy and higher potential to influence the growth, migration, invasion and chemoresistance of cocultured breast cancer cells than NFs. In addition, the miRNAs that are differentially expressed in CAFs when compared to NFs display substantial variability across patients with distinct breast cancer subtypes, while the enrichment of target genes regulated by these miRNAs, within GO terms and KEGG pathways, remains remarkably consistent among patients with varying profiles.
C1 [Hu, Dengdi; Zhuo, Wenying; Gong, Peirong; Pan, Yuehong] Wenzhou Med Univ, Affiliated Cixi Hosp, Ningbo 315300, Zhejiang, Peoples R China.
   [Zhuo, Wenying; Ji, Feiyang; Zhang, Xun; Chen, Yongxia; Mao, Misha; Ju, Siwei; Shen, Jun] Zhejiang Univ, Sch Med, Affiliated Sir Run Run Shaw Hosp, Hangzhou 310016, Zhejiang, Peoples R China.
   [Zhuo, Wenying; Ji, Feiyang; Zhang, Xun; Chen, Yongxia; Mao, Misha; Ju, Siwei; Shen, Jun] Minist Educ, Key Lab Canc Prevent & Intervent, Hangzhou, Zhejiang, Peoples R China.
   [Zhuo, Wenying; Ji, Feiyang; Zhang, Xun; Chen, Yongxia; Mao, Misha; Ju, Siwei; Shen, Jun] Biomed Res Ctr, Hangzhou 310016, Zhejiang, Peoples R China.
   [Zhuo, Wenying; Ji, Feiyang; Zhang, Xun; Chen, Yongxia; Mao, Misha; Ju, Siwei; Shen, Jun] Key Lab Biotherapy Zhejiang Prov, 3 Eastern Qingchun Rd, Hangzhou 310016, Zhejiang, Peoples R China.
   [Shen, Jun] Zhejiang Univ, Affiliated Sir Run Run Shaw Hosp, Biomed Res Ctr, Dept Surg Oncol,Sch Med, 3 Eastern Qingchun Rd, Hangzhou 310016, Zhejiang, Peoples R China.
C3 Wenzhou Medical University; Zhejiang University; Zhejiang University
RP Shen, J (corresponding author), Minist Educ, Key Lab Canc Prevent & Intervent, Hangzhou, Zhejiang, Peoples R China.; Shen, J (corresponding author), Key Lab Biotherapy Zhejiang Prov, 3 Eastern Qingchun Rd, Hangzhou 310016, Zhejiang, Peoples R China.; Shen, J (corresponding author), Zhejiang Univ, Affiliated Sir Run Run Shaw Hosp, Biomed Res Ctr, Dept Surg Oncol,Sch Med, 3 Eastern Qingchun Rd, Hangzhou 310016, Zhejiang, Peoples R China.
EM shenjun0909@zju.edu.cn
OI Shen, Jun/0000-0002-8384-3526
FU Ningbo Natural Science Foundation [2019A610315]; Cixi Agricultural and
   Social Development Science and Technology Project [CN2020006]
FX The work was supported by Ningbo Natural Science Foundation (Grant No.
   2019A610315) and Cixi Agricultural and Social Development Science and
   Technology Project (CN2020006) .
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NR 39
TC 3
Z9 3
U1 2
U2 5
PU CELL PRESS
PI CAMBRIDGE
PA 50 HAMPSHIRE ST, FLOOR 5, CAMBRIDGE, MA 02139 USA
EI 2405-8440
J9 HELIYON
JI Heliyon
PD SEP
PY 2023
VL 9
IS 9
AR e19803
DI 10.1016/j.heliyon.2023.e19803
PG 13
WC Multidisciplinary Sciences
WE Science Citation Index Expanded (SCI-EXPANDED)
SC Science & Technology - Other Topics
GA ER5C4
UT WOS:001140653300001
PM 37810030
OA Green Published, gold
DA 2025-03-13
ER

PT J
AU Chen, PB
   Mo, QQ
   Wang, BB
   Weng, DH
   Wu, P
   Chen, G
AF Chen, Pingbo
   Mo, Qingqing
   Wang, Beibei
   Weng, Danhui
   Wu, Peng
   Chen, Gang
TI Breast Cancer Associated Fibroblasts Promote MCF-7 Invasion <i>in
   vitro</i> by Secretion of HGF
SO JOURNAL OF HUAZHONG UNIVERSITY OF SCIENCE AND TECHNOLOGY-MEDICAL
   SCIENCES
LA English
DT Article
DE cancer associated fibroblasts; breast cancer; hepatocyte growth factor;
   invasion
ID TUMOR PROGRESSION; EXPRESSION; RECEPTOR; GROWTH
AB This study was aimed to explore the influence of breast cancer associated fibroblasts (CAFs) in migration and invasion of breast cancer cell line MCF-7, and investigate whether hepatocyte growth factor (HGF) is involved in this process. Primary breast CAFs and their corresponding normal breast fibroblasts (NFs) were obtained by collagenase digestion. On the basis of the co-culture, the migration and invasion capacity of MCF-7 cells was compared between CAFs and NFs by Transwell. The difference in the HGF expression between them was detected by ELISA. The secretion of HGF was knocked down by using RNA interference technology in CAFs. Then the changes of migration and invasion capacity of MCF-7 cells were investigated by Transwell. Eventually, we isolated high-purity CAFs and NFs, and the CAFs had a stronger ability in promoting MCF-7 migration and invasion than the NFs. ELISA results demonstrated that CAFs secreted higher HGF, and the capacity of MCF-7 migration and invasion was declined after knocking down the secretion of HGF in CAFs by RNA interference. It is suggested that CAFs can promote MCF-7 migration and invasion through HGF in vitro.
C1 [Chen, Pingbo; Mo, Qingqing; Wang, Beibei; Weng, Danhui; Wu, Peng; Chen, Gang] Huazhong Univ Sci & Technol, Tongji Med Coll, Tongji Hosp, Dept Obstet & Gynecol, Wuhan 430030, Peoples R China.
C3 Huazhong University of Science & Technology
RP Chen, G (corresponding author), Huazhong Univ Sci & Technol, Tongji Med Coll, Tongji Hosp, Dept Obstet & Gynecol, Wuhan 430030, Peoples R China.
EM supercpb520@gmail.com; gumpc@126.com
RI wu, peng/M-1812-2019
FU National Natural Science Foundation of China [81000979, 30901584,
   30801224]; National Key Basic Research Program Foundation of China
   [2009CB521800]
FX This project was supported by grants from the National Natural Science
   Foundation of China (No. 81000979; No. 30901584; No. 30801224) and the
   National Key Basic Research Program Foundation of China (Program 973)
   (No. 2009CB521800).
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NR 11
TC 8
Z9 12
U1 0
U2 18
PU SPRINGER
PI NEW YORK
PA 233 SPRING ST, NEW YORK, NY 10013 USA
SN 1672-0733
J9 J HUAZHONG U SCI-MED
JI J. Huazhong Univ. Sci. Tech.-Med.
PD FEB
PY 2012
VL 32
IS 1
BP 92
EP 96
DI 10.1007/s11596-012-0016-8
PG 5
WC Biochemistry & Molecular Biology
WE Science Citation Index Expanded (SCI-EXPANDED)
SC Biochemistry & Molecular Biology
GA 927QR
UT WOS:000302925500016
PM 22282252
DA 2025-03-13
ER

PT J
AU Berdiel-Acer, M
   Maia, A
   Hristova, Z
   Borgoni, S
   Vetter, M
   Burmester, S
   Becki, C
   Michels, B
   Abnaof, K
   Binenbaum, I
   Bethmann, D
   Chatziioannou, A
   Hasmann, M
   Thomssen, C
   Espinet, E
   Wiemann, S
AF Berdiel-Acer, Mireia
   Maia, Ana
   Hristova, Zhivka
   Borgoni, Simone
   Vetter, Martina
   Burmester, Sara
   Becki, Corinna
   Michels, Birgitta
   Abnaof, Khalid
   Binenbaum, Ilona
   Bethmann, Daniel
   Chatziioannou, Aristotelis
   Hasmann, Max
   Thomssen, Christoph
   Espinet, Elisa
   Wiemann, Stefan
TI Stromal NRG1 in luminal breast cancer defines pro-fibrotic and migratory
   cancer-associated fibroblasts
SO ONCOGENE
LA English
DT Article
ID INTRACELLULAR DOMAIN; ERBB RECEPTORS; GENE ONTOLOGY; EXPRESSION; HER3;
   SUBTYPES; ANTIBODY; HETEROGENEITY; METASTASIS; DISCOVERY
AB HER3 is highly expressed in luminal breast cancer subtypes. Its activation by NRG1 promotes activation of AKT and ERK1/2, contributing to tumour progression and therapy resistance. HER3-targeting agents that block this activation, are currently under phase 1/2 clinical studies, and although they have shown favorable tolerability, their activity as a single agent has proven to be limited. Here we show that phosphorylation and activation of HER3 in luminal breast cancer cells occurs in a paracrine manner and is mediated by NRG1 expressed by cancer-associated fibroblasts (CAFs). Moreover, we uncover a HER3-independent NRG1 signaling in CAFs that results in the induction of a strong migratory and pro-fibrotic phenotype, describing a subtype of CAFs with elevated expression of NRG1 and an associated transcriptomic profile that determines their functional properties. Finally, we identified Hyaluronan Synthase 2 (HAS2), a targetable molecule strongly correlated with NRG1, as an attractive player supporting NRG1 signaling in CAFs.
C1 [Berdiel-Acer, Mireia; Maia, Ana; Hristova, Zhivka; Borgoni, Simone; Burmester, Sara; Becki, Corinna; Michels, Birgitta; Abnaof, Khalid; Wiemann, Stefan] German Canc Res Ctr, Div Mol Genome Anal, Heidelberg, Germany.
   [Maia, Ana; Hristova, Zhivka; Borgoni, Simone] Ruprecht Karls Univ Heidelberg, Fac Biosci, Heidelberg, Germany.
   [Vetter, Martina; Thomssen, Christoph] Martin Luther Univ Halle Wittenberg, Dept Gynecol, Halle, Germany.
   [Binenbaum, Ilona] German Canc Res Ctr, Div Med Informat Translat Oncol, Heidelberg, Germany.
   [Binenbaum, Ilona] Univ Patras, Dept Biol, Patras, Greece.
   [Binenbaum, Ilona; Chatziioannou, Aristotelis] Natl Hellen Res Fdn, Inst Chem Biol, Athens, Greece.
   [Bethmann, Daniel] Martin Luther Univ Halle Wittenberg, Inst Pathol, Halle, Germany.
   [Chatziioannou, Aristotelis] E NIOS Pc, Kallithea Athens, Greece.
   [Hasmann, Max] Roche Diagnostics, Penzberg, Germany.
   [Espinet, Elisa] German Canc Res Ctr, Div Stem Cells & Canc, Heidelberg, Germany.
   [Espinet, Elisa] Heidelberg Inst Stem Cell Technol & Expt Med HI S, Heidelberg, Germany.
C3 Helmholtz Association; German Cancer Research Center (DKFZ); Ruprecht
   Karls University Heidelberg; Martin Luther University Halle Wittenberg;
   Helmholtz Association; German Cancer Research Center (DKFZ); University
   of Patras; National Hellenic Research Foundation; Martin Luther
   University Halle Wittenberg; Helmholtz Association; German Cancer
   Research Center (DKFZ)
RP Berdiel-Acer, M; Wiemann, S (corresponding author), German Canc Res Ctr, Div Mol Genome Anal, Heidelberg, Germany.
EM mireia.berdiel@gmail.com; s.wiemann@dkfz-heidelberg.de
RI Thomssen, Christoph/ABC-3102-2021; Espinet, Elisa/ABI-5385-2020;
   Wiemann, Stefan/E-4424-2013
OI Hristova, Zhivka/0000-0003-2609-3623; Binenbaum,
   Ilona/0000-0002-1045-5725; Wiemann, Stefan/0000-0003-4683-3174;
   Berdiel-Acer, Mireia/0000-0002-9777-9457; Michels, Birgitta
   E./0000-0001-9948-4567; Espinet, Elisa/0000-0002-0690-9878; Maia,
   Ana/0000-0003-1261-7211
FU Projekt DEAL
FX Open Access funding enabled and organized by Projekt DEAL.
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NR 76
TC 14
Z9 14
U1 0
U2 11
PU SPRINGERNATURE
PI LONDON
PA CAMPUS, 4 CRINAN ST, LONDON, N1 9XW, ENGLAND
SN 0950-9232
EI 1476-5594
J9 ONCOGENE
JI Oncogene
PD APR 15
PY 2021
VL 40
IS 15
BP 2651
EP 2666
DI 10.1038/s41388-021-01719-3
EA MAR 2021
PG 16
WC Biochemistry & Molecular Biology; Oncology; Cell Biology; Genetics &
   Heredity
WE Science Citation Index Expanded (SCI-EXPANDED)
SC Biochemistry & Molecular Biology; Oncology; Cell Biology; Genetics &
   Heredity
GA RN8NW
UT WOS:000627285600003
PM 33692466
OA hybrid, Green Published, Green Submitted
DA 2025-03-13
ER

PT J
AU Liu, TH
   Wang, QS
   Geng, WX
   Jiang, X
   Lu, CS
   Zhang, Z
   Feng, XR
AF Liu, Tianhui
   Wang, Qingshuang
   Geng, Wenxin
   Jiang, Xue
   Lu, Changshun
   Zhang, Zhe
   Feng, Xiangru
TI Thermosensitive Hydrogel Loaded with α-Mangostin for Enhanced Antitumor
   Effect of Doxorubicin
SO ACS BIOMATERIALS SCIENCE & ENGINEERING
LA English
DT Article
DE breast cancer; tumor microenvironment; alpha-Mangostin; GSH
   responsiveness
ID CANCER-ASSOCIATED FIBROBLASTS; DELIVERY; NANOPARTICLES; AUTOPHAGY; PH
AB The cancer-associated fibroblasts (CAFs) in tumor stroma present substantial barriers to drug penetration, resulting in tumor resistance and progression. One promising strategy is to reprogram CAFs into a quiescent state, which necessitates novel approaches. Our study introduces a sequential treatment strategy using chitosan thermosensitive hydrogels loaded with alpha-Mangostin (alpha-M), a small molecule drug with antifibrotic properties, aimed at reprogramming CAFs within the breast cancer tumor microenvironment (TME). We developed glutathione (GSH)-responsive nanoparticles (NPc) that carry the chemotherapeutic drug doxorubicin (DOX). Treatment with alpha-M results in the downregulation of CAF-specific biomarkers and a remodeled TME, which improves the penetration of NPc/DOX deep into the tumor tissue. This strategy holds great promise in enhancing cancer therapeutic outcomes in tumors rich in CAFs, particularly in the case of breast cancer.
C1 [Liu, Tianhui; Wang, Qingshuang; Geng, Wenxin; Jiang, Xue; Lu, Changshun; Feng, Xiangru] Changchun Univ Sci & Technol, Changchun 130022, Jilin, Peoples R China.
   [Zhang, Zhe] Panzhihua Univ, Panzhihua 617000, Sichuan, Peoples R China.
C3 Changchun University of Science & Technology; Panzhihua University
RP Wang, QS; Feng, XR (corresponding author), Changchun Univ Sci & Technol, Changchun 130022, Jilin, Peoples R China.
EM wangqingshuang@163.com; xrfeng@cust.edu.cn
FU Department of Science and Technology of Jilin Province
   [YDZJ202201ZYTS670]; Science and Technology Development Program of Jilin
   Province
FX This work was jointly supported by the Science and Technology
   Development Program of Jilin Province (Grant number: YDZJ202201ZYTS670).
CR Chen XX, 2021, THERANOSTICS, V11, P8692, DOI 10.7150/thno.60437
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NR 24
TC 0
Z9 0
U1 3
U2 3
PU AMER CHEMICAL SOC
PI WASHINGTON
PA 1155 16TH ST, NW, WASHINGTON, DC 20036 USA
SN 2373-9878
J9 ACS BIOMATER SCI ENG
JI ACS Biomater. Sci. Eng.
PD JAN 30
PY 2025
VL 11
IS 2
BP 1000
EP 1012
DI 10.1021/acsbiomaterials.4c02408
EA JAN 2025
PG 13
WC Materials Science, Biomaterials
WE Science Citation Index Expanded (SCI-EXPANDED)
SC Materials Science
GA W3A7V
UT WOS:001411234100001
PM 39884961
DA 2025-03-13
ER

PT J
AU Aboussekhra, A
   Alraouji, NN
   Al-Mohanna, FH
   Al-Khalaf, H
AF Aboussekhra, Abdelilah
   Alraouji, Noura N.
   Al-Mohanna, Falah H.
   Al-Khalaf, Huda
TI Ionizing radiation normalizes the features of active breast cancer
   stromal fibroblasts and suppresses their paracrine pro-carcinogenic
   effects
SO TRANSLATIONAL ONCOLOGY
LA English
DT Article
DE Breast cancer; CAFs; Ionizing radiation; Senescence
ID MESENCHYMAL TRANSITION; TUMOR MICROENVIRONMENT; CELLS; MECHANISMS;
   SENESCENCE; EXPRESSION; CAPACITY; ONCOLOGY; ENHANCE
AB Background: Radiotherapy is an important therapeutic strategy for breast cancer patients through reducing the chances of recurrence and metastasis, which are fueled by cancer-associated fibroblasts (CAFs). Thereby, we addressed here the effect of various doses of X-rays on breast CAFs and their adjacent counterparts. Methods: We have used WST1 and annexin V-associated with flow cytometry to test the cytotoxic effects of Xrays. Immunoblotting and ELISA was used to assess the expression/secretion of various proteins. Immunohistochemistry was utilized to determine the level of beta-galactosidase and Ki-67. Sphere formation assay was used to test the ability of breast cancer cells to form tumorspheres. Orthotopic tumor xenografts were also used to evaluate the effect of X-ray-treated breast stromal fibroblasts on breast cancer tumor growth in vivo. Results: Breast stromal fibroblasts showed high resistance to X-rays. While the low dose (5 Gy) inhibited cell proliferation and the active features of CAFs, the higher doses (16 and 50 Gy) promoted senescence. However, this was not accompanied by the senescence-associated secretory phenotype (SASP), but rather a reduction in the synthesis/secretion of various cancer-associated cytokines. Additionally, X-rays suppressed the features of active breast stromal fibroblasts, and their paracrine pro-carcinogenic effects. The ablative dose (16 Gy) inhibited the capacity of active stromal fibroblasts to promote the pro-metastatic processes epithelial-to-mesenchymal transition, the formation of cancer stem cells, as well as the growth of humanized orthotopic breast tumor xenografts. Conclusion: Together, these findings indicate that X-rays can normalize the features of active breast stromal fibroblasts through promoting senescence without SASP.
C1 [Aboussekhra, Abdelilah; Alraouji, Noura N.; Al-Khalaf, Huda] King Faisal Specialist Hosp & Res Ctr, Dept Mol Oncol, Canc Biol & Expt Therapeut Sect, MBC 03,POB 3354, Riyadh 11211, Saudi Arabia.
   [Al-Mohanna, Falah H.] King Faisal Specialist Hosp & Res Ctr, Dept Comparat Med, Riyadh 11211, Saudi Arabia.
   [Al-Khalaf, Huda] King Abdulaziz City Sci & Technol KACST, Hlth Aging Inst, Hlth Sect, Riyadh 11442, Saudi Arabia.
C3 King Faisal Specialist Hospital & Research Center; King Faisal
   Specialist Hospital & Research Center
RP Aboussekhra, A (corresponding author), King Faisal Specialist Hosp & Res Ctr, Dept Mol Oncol, Canc Biol & Expt Therapeut Sect, MBC 03,POB 3354, Riyadh 11211, Saudi Arabia.
EM aboussekhra@kfshrc.edu.sa
RI Alraouji, Noura/JGL-6423-2023; Aboussekhra, Abdelilah/JCD-8138-2023
OI Alraouji, Noura/0009-0008-4177-149X
FU Research Center Administration
FX We are thankful to F. Hendrayani for her technical help. We also
   grateful to Dr Ghazi Alsbeih and Sara Bin Judia for their help with
   X-rays treatments. We also appreciate the continuous support of the
   Research Center Administration.
CR Al-Ansari MM, 2013, ONCOGENE, V32, P2356, DOI 10.1038/onc.2012.270
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NR 27
TC 1
Z9 1
U1 3
U2 3
PU ELSEVIER SCIENCE INC
PI NEW YORK
PA STE 800, 230 PARK AVE, NEW YORK, NY 10169 USA
SN 1936-5233
J9 TRANSL ONCOL
JI Transl. Oncol.
PD NOV
PY 2023
VL 37
AR 101780
DI 10.1016/j.tranon.2023.101780
EA SEP 2023
PG 8
WC Oncology
WE Science Citation Index Expanded (SCI-EXPANDED)
SC Oncology
GA T5QA7
UT WOS:001078521200001
PM 37672859
OA Green Published, gold
DA 2025-03-13
ER

PT J
AU Lin, SY
   Zhou, MN
   Cheng, LY
   Shuai, ZF
   Zhao, MY
   Jie, RX
   Wan, Q
   Peng, F
   Ding, SP
AF Lin, Shuangyan
   Zhou, Miaoni
   Cheng, Liying
   Shuai, Zhifeng
   Zhao, Mingyuan
   Jie, Ruixia
   Wan, Qun
   Peng, Fang
   Ding, Shiping
TI Exploring the association of POSTN plus cancer-associated fibroblasts
   with triple-negative breast cancer
SO INTERNATIONAL JOURNAL OF BIOLOGICAL MACROMOLECULES
LA English
DT Article
DE Triple-negative breast cancer; Cancer-associated fibroblasts; POSTN plus
   CAFs
ID MICROENVIRONMENT; CHEMORESISTANCE; HETEROGENEITY; LANDSCAPE; PERIOSTIN;
   GROWTH
AB Triple-negative breast cancer (TNBC) is a subtype of breast cancer with a poor prognosis. Cancer-associated fibroblasts (CAFs) play a critical role in regulating TNBC tumor development. This study aimed to identify and characterize a specific subtype of CAFs associated with TNBC. Initially, using high-throughput bulk transcriptomic data in two cohorts, we identified three CAF-related subtypes (CS1, CS2, CS3) in TNBC samples. These three CAFs subtypes were closely linked to the tumor microenvironment. The CS1 subtype exhibited a relatively immune-rich microenvironment and a favourable prognosis, whereas the CS3 subtype displayed an immunedeprived tumor microenvironment and an unfavourable prognosis. Through WGCNA analysis, POSTN was identified as a key biomarker for CAFs associated with TNBC. Then, POSTN+CAFs was identified and characterized. Both POSTN and POSTN+CAFs showed significant positive correlations with stromal molecules HGF and MET at both the transcriptional and protein levels. Specifically co-localized with CAFs in the tumor stromal area, POSTN, produced by POSTN+CAFs, could modulate the HGF-MET axis, serving as a bypass activation pathway to regulate tumor cell proliferation in response to EGFR inhibitor and MET inhibitor. This study underscores the significance of POSTN and POSTN+CAFs as crucial targets for the diagnosis and treatment of TNBC.
C1 [Lin, Shuangyan; Ding, Shiping] Zhejiang Univ, Childrens Hosp, Natl Clin Res Ctr Child Hlth, Dept Cell Biol,Sch Med, 57 Zhugan Lane, Hangzhou 310000, Zhejiang, Peoples R China.
   [Lin, Shuangyan; Ding, Shiping] Zhejiang Univ, Childrens Hosp, Natl Clin Res Ctr Child Hlth, Dept Cardiovasc Surg,Sch Med, 57 Zhugan Lane, Hangzhou 310000, Zhejiang, Peoples R China.
   [Ding, Shiping] Zhejiang Univ, Sch Med, Dept Cell Biol, 866 Yuhangtang Rd, Hangzhou 310058, Zhejiang, Peoples R China.
   [Lin, Shuangyan] Zhejiang Univ, Zhejiang Hosp, Dept Pathol, Sch Med, 12 Lingyin Rd, Hangzhou 310013, Zhejiang, Peoples R China.
   [Zhou, Miaoni] Zhejiang Univ, Hangzhou Peoples Hosp 3, Affiliated Hangzhou Dermatol Hosp, Dept Dermatol,Sch Med, 38 Xihu Rd, Hangzhou 310009, Zhejiang, Peoples R China.
   [Cheng, Liying] Jiaxing Univ, Med Coll, 899 Shiguang Rd, Jiaxing 314001, Zhejiang, Peoples R China.
   [Shuai, Zhifeng; Zhao, Mingyuan; Jie, Ruixia; Peng, Fang] Zhejiang Hosp, Dept Pathol, 12 Lingyin Rd, Hangzhou 310013, Zhejiang, Peoples R China.
   [Wan, Qun] Zhejiang Univ, Affiliated Hosp 1, Dept Urinary Surg, Sch Med, 79 Qingchun Rd, Hangzhou 310003, Zhejiang, Peoples R China.
C3 Zhejiang University; Zhejiang University; Zhejiang University; Zhejiang
   University; Zhejiang University; Jiaxing University; Zhejiang University
RP Ding, SP (corresponding author), Zhejiang Univ, Childrens Hosp, Natl Clin Res Ctr Child Hlth, Dept Cell Biol,Sch Med, 57 Zhugan Lane, Hangzhou 310000, Zhejiang, Peoples R China.; Ding, SP (corresponding author), Zhejiang Univ, Childrens Hosp, Natl Clin Res Ctr Child Hlth, Dept Cardiovasc Surg,Sch Med, 57 Zhugan Lane, Hangzhou 310000, Zhejiang, Peoples R China.; Peng, F (corresponding author), Zhejiang Hosp, Dept Pathol, 12 Lingyin Rd, Hangzhou 310013, Zhejiang, Peoples R China.
EM pengfang999@139.com; dingshiping@zju.edu.cn
OI ding, shiping/0000-0002-9424-0464
FU National Natural Science Foundation of China [81072339]; Key Disciplines
   of Zhejiang Hospital [Z210071]; Zhejiang Provincial Health Bureau
   Foundation [2019KY257]; Zhejiang Basic Public Welfare Research
   Foundation [LGF19260013, 2020KYB007]
FX This work was supported by National Natural Science Foundation of China
   (81072339) , the Key Disciplines of Zhejiang Hospital (Z210071) ,
   Zhejiang Provincial Health Bureau Foundation (2019KY257) , Zhejiang
   Basic Public Welfare Research Foundation (LGF19260013) and
   Hospi-tal-level Projects of Zhejiang Hospital from Jie Ruixia
   (2020KYB007) .
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NR 33
TC 1
Z9 1
U1 4
U2 6
PU ELSEVIER
PI AMSTERDAM
PA RADARWEG 29, 1043 NX AMSTERDAM, NETHERLANDS
SN 0141-8130
EI 1879-0003
J9 INT J BIOL MACROMOL
JI Int. J. Biol. Macromol.
PD MAY
PY 2024
VL 268
AR 131560
DI 10.1016/j.ijbiomac.2024.131560
EA APR 2024
PN 1
PG 12
WC Biochemistry & Molecular Biology; Chemistry, Applied; Polymer Science
WE Science Citation Index Expanded (SCI-EXPANDED)
SC Biochemistry & Molecular Biology; Chemistry; Polymer Science
GA C0B8E
UT WOS:001286108200001
PM 38631570
OA hybrid
DA 2025-03-13
ER

PT J
AU Halperin, C
   Hey, J
   Weichenhan, D
   Stein, Y
   Mayer, S
   Lutsik, P
   Plass, C
   Scherz-Shouval, R
AF Halperin, Coral
   Hey, Joschka
   Weichenhan, Dieter
   Stein, Yaniv
   Mayer, Shimrit
   Lutsik, Pavlo
   Plass, Christoph
   Scherz-Shouval, Ruth
TI Global DNA Methylation Analysis of Cancer-Associated Fibroblasts Reveals
   Extensive Epigenetic Rewiring Linked with RUNX1 Upregulation in Breast
   Cancer Stroma
SO CANCER RESEARCH
LA English
DT Article
ID SEQ DATA; RNA-SEQ; HETEROGENEITY; RECRUITMENT; EXPRESSION; MUTATIONS;
   BINDING; CELLS
AB Cancer cells recruit and rewire normal fibroblasts in their microenvironment to become protumorigenic cancer-associated fibroblasts (CAF). These CAFs are genomically stable, yet their transcriptional programs are distinct from those of their normal counterparts. Transcriptional regulation plays a major role in this reprogramming, but the extent to which epigenetic modifications of DNA also contribute to the rewiring of CAF transcription is not clear. Here we address this question by dissecting the epigenetic landscape of breast CAFs. Applying tagmentation-based whole-genome bisulfite sequencing in a mouse model of breast cancer, we found that fibroblasts undergo massive DNA methylation changes as they transition into CAFs. Transcrip-tional and epigenetic analyses revealed RUNX1 as a potential mediator of this process and identified a RUNX1-dependent stromal gene signature. Coculture and mouse models showed that both RUNX1 and its stromal signature are induced as normal fibroblasts transition into CAFs. In breast cancer patients, RUNX1 was upregulated in CAFs, and expression of the RUNX1 signature was associated with poor disease outcome, highlighting the relevance of these findings to human disease. This work presents a comprehensive genome-wide map of DNA methylation in CAFs and reveals a previously unknown facet of the dynamic plasticity of the stroma.Significance: The first genome-wide map of DNA methylation in breast cancer-associated fibroblasts unravels a previously unknown facet of the dynamic plasticity of the stroma, with far-reaching therapeutic implications.
C1 [Halperin, Coral; Stein, Yaniv; Mayer, Shimrit; Scherz-Shouval, Ruth] Weizmann Inst Sci, Dept Biomol Sci, Rehovot, Israel.
   [Hey, Joschka; Weichenhan, Dieter; Lutsik, Pavlo; Plass, Christoph] German Canc Res Ctr, Div Canc Epigenom, Heidelberg, Germany.
   [Hey, Joschka] Ruprecht Karl Univ Heidelberg, Fac Biosci, Heidelberg, Germany.
   [Plass, Christoph] German Canc Res Ctr, Div Canc Epigen, Neuenheimer Feld 280, D-69120 Heidelberg, Germany.
   [Scherz-Shouval, Ruth] Weizmann Inst Sci, Dept Biomol Sci, Benoziyo Bldg 275, IL-76100 Rehovot, Israel.
C3 Weizmann Institute of Science; Helmholtz Association; German Cancer
   Research Center (DKFZ); Ruprecht Karls University Heidelberg; Helmholtz
   Association; German Cancer Research Center (DKFZ); Weizmann Institute of
   Science
RP Plass, C (corresponding author), German Canc Res Ctr, Div Canc Epigen, Neuenheimer Feld 280, D-69120 Heidelberg, Germany.; Scherz-Shouval, R (corresponding author), Weizmann Inst Sci, Dept Biomol Sci, Benoziyo Bldg 275, IL-76100 Rehovot, Israel.
EM c.plass@dkfz-heidelberg.de; ruth.shouval@weizmann.ac.il
RI Lutsik, Pavlo/T-8337-2019
OI Halperin, Coral/0000-0001-9987-3888; Mayer, Shimrit/0000-0003-4634-3562
FU German -Israeli Helmholtz International Research School; Helmholtz
   Associations Initiative and Networking Fund; Initiative and Networking
   Fund; Cooperation Program in Cancer Research of the Deutsches
   Krebsforschungszentrum (DKFZ); Ministry of Science, Technology and Space
   (MOST); European Research Council (ERC); Kaethe Ascher Career
   Development Chair in Life Sciences; Israels Ministry of Science,
   Technology and Space (MOST) [713388];  [754320]
FX The authors thank Prof. Groner and Dr. Levanon (Department of Molecular
   Genetics, WIS) for providing the RUNX1 antibody. They thank Z. Granot
   (HUJI) for providing 4T1 cells. The authors thank members of the
   Scherz-Shouval laboratory for valuable input on the manuscript. They
   thank the DKFZ Genomics and Proteomics Core Facility for assisting in
   sequencing. C. Halperin and J. Hey were supported by the German -Israeli
   Helmholtz International Research School: Cancer-TRAX (HIRS-0003) , a
   grant from the Helmholtz Associations Initiative and Networking Fund.
   This work was supported in part by the Cooperation Program in Cancer
   Research of the Deutsches Krebsforschungszentrum (DKFZ) and Israels
   Ministry of Science, Technology and Space (MOST; Project number: 713388)
   . R. Scherz-Shouval is supported by the European Research Council (ERC
   grant agreement 754320) and is the incumbent of the Ernst and Kaethe
   Ascher Career Development Chair in Life Sciences.
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NR 65
TC 14
Z9 14
U1 2
U2 16
PU AMER ASSOC CANCER RESEARCH
PI PHILADELPHIA
PA 615 CHESTNUT ST, 17TH FLOOR, PHILADELPHIA, PA 19106-4404 USA
SN 0008-5472
EI 1538-7445
J9 CANCER RES
JI Cancer Res.
PD NOV 15
PY 2022
VL 82
IS 22
BP 4139
EP 4152
DI 10.1158/0008-5472.CAN-22-0209
PG 14
WC Oncology
WE Science Citation Index Expanded (SCI-EXPANDED)
SC Oncology
GA 6I5ZP
UT WOS:000886206500001
PM 36287637
OA Green Submitted, Green Accepted, Bronze
DA 2025-03-13
ER

PT J
AU Pupo, M
   Pisano, A
   Abonante, S
   Maggiolini, M
   Musti, AM
AF Pupo, Marco
   Pisano, Assunta
   Abonante, Sergio
   Maggiolini, Marcello
   Musti, Anna Maria
TI GPER activates Notch signaling in breast cancer cells and
   cancer-associated fibroblasts (CAFs)
SO INTERNATIONAL JOURNAL OF BIOCHEMISTRY & CELL BIOLOGY
LA English
DT Article
DE GPER; Estrogens signaling; Notch signaling; Breast cancer;
   Cancer-associated fibroblasts
ID ESTROGEN-RECEPTOR-ALPHA; GENE-EXPRESSION CHANGES; EPITHELIAL-MESENCHYMAL
   TRANSITION; G-PROTEIN; CROSS-TALK; UP-REGULATION; E-CADHERIN; GPR30;
   17-BETA-ESTRADIOL; ANTAGONIST
AB The G protein-coupled receptor GPR30/GPER has been shown to mediate rapid effects of 17 beta-estradiol (E2) in diverse types of cancer cells. Here, we provide evidence for a novel crosstalk between GPER and the Notch signaling pathway in breast cancer cells and cancer-associated fibroblasts (CAFs). We show that E2 and the GPER selective ligand G-1 induce both the gamma-secretase-dependent activation of Notch-1 and the expression of the Notch target gene Hes-1. These inductions are prevented by knocking down GPER or by using a dominant-negative mutant of the Notch transcriptional co-activator Master-mind like-1 (DN-MAML-1), hence suggesting the involvement of GPER in the Notch-dependent transcription. By performing chromatin-immunoprecipitation experiments and luciferase assays, we also demonstrate that E2 and G-1 induce the recruitment of the intracellular domain of Notch-1 (N1ICD) to the Hes-1 promoter and the transactivation of a Hes-1-reporter gene, respectively. Functionally, the E2 and G-1-induced migration of breast cancer cells and CAFs is abolished in presence of the gamma-secretase inhibitor GSI or DN-MAML-1, which both inhibit the Notch signaling pathway. In addition, we demonstrate that E2 and G-1 prevent the expression of VE-Cadherin, while both compounds induce the expression of Snail, a Notch target gene acting as a repressor of cadherins expression. Notably, both GSI and DN-MAML-1 abolish the up-regulation of Snail-1 by E2 and G-1, whereas the use of GSI rescues VE-Cadherin expression. Taken together, our results prove the involvement of the Notch signaling pathway in mediating the effects of estrogenic GPER signaling in breast cancer cells and CAFs. (C) 2013 Elsevier Ltd. All rights reserved.
C1 [Pupo, Marco; Pisano, Assunta; Maggiolini, Marcello; Musti, Anna Maria] Univ Calabria, Dept Pharm Hlth & Nutr Sci, I-87036 Arcavacata Di Rende, Italy.
   [Abonante, Sergio] Reg Hosp, Cosenza, Italy.
   [Musti, Anna Maria] Univ Wurzburg, Inst Clin Neurobiol, D-97070 Wurzburg, Germany.
C3 University of Calabria; University of Wurzburg
RP Maggiolini, M (corresponding author), Univ Calabria, Dept Pharm Hlth & Nutr Sci, I-87036 Arcavacata Di Rende, Italy.
EM marcellomaggiolini@yahoo.it; E_Musti_A@klinik.uni-wuerzburg.de
RI Musti, Anna/M-2520-2019; Maggiolini, Marcello/Z-4729-2019
OI Abonante, Sergio/0000-0003-4686-6961; MUSTI, Anna
   Maria/0000-0003-1443-2739; Maggiolini, Marcello/0000-0002-7485-854X
FU Associazione Italiana per la Ricerca sul Cancro (AIRC) [12849/2012];
   AIRC project Calabria; Fondazione Cassa di Risparmio di Calabria e
   Lucania
FX This work was supported by Associazione Italiana per la Ricerca sul
   Cancro (AIRC, project n.12849/2012), AIRC project Calabria 2011 and
   Fondazione Cassa di Risparmio di Calabria e Lucania.
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NR 53
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Z9 56
U1 0
U2 23
PU PERGAMON-ELSEVIER SCIENCE LTD
PI OXFORD
PA THE BOULEVARD, LANGFORD LANE, KIDLINGTON, OXFORD OX5 1GB, ENGLAND
SN 1357-2725
EI 1878-5875
J9 INT J BIOCHEM CELL B
JI Int. J. Biochem. Cell Biol.
PD JAN
PY 2014
VL 46
BP 56
EP 67
DI 10.1016/j.biocel.2013.11.011
PG 12
WC Biochemistry & Molecular Biology; Cell Biology
WE Science Citation Index Expanded (SCI-EXPANDED)
SC Biochemistry & Molecular Biology; Cell Biology
GA 301QI
UT WOS:000330546600007
PM 24275097
DA 2025-03-13
ER

PT J
AU Sanchez-Alvarez, R
   Martinez-Outschoorn, UE
   Lin, Z
   Lamb, R
   Hulit, J
   Howell, A
   Sotgia, F
   Rubin, E
   Lisanti, MP
AF Sanchez-Alvarez, Rosa
   Martinez-Outschoorn, Ubaldo E.
   Lin, Zhao
   Lamb, Rebecca
   Hulit, James
   Howell, Anthony
   Sotgia, Federica
   Rubin, Emanuel
   Lisanti, Michael P.
TI Ethanol exposure induces the cancer-associated fibroblast phenotype and
   lethal tumor metabolism Implications for breast cancer prevention
SO CELL CYCLE
LA English
DT Article
DE ethanol; alcohol consumption; reactive oxygen species (ROS);
   myofibroblast; oxidative stress; ketone bodies; oxidative
   phosphorylation (OXPHOS); mitochondrial biogenesis; cancer metabolism;
   breast cancer prevention; caveolin-1; MCT4
ID STROMAL CAVEOLIN-1 EXPRESSION; ALCOHOL-CONSUMPTION; OXIDATIVE STRESS;
   STEM-CELLS; MITOCHONDRIAL BIOGENESIS; KETONE PRODUCTION; GENETIC
   ABLATION; LIVER FIBROSIS; UP-REGULATION; GROWTH
AB Little is known about how alcohol consumption promotes the onset of human breast cancer(s). One hypothesis is that ethanol induces metabolic changes in the tumor microenvironment, which then enhances epithelial tumor growth. To experimentally test this hypothesis, we used a co-culture system consisting of human breast cancer cells (MCF7) and hTERT-immortalized fibroblasts. Here, we show that ethanol treatment (100 mM) promotes ROS production and oxidative stress in cancer-associated fibroblasts, which is sufficient to induce myofibroblastic differentiation. Oxidative stress in stromal fibroblasts also results in the onset of autophagy/mitophagy, driving the induction of ketone body production in the tumor microenvironment. Interestingly, ethanol has just the opposite effect in epithelial cancer cells, where it confers autophagy resistance, elevates mitochondrial biogenesis and induces key enzymes associated with ketone re-utilization (ACAT1/OXCT1). During co-culture, ethanol treatment also converts MCF7 cells from an ER(+) to an ER(-) status, which is thought to be associated with "stemness," more aggressive behavior and a worse prognosis. Thus, ethanol treatment induces ketone production in cancer-associated fibroblasts and ketone re-utilization in epithelial cancer cells, fueling tumor cell growth via oxidative mitochondrial metabolism (OXPHOS). This "two-compartment" metabolic model is consistent with previous historical observations that ethanol is first converted to acetaldehyde (which induces oxidative stress) and then ultimately to acetyl-CoA (a high-energy mitochondrial fuel), or can be used to synthesize ketone bodies. As such, our results provide a novel mechanism by which alcohol consumption could metabolically convert "low-risk" breast cancer patients to "high-risk" status, explaining tumor recurrence or disease progression. Hence, our findings have clear implications for both breast cancer prevention and therapy. Remarkably, our results also show that antioxidants [such as N-acetyl cysteine (NAC)] can effectively reverse or prevent ethanol-induced oxidative stress in cancer-associated fibroblasts, suggesting a novel strategy for cancer prevention. We also show that caveolin-1 and MCT4 protein expression can be effectively used as new biomarkers to monitor oxidative stress induced by ethanol.
C1 [Sanchez-Alvarez, Rosa; Martinez-Outschoorn, Ubaldo E.; Lin, Zhao; Sotgia, Federica; Lisanti, Michael P.] Thomas Jefferson Univ, Kimmel Canc Ctr, Philadelphia, PA 19107 USA.
   [Lamb, Rebecca; Hulit, James; Howell, Anthony; Sotgia, Federica; Lisanti, Michael P.] Univ Manchester, Inst Canc Sci, Breakthrough Breast Canc Res Unit, Manchester, Lancs, England.
   [Rubin, Emanuel] Thomas Jefferson Univ, Dept Pathol, Philadelphia, PA 19107 USA.
C3 Thomas Jefferson University; University of Manchester; Thomas Jefferson
   University
RP Lisanti, MP (corresponding author), Thomas Jefferson Univ, Kimmel Canc Ctr, Philadelphia, PA 19107 USA.
EM emanuel.rubin@jefferson.edu; michaelp.lisanti@gmail.com
RI Lisanti, Michael/C-6866-2013; Martinet, Wim/I-7375-2015
OI Martinez-Outschoorn, Ubaldo/0000-0003-1483-4551; Lisanti,
   Michael/0000-0003-2034-1382; Sotgia, Federica/0000-0003-2826-4529;
   Howell, Anthony/0000-0002-6233-719X
FU Young Investigator Award from the Breast Cancer Alliance; Margaret Q.
   Landenberger Research Foundation; National Institute on Alcohol Abuse
   and Alcoholism (NIAAA) [T32 AA007467]; Centre grant in Manchester from
   Breakthrough Breast Cancer in the UK; European Research Council
FX F.S. was the recipient of a Young Investigator Award from the Breast
   Cancer Alliance. U.E.M. was supported by a Young Investigator Award from
   the Margaret Q. Landenberger Research Foundation. Funds were also
   contributed by the Margaret Q. Landenberger Research Foundation (to
   M.P.L.). R.S.A. was supported by National Institute on Alcohol Abuse and
   Alcoholism (NIAAA) training grant T32 AA007467. This work was also
   supported, in part, by a Centre grant in Manchester from Breakthrough
   Breast Cancer in the UK and an Advanced ERC Grant from the European
   Research Council.
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NR 64
TC 44
Z9 45
U1 2
U2 26
PU TAYLOR & FRANCIS INC
PI PHILADELPHIA
PA 530 WALNUT STREET, STE 850, PHILADELPHIA, PA 19106 USA
SN 1538-4101
EI 1551-4005
J9 CELL CYCLE
JI Cell Cycle
PD JAN 15
PY 2013
VL 12
IS 2
BP 289
EP 301
DI 10.4161/cc.23109
PG 13
WC Cell Biology
WE Science Citation Index Expanded (SCI-EXPANDED)
SC Cell Biology
GA 085FZ
UT WOS:000314601500019
PM 23257780
OA Green Published, Bronze
DA 2025-03-13
ER

PT J
AU Truffi, M
   Mazzucchelli, S
   Bonizzi, A
   Sorrentino, L
   Allevi, R
   Vanna, R
   Morasso, C
   Corsi, F
AF Truffi, Marta
   Mazzucchelli, Serena
   Bonizzi, Arianna
   Sorrentino, Luca
   Allevi, Raffaele
   Vanna, Renzo
   Morasso, Carlo
   Corsi, Fabio
TI Nano-Strategies to Target Breast Cancer-Associated Fibroblasts:
   Rearranging the Tumor Microenvironment to Achieve Antitumor Efficacy
SO INTERNATIONAL JOURNAL OF MOLECULAR SCIENCES
LA English
DT Review
DE cancer-associated fibroblasts; tumor microenvironment; nanoparticles;
   breast cancer; antitumor efficacy
ID PHASE-II TRIAL; ACTIVATION PROTEIN-ALPHA; STROMAL FIBROBLASTS;
   EXTRACELLULAR-MATRIX; T-CELLS; CHEMOTHERAPY; THERAPY; DELIVERY; GROWTH;
   HETEROGENEITY
AB Cancer-associated fibroblasts (CAF) are the most abundant cells of the tumor stroma and they critically influence cancer growth through control of the surrounding tumor microenvironment (TME). CAF-orchestrated reactive stroma, composed of pro-tumorigenic cytokines and growth factors, matrix components, neovessels, and deregulated immune cells, is associated with poor prognosis in multiple carcinomas, including breast cancer. Therefore, beyond cancer cells killing, researchers are currently focusing on TME as strategy to fight breast cancer. In recent years, nanomedicine has provided a number of smart delivery systems based on active targeting of breast CAF and immune-mediated overcome of chemoresistance. Many efforts have been made both to eradicate breast CAF and to reshape their identity and function. Nano-strategies for CAF targeting profoundly contribute to enhance chemosensitivity of breast tumors, enabling access of cytotoxic T-cells and reducing immunosuppressive signals. TME rearrangement also includes reorganization of the extracellular matrix to enhance permeability to chemotherapeutics, and nano-systems for smart coupling of chemo- and immune-therapy, by increasing immunogenicity and stimulating antitumor immunity. The present paper reviews the current state-of-the-art on nano-strategies to target breast CAF and TME. Finally, we consider and discuss future translational perspectives of proposed nano-strategies for clinical application in breast cancer.
C1 [Truffi, Marta; Mazzucchelli, Serena; Bonizzi, Arianna; Sorrentino, Luca; Allevi, Raffaele; Corsi, Fabio] Univ Milan, Dept Biomed & Clin Sci L Sacco, Via GB Grassi 74, I-20157 Milan, Italy.
   [Vanna, Renzo; Morasso, Carlo; Corsi, Fabio] Ist Clin Sci Maugeri, IRCCS, Nanomed & Mol Imaging Lab, Via Maugeri 4, I-27100 Pavia, Italy.
   [Corsi, Fabio] Ist Clin Sci Maugeri, IRCCS, Breast Unit, Surg Dept, Via Maugeri 4, I-27100 Pavia, Italy.
C3 University of Milan; Luigi Sacco Hospital; University of Pavia; Istituti
   Clinici Scientifici Maugeri IRCCS; University of Pavia; Istituti Clinici
   Scientifici Maugeri IRCCS
RP Corsi, F (corresponding author), Univ Milan, Dept Biomed & Clin Sci L Sacco, Via GB Grassi 74, I-20157 Milan, Italy.; Corsi, F (corresponding author), Ist Clin Sci Maugeri, IRCCS, Nanomed & Mol Imaging Lab, Via Maugeri 4, I-27100 Pavia, Italy.; Corsi, F (corresponding author), Ist Clin Sci Maugeri, IRCCS, Breast Unit, Surg Dept, Via Maugeri 4, I-27100 Pavia, Italy.
EM marta.truffi@unimi.it; serena.mazzucchelli@unimi.it;
   arianna.bonizzi@unimi.it; luca.sorrentino1@unimi.it;
   raffaele.allevi@unimi.it; renzo.vanna@icsmaugeri.it;
   carlo.morasso@icsmaugeri.it; fabio.corsi@unimi.it
RI Bonizzi, Arianna/AHE-5627-2022; Corsi, Fabio/ABH-9554-2020; Vanna,
   Renzo/K-4670-2016; Sorrentino, Luca/KHT-6228-2024; Truffi,
   Marta/AAB-2272-2019; Corsi, Fabio/E-9204-2017; Mazzucchelli,
   Serena/I-9982-2018; Morasso, Carlo Francesco/ABI-2185-2020
OI Sorrentino, Luca/0000-0002-3963-2385; allevi,
   raffaele/0000-0002-9904-0947; Truffi, Marta/0000-0002-1095-4188; Corsi,
   Fabio/0000-0002-6469-4086; Mazzucchelli, Serena/0000-0001-6904-8895;
   Morasso, Carlo Francesco/0000-0001-9185-0198
FU Associazione Italiana per la Ricerca sul Cancro [AIRC IG 20172]
FX This paper was funded by Associazione Italiana per la Ricerca sul Cancro
   (AIRC IG 20172 to F.C.).
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NR 103
TC 75
Z9 77
U1 7
U2 80
PU MDPI
PI BASEL
PA ST ALBAN-ANLAGE 66, CH-4052 BASEL, SWITZERLAND
SN 1422-0067
J9 INT J MOL SCI
JI Int. J. Mol. Sci.
PD MAR 13
PY 2019
VL 20
IS 6
AR 1263
DI 10.3390/ijms20061263
PG 18
WC Biochemistry & Molecular Biology; Chemistry, Multidisciplinary
WE Science Citation Index Expanded (SCI-EXPANDED)
SC Biochemistry & Molecular Biology; Chemistry
GA HT0ZA
UT WOS:000464292500013
PM 30871158
OA gold, Green Published, Green Submitted
DA 2025-03-13
ER

PT J
AU Gao, YY
   Huang, Y
   Zhao, YJ
   Hu, P
AF Gao, Yuanyuan
   Huang, Ying
   Zhao, Yanjiao
   Hu, Ping
TI Cancer-associated fibroblast-secreted exosomal miR-454-3p inhibits lipid
   metabolism and ferroptosis in breast cancer by targeting ACSL4
SO NAUNYN-SCHMIEDEBERGS ARCHIVES OF PHARMACOLOGY
LA English
DT Article; Early Access
DE Breast cancer; CAFs; Exosomes; Ferroptosis; MiR-454-3p
AB Cancer-associated fibroblasts (CAFs) participate in the development of the tumor microenvironment through the secretion of exosomes. Acyl-CoA synthetase long-chain family member 4 (ACSL4) is an essential component of ferroptosis. However, the regulatory mechanism of ACSL4 in breast cancer remains unexplored. The study aimed to determine the influence of exosomal miR-454-3p from CAFs on lipid metabolism and ferroptosis. CAF-derived exosomes (CAF-exo) were isolated from breast cancer tissue of breast cancer patients and characterized using transmission electron microscopy (TEM) and Western blot. Luciferase reporter assay and RNA immunoprecipitation (RIP) were used to demonstrate the relationship between miR-454-3p and ACSL4. Cell viability and ferroptosis-related markers were detected by CCK-8 and Western blot. Malondialdehyde (MDA), glutathione (GSH), and iron levels were detected. Reverse transcription-quantitative PCR (RT-qPCR) and fluorescence in situ hybridization (FISH) were used to assess miR-454-3p expression. miR-454-3p and ACSL4 levels were abnormally expressed in breast cancer tissues. CAF-exo significantly enhanced cell viability and GSH levels and suppressed MDA, and iron levels. CAF-exo upregulated ferroptosis suppressor protein 1 (FSP1) and glutathione peroxidase 4 (GPX4) expression, and reduced ACSL4 levels. miR-454-3p was strongly expressed in CAF-exo, and exosomal miR-454-3p suppressed lipid metabolism and ferroptosis in breast cancer cells. The effects of miR-454-3p inhibitor on lipid metabolism and ferroptosis were eliminated by ACSL4 knockdown. CAF-secreted exosomal miR-454-3p inhibited lipid metabolism and ferroptosis by targeting ACSL4 in breast cancer. This study revealed a novel molecular mechanism that offers a potential therapeutic intervention in breast cancer treatment.
C1 [Gao, Yuanyuan; Huang, Ying; Zhao, Yanjiao; Hu, Ping] Ningxia Med Univ, Dept Internal Oncol, Gen Hosp, 804 Shengli St, Yinchuan, Peoples R China.
C3 Ningxia Medical University
RP Hu, P (corresponding author), Ningxia Med Univ, Dept Internal Oncol, Gen Hosp, 804 Shengli St, Yinchuan, Peoples R China.
EM huping8782810@163.com
RI gao, yuanyuan/GSE-5627-2022
FU Ningxia Natural Science Foundation [2022AAC03511]
FX This study was supported by a study on molecular mecha-nism of PTEN
   inhibition of breast cancer by competitive binding of long-chain
   non-coding RNA ADAMTS9-AS1 to miR-5590-3p (Ningxia Natural Science
   Foundation Project, 2022AAC03511).
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NR 42
TC 1
Z9 1
U1 8
U2 8
PU SPRINGER
PI NEW YORK
PA ONE NEW YORK PLAZA, SUITE 4600, NEW YORK, NY, UNITED STATES
SN 0028-1298
EI 1432-1912
J9 N-S ARCH PHARMACOL
JI Naunyn-Schmiedebergs Arch. Pharmacol.
PD 2024 OCT 7
PY 2024
DI 10.1007/s00210-024-03488-8
EA OCT 2024
PG 13
WC Pharmacology & Pharmacy
WE Science Citation Index Expanded (SCI-EXPANDED)
SC Pharmacology & Pharmacy
GA I0Y9F
UT WOS:001327611000001
PM 39373750
DA 2025-03-13
ER

PT J
AU Marusyk, A
   Tabassum, DP
   Janiszewska, M
   Place, AE
   Trinh, A
   Rozhok, AI
   Pyne, S
   Guerriero, JL
   Shu, S
   Ekram, M
   Ishkin, A
   Cahill, DP
   Nikolsky, Y
   Chan, TA
   Rimawi, MF
   Hilsenbeck, S
   Schiff, R
   Osborne, KC
   Letai, A
   Polyak, K
AF Marusyk, Andriy
   Tabassum, Doris P.
   Janiszewska, Michalina
   Place, Andrew E.
   Trinh, Anne
   Rozhok, Andrii I.
   Pyne, Saumyadipta
   Guerriero, Jennifer L.
   Shu, Shaokun
   Ekram, Muhammad
   Ishkin, Alexander
   Cahill, Daniel P.
   Nikolsky, Yuri
   Chan, Timothy A.
   Rimawi, Mothaffar F.
   Hilsenbeck, Susan
   Schiff, Rachel
   Osborne, Kent C.
   Letai, Antony
   Polyak, Kornelia
TI Spatial Proximity to Fibroblasts Impacts Molecular Features and
   Therapeutic Sensitivity of Breast Cancer Cells Influencing Clinical
   Outcomes
SO CANCER RESEARCH
LA English
DT Article
ID MEDIATED DRUG-RESISTANCE; TUMOR MICROENVIRONMENT; GENE-EXPRESSION;
   PANCREAS CANCER; IN-SITU; LAPATINIB; HETEROGENEITY; CHEMOTHERAPY;
   HYALURONAN; EVOLUTION
AB Using a three-dimensional coculture model, we identified significant subtype-specific changes in gene expression, metabolic, and therapeutic sensitivity profiles of breast cancer cells in contact with cancer-associated fibroblasts (CAF). CAF-induced gene expression signatures predicted clinical outcome and immune-related differences in the microenvironment. We found that fibroblasts strongly protect carcinoma cells from lapatinib, attributable to its reduced accumulation in carcinoma cells and an elevated apoptotic threshold. Fibroblasts from normal breast tissues and stromal cultures of brain metastases of breast cancer had similar effects as CAFs. Using synthetic lethality approaches, we identified molecular pathways whose inhibition sensitizes HER2(+) breast cancer cells to lapatinib both in vitro and in vivo, including JAK2/STAT3 and hyaluronic acid. Neoadjuvant lapatinib therapy in HER2(+) breast tumors lead to a significant increase of phospho-STAT3(+) cancer cells and a decrease in the spatial proximity of proliferating (Ki67(+)) cells to CAFs impacting therapeutic responses. Our studies identify CAF-induced physiologically and clinically relevant changes in cancer cells and offer novel approaches for overcoming microenvironment-mediated therapeutic resistance. (C) 2016 AACR.
C1 [Marusyk, Andriy; Tabassum, Doris P.; Janiszewska, Michalina; Trinh, Anne; Pyne, Saumyadipta; Guerriero, Jennifer L.; Shu, Shaokun; Ekram, Muhammad; Letai, Antony; Polyak, Kornelia] Dana Farber Canc Inst, Dept Med Oncol, Boston, MA 02115 USA.
   [Marusyk, Andriy; Janiszewska, Michalina; Trinh, Anne; Guerriero, Jennifer L.; Shu, Shaokun; Ekram, Muhammad; Letai, Antony; Polyak, Kornelia] Brigham & Womens Hosp, Dept Med, 75 Francis St, Boston, MA 02115 USA.
   [Marusyk, Andriy; Janiszewska, Michalina; Trinh, Anne; Guerriero, Jennifer L.; Shu, Shaokun; Ekram, Muhammad; Letai, Antony; Polyak, Kornelia] Harvard Med Sch, Dept Med, Boston, MA USA.
   [Tabassum, Doris P.; Polyak, Kornelia] Harvard Med Sch, BBS Program, Boston, MA USA.
   [Place, Andrew E.] Dana Farber Canc Inst, Dept Pediat Oncol, Boston, MA 02115 USA.
   [Place, Andrew E.] Childrens Hosp, 300 Longwood Ave, Boston, MA 02115 USA.
   [Rozhok, Andrii I.] Univ Colorado, Dept Biochem & Mol Genet, Aurora, CO USA.
   [Ishkin, Alexander; Nikolsky, Yuri] Thomson Reuters Healthcare & Sci, Encinitas, CA USA.
   [Cahill, Daniel P.] Massachusetts Gen Hosp, Boston, MA 02114 USA.
   [Cahill, Daniel P.] Harvard Med Sch, Dept Neurosurg, Boston, MA USA.
   [Chan, Timothy A.] Mem Sloan Kettering Canc Ctr, Dept Radiat Oncol, 1275 York Ave, New York, NY 10021 USA.
   [Rimawi, Mothaffar F.; Hilsenbeck, Susan; Schiff, Rachel; Osborne, Kent C.] Baylor Coll Med, Lester & Sue Smith Breast Ctr, Houston, TX 77030 USA.
   [Rimawi, Mothaffar F.; Hilsenbeck, Susan; Schiff, Rachel; Osborne, Kent C.] Baylor Coll Med, Dan L Duncan Comprehens Canc Ctr, Dept Mol & Cellular Biol, Houston, TX 77030 USA.
   [Polyak, Kornelia] Broad Inst, Cambridge, MA USA.
C3 Harvard University; Harvard University Medical Affiliates; Dana-Farber
   Cancer Institute; Harvard University; Harvard University Medical
   Affiliates; Brigham & Women's Hospital; Harvard University; Harvard
   Medical School; Harvard University; Harvard Medical School; Harvard
   University; Harvard University Medical Affiliates; Dana-Farber Cancer
   Institute; Harvard University; Harvard University Medical Affiliates;
   Boston Children's Hospital; University of Colorado System; University of
   Colorado Anschutz Medical Campus; Clarivate; Harvard University; Harvard
   University Medical Affiliates; Massachusetts General Hospital; Harvard
   University; Harvard Medical School; Memorial Sloan Kettering Cancer
   Center; Baylor College of Medicine; Baylor College of Medicine; Harvard
   University; Massachusetts Institute of Technology (MIT); Broad Institute
RP Polyak, K (corresponding author), Harvard Med Sch, Dana Farber Canc Inst, 450 Brookline Ave, Boston, MA 02215 USA.; Marusyk, A (corresponding author), H Lee Moffitt Canc Ctr & Res Inst, 12901 Magnolia Dr, Tampa, FL 33612 USA.
EM andriy.marusyk@moffitt.org; Kornelia_polyak@dfci.harvard.edu
RI Polyak, Kornelia/ACJ-5837-2022; Rimawi, Mothaffar/AAI-3520-2020; Chan,
   Timothy/ABD-5850-2021
OI Trinh, Anne/0000-0001-7261-6734; Cahill, Daniel/0000-0003-2552-6546
FU DBT-Ramalingaswami Fellowship; CDRMP [W81XWH-09-1-0561]; Shula fund; NIH
   [CA116235]; Breast Cancer Alliance; Breast Cancer Research Foundation
FX This work was supported by the DBT-Ramalingaswami Fellowship (S. Pyne),
   CDRMP W81XWH-09-1-0561 and Shula fund (A. Marusyk), NIH CA116235, Breast
   Cancer Alliance, and Breast Cancer Research Foundation (K. Polyak).
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NR 40
TC 95
Z9 105
U1 1
U2 21
PU AMER ASSOC CANCER RESEARCH
PI PHILADELPHIA
PA 615 CHESTNUT ST, 17TH FLOOR, PHILADELPHIA, PA 19106-4404 USA
SN 0008-5472
EI 1538-7445
J9 CANCER RES
JI Cancer Res.
PD NOV 15
PY 2016
VL 76
IS 22
BP 6495
EP 6506
DI 10.1158/0008-5472.CAN-16-1457
PG 12
WC Oncology
WE Science Citation Index Expanded (SCI-EXPANDED)
SC Oncology
GA ED3IF
UT WOS:000388742100009
PM 27671678
OA Green Submitted, Green Accepted
DA 2025-03-13
ER

PT J
AU Roswall, P
   Pietras, K
AF Roswall, Pernilla
   Pietras, Kristian
TI Of mice and men: a comparative study of cancer-associated fibroblasts in
   mammary carcinoma
SO UPSALA JOURNAL OF MEDICAL SCIENCES
LA English
DT Article
DE Biomarkers; breast neoplasms; fibroblast
ID BREAST-CANCER; CHEMOTHERAPY; EXPRESSION; GROWTH
AB Introduction. The initial clinical experience from targeted therapy for breast cancer has been mixed. While important progress has been made in the care of a subset of patients characterized by amplification of HER2 through the use of trastuzumab, other targeted therapies have failed to improve the outcome for large, unselected groups of patients. Thus, efforts to find prognostic or predictive biomarkers to enable tailored therapy are highly warranted. Genetically engineered mouse models of human cancer provide a convenient setting in which to perform explorative studies. However, there is a paucity of comparative studies between mouse and human tumours in order to validate the use of mouse models as discovery tools.
   Materials and methods. Here, we have compared the localization of markers for cancer-associated fibroblasts in the MMTV-PyMT mouse model of mammary carcinoma with that of human breast cancer. The expression of alpha-smooth muscle actin, platelet-derived growth factor receptor-alpha, and fibroblast-specific protein-1 was assessed by immunostaining of sections from tumours of MMTV-PyMT mice. Information about the distribution of the same markers in human breast cancer was derived from the publicly available database the Human Protein Atlas.
   Results. Both mouse and human mammary carcinomas were infused by a rich fibrotic stroma. While no marker was capable of identifying all stromal fibroblasts, the expression pattern of each marker was remarkably similar in mouse and human.
   Discussion. We conclude that the MMTV-PyMT mouse model of breast cancer will have utility as a discovery tool for biomarkers of cancer-associated fibroblasts during malignant conversion.
C1 [Roswall, Pernilla; Pietras, Kristian] Karolinska Inst, Dept Med Biochem & Biophys, Div Vasc Biol, SE-17177 Stockholm, Sweden.
C3 Karolinska Institutet
RP Pietras, K (corresponding author), Karolinska Inst, Dept Med Biochem & Biophys, Div Vasc Biol, Scheeles Vag 2,House A4,Level 4, SE-17177 Stockholm, Sweden.
EM Kristian.Pietras@ki.se
RI Pietras, Kristian/ABE-8727-2020
OI Pietras, Kristian/0000-0001-6738-4705
FU Swedish Cancer Society; Swedish Research Council [K2011-67X-21865-01-6];
   Swedish Childhood Cancer Society; KI Cancer network; Jeansson's
   foundation; Magnus Bergvall's foundation; Ake Wiberg's foundation;
   Karolinska Institutet; Stockholm County
FX K.P. is the recipient of a Young Investigator Award from the Swedish
   Cancer Society. This work was supported by grants to K.P. from the
   Swedish Cancer Society, the Swedish Research Council (project#
   K2011-67X-21865-01-6), the Swedish Childhood Cancer Society, the KI
   Cancer network, Jeansson's foundation, Magnus Bergvall's foundation, and
   Ake Wiberg's foundation. In addition, support was provided by a Linnaeus
   grant to the STARGET consortium from the Swedish Research Council, and
   by strategic funds to the BRECT network from Karolinska Institutet and
   Stockholm County.
CR Anderberg C, 2009, CELL CYCLE, V8, P1461, DOI 10.4161/cc.8.10.8557
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NR 19
TC 7
Z9 7
U1 0
U2 2
PU TAYLOR & FRANCIS LTD
PI ABINGDON
PA 2-4 PARK SQUARE, MILTON PARK, ABINGDON OR14 4RN, OXON, ENGLAND
SN 0300-9734
EI 2000-1967
J9 UPSALA J MED SCI
JI Ups. J. Med. Sci.
PD MAY
PY 2012
VL 117
IS 2
BP 196
EP 201
DI 10.3109/03009734.2012.658973
PG 6
WC Medicine, General & Internal
WE Science Citation Index Expanded (SCI-EXPANDED)
SC General & Internal Medicine
GA 927ZM
UT WOS:000302949200013
PM 22432595
OA gold, Green Published
DA 2025-03-13
ER

PT J
AU Fernández-Nogueira, P
   Mancino, M
   Fuster, G
   López-Plana, A
   Jauregui, P
   Almendro, V
   Enreig, E
   Menéndez, S
   Rojo, F
   Noguera-Castells, A
   Bill, A
   Gaither, LA
   Serrano, L
   Recalde-Percaz, L
   Moragas, N
   Alonso, R
   Ametller, E
   Rovira, A
   Lluch, A
   Albanell, J
   Gascon, P
   Bragado, P
AF Fernandez-Nogueira, Patricia
   Mancino, Mario
   Fuster, Gemma
   Lopez-Plana, Anna
   Jauregui, Patricia
   Almendro, Vanesa
   Enreig, Estel
   Menendez, Silvia
   Rojo, Federico
   Noguera-Castells, Aleix
   Bill, Anke
   Gaither, L. Alex
   Serrano, Laia
   Recalde-Percaz, Leire
   Moragas, Nuria
   Alonso, Raul
   Ametller, Elisabet
   Rovira, Ana
   Lluch, Ana
   Albanell, Joan
   Gascon, Pere
   Bragado, Paloma
TI Tumor-Associated Fibroblasts Promote HER2-Targeted Therapy Resistance
   through FGFR2 Activation
SO CLINICAL CANCER RESEARCH
LA English
DT Article
ID CANCER-ASSOCIATED FIBROBLASTS; GENE-EXPRESSION PATTERNS; TRASTUZUMAB
   RESISTANCE; ACQUIRED-RESISTANCE; STROMAL FIBROBLASTS; BREAST; HER2; SRC;
   KINASE; CELLS
AB Purpose: Despite the therapeutic success of existing HER2-targeted therapies, tumors invariably relapse. This study aimed at identifying new mechanisms responsible for HER2-targeted therapy resistance.
   Experimental Design: We have used a platform of HER2-targeted therapy-resistant cell lines and primary cultures of healthy and tumor-associated fibroblasts (TAF) to identify new potential targets related to tumor escape from anti-HER2 therapies.
   Results: We have shown that TAFs promote resistance to HER2-targeted therapies. TAFs produce and secrete high levels of FGF5, which induces FGFR2 activation in the surrounding breast cancer cells. FGFR2 transactivates HER2 via c-Src, leading to resistance to HER2-targeted therapies. In vivo, coinoculating nonresistant cell lines with TAFs results in more aggressive and resistant tumors. Resistant cells activate fibroblasts and secrete FGFR ligands, creating a positive feedback loop that fuels resistance. FGFR2 inhibition not only inhibits HER2 activation, but also induces apoptosis in cells resistant to HER2-targeted therapies. In vivo, inhibitors of FGFR2 reverse resistance and resensitize resistant cells to HER2-targeted therapies. In HER2 patients' samples, alpha-SMA, FGF5, and FGFR2 contribute to poor outcome and correlate with c-Src activation. Importantly, expression of FGF5 and phospho-HER2 correlated with a reduced pathologic complete response rate in patients with HER2-positive breast cancer treated with neoadjuvant trastuzumab, which highlights the significant role of TAFs/FGF5 in HER2 breast cancer progression and resistance.
   Conclusions: We have identified the TAF/FGF5/FGFR2/c-Src/HER2 axis as an escape pathway responsible for HER2-targeted therapy resistance in breast cancer, which can be reversed by FGFR inhibitors.
C1 [Fernandez-Nogueira, Patricia; Mancino, Mario; Fuster, Gemma; Lopez-Plana, Anna; Jauregui, Patricia; Enreig, Estel; Noguera-Castells, Aleix; Recalde-Percaz, Leire; Moragas, Nuria; Alonso, Raul; Ametller, Elisabet; Gascon, Pere; Bragado, Paloma] Inst Invest Biomed August Pi & Sunyer IDIBAPS, Mol & Translat Oncol Grp, Barcelona, Spain.
   [Fernandez-Nogueira, Patricia; Mancino, Mario; Enreig, Estel; Noguera-Castells, Aleix; Recalde-Percaz, Leire; Moragas, Nuria; Gascon, Pere] Univ Barcelona, Dept Med, Barcelona, Spain.
   [Almendro, Vanesa; Bill, Anke] Harvard Med Sch, Div Med Oncol, Dept Med, Dana Farber Canc Inst,Brigham & Womens Hosp, Boston, MA 02115 USA.
   [Menendez, Silvia; Serrano, Laia] Hosp Mar, Dept Pathol, Barcelona, Spain.
   [Rojo, Federico] CIBERONC IIS Fdn Jimenez Diaz, Dept Pathol, Madrid, Spain.
   [Gaither, L. Alex] Novartis Inst BioMed Res Inc, Cambridge, MA USA.
   [Rovira, Ana; Albanell, Joan] IMIM Hosp Mar Res Inst, Canc Res Program, Barcelona, Spain.
   [Rovira, Ana; Albanell, Joan] Hosp Mar CIBERONC, Dept Med Oncol, Barcelona, Spain.
   [Lluch, Ana] Univ Valencia, INCLIVA Biomed Res Inst, Valencia, Spain.
   [Lluch, Ana] CIBERONC Hosp Clin Univ, Oncol & Hematol Dept, Valencia, Spain.
   [Albanell, Joan] Univ Pompeu Fabra, Barcelona, Spain.
   [Gascon, Pere] Hosp Clin Barcelona, Dept Med Oncol, Barcelona, Spain.
   [Bragado, Paloma] Univ Complutense Madrid, Dept Biochem & Mol Biol, Fac Pharm, Hlth Res Inst,Hosp Clin San Carlos, Madrid, Spain.
C3 University of Barcelona; Hospital Clinic de Barcelona; IDIBAPS;
   University of Barcelona; Harvard University; Harvard University Medical
   Affiliates; Dana-Farber Cancer Institute; Harvard Medical School;
   Brigham & Women's Hospital; Hospital del Mar Research Institute;
   Hospital del Mar; Novartis; Novartis USA; Hospital del Mar Research
   Institute; University of Valencia; Pompeu Fabra University; University
   of Barcelona; Hospital Clinic de Barcelona; Hospital Clinico San Carlos;
   Complutense University of Madrid
RP Bragado, P (corresponding author), Univ Complutense Madrid, Dept Biochem & Mol Biol, Fac Pharm, Plaza Ramon y Cajal S-N, Madrid 28040, Spain.; Gascon, P (corresponding author), Inst Invest Biomed August Pi & Sunyer IDIBAPS, Carrer Rosello 149-153, Barcelona 08036, Spain.
EM gascon@clinic.cat; pbragado@ucm.es
RI fernandez, patricia/KTI-2987-2024; Menendez, Silvia/AAE-9420-2021;
   Recalde-Percaz, Leire/AAI-7737-2021; Castells, Aleix/AAH-1961-2019;
   Domingo, Paloma/A-8679-2015; Fuster, Gemma/ACH-5814-2022; Rojo,
   Federico/S-6551-2016; Rovira, Ana/ABH-5661-2020; Fuster Orellana,
   Gemma/B-5468-2019
OI Bill, Anke/0000-0003-1244-7574; Recalde-Percaz,
   Leire/0000-0002-4844-8440; Noguera Castells, Aleix/0000-0001-7436-6513;
   Fernandez Nogueira, Patricia/0000-0002-7246-490X; Rovira,
   Ana/0000-0003-1301-2599; Menendez Romero, Silvia/0000-0002-9116-8743;
   Mancino, Mario/0000-0003-1957-3119; Fuster Orellana,
   Gemma/0000-0002-4501-2422
FU Cellex Foundation; FROI Foundation; Instituto de Salud Carlos III
   (European Regional Development Fund) - Investing in your future-"
   [PI18/00382, PI15/00661, PIE15/00008, PI15/00146, PI15/00934,
   PI15/01617, PI18/00006, CIBERONCO CB16/12/00241, RD12/00360055,
   RD12/0036/0070]; Secretaria d'Universitats i Recerca del Departament
   d'Economia i Coneixement [2014_SGR_530, 2014_SGR_740, 2017_SGR_1305,
   2017 _SGR _507]; BBVA (becas Leonardo 2018) [BBM-TRA-0041]; ISCiii/FEDER
   [PT17/0015/0011]; "Xarxa de Bancs de tumors" - Pla Director d' Oncologia
   de Catalunya (XBTC); Beatriu Pinos postdoctoral fellowship "AGAUR;
   European Union [BP-B 0016000]; APIF fellowships from the University of
   Barcelona, School of Medicine; Sara Borrell Fellowship program; Juan de
   la Cierva program
FX The authors thank Darya Kulyk for her help preparing the schemes that
   are shown in the figures and for the preparation of the graphical
   abstract and the summary scheme in Fig. 6F. They also thank Inga Hansine
   Rye and Hege Elisabeth Giercksky (Institute for Cancer Research, Oslo
   University Hospital Radiumhospitalet, Oslo, Norway) for their help in
   optimizing some of the techniques used in the project. This work was
   performed at IDIBAPS (CERCA Programme/Generalitat de Catalunya). This
   work was supported by grants from Cellex Foundation, FROI Foundation,
   Instituto de Salud Carlos III through the projects PI18/00382,
   PI15/00661, PIE15/00008, PI15/00146, PI15/00934, PI15/01617, PI18/00006,
   CIBERONCO CB16/12/00241 and RTICC, RD12/00360055, and RD12/0036/0070
   (cofunded by European Regional Development Fund) - Investing in your
   future-", Secretaria d'Universitats i Recerca del Departament d'Economia
   i Coneixement (2014_SGR_530, 2014_SGR_740, 2017_SGR_1305 and 2017 _SGR
   _507) and BBVA (becas Leonardo 2018, BBM-TRA-0041). MARBiobanc is
   supported by ISCiii/FEDER (PT17/0015/0011) and the "Xarxa de Bancs de
   tumors" sponsored by Pla Director d' Oncologia de Catalunya (XBTC). P.
   Bragado has been funded by a Beatriu Pinos postdoctoral fellowship
   "AGAUR; BP-B 0016000 (cofunded by European Union). P. FernandezNogueira,
   E. Enreig, and A. Noguera-Castells have been funded by APIF fellowships
   from the University of Barcelona, School of Medicine. M. Mancino is
   supported by the Sara Borrell Fellowship program, and G. Fuster is
   supported by the Juan de la Cierva program.
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NR 48
TC 62
Z9 68
U1 1
U2 28
PU AMER ASSOC CANCER RESEARCH
PI PHILADELPHIA
PA 615 CHESTNUT ST, 17TH FLOOR, PHILADELPHIA, PA 19106-4404 USA
SN 1078-0432
EI 1557-3265
J9 CLIN CANCER RES
JI Clin. Cancer Res.
PD MAR
PY 2020
VL 26
IS 6
BP 1432
EP 1448
DI 10.1158/1078-0432.CCR-19-0353
PG 17
WC Oncology
WE Science Citation Index Expanded (SCI-EXPANDED)
SC Oncology
GA KY8PM
UT WOS:000522838400025
PM 31699826
OA Green Submitted
DA 2025-03-13
ER

PT J
AU Peraldi, P
   Ladoux, A
   Giorgetti-Peraldi, S
   Dani, C
AF Peraldi, Pascal
   Ladoux, Annie
   Giorgetti-Peraldi, Sophie
   Dani, Christian
TI The Primary Cilium of Adipose Progenitors Is Necessary for Their
   Differentiation into Cancer-Associated Fibroblasts that Promote
   Migration of Breast Cancer Cells In Vitro
SO CELLS
LA English
DT Article
DE adipose progenitor; primary cilium; cancer associated fibroblasts;
   breast cancer cells
ID SMALL-MOLECULE INHIBITORS; ADIPOCYTE DIFFERENTIATION; HETEROGENEITY;
   MYOFIBROBLASTS; SIZE
AB Cancer associated fibroblasts (CAFs) are central elements of the microenvironment that control tumor development. In breast cancer, CAFs can originate from adipose progenitors (APs). We, and others, have shown that the primary cilium, an antenna-shaped organelle, controls several aspects of APs' biology. We studied the conversion of human APs into CAFs by breast cancer cell lines (BCCs). Deletion of the cilium of APs by a pharmacological inhibitor, or by siRNA, allow us to demonstrate that the cilium is necessary for the differentiation of APs into CAFs. BCCs increase production of TGF-beta 1 by APs, which is a known inducer of CAFs. Pharmacological inhibition of TGF-beta 1 signaling in APs prevents their conversion into CAFs. Since we previously showed that deletion of the APs' cilium inhibits TGF-beta 1 signaling, we propose that BCCs induce TGF-beta 1 production in Aps, which binds to the primary cilium of Aps and leads to their differentiation into CAFs. Inhibition of APs conversion into CAFs induces a loss in some of the biological effects of CAFs since deletion of the cilium of APs decreases their effect on the migration of BCCs. This is the first observation of a function of the cilium of APs in their conversion into CAFs, and its consequences on BCCs.
C1 [Peraldi, Pascal; Ladoux, Annie; Dani, Christian] Univ Cote Azur, CNRS, INSERM, Fac Med,UMR7277,U1091,IBV, F-06107 Nice, France.
   [Giorgetti-Peraldi, Sophie] Univ Cote Azur, Team Cellular & Mol Physiopathol Obes, INSERM, C3M, Batiment Univ ARCHIMED, F-06204 Nice, France.
C3 Institut National de la Sante et de la Recherche Medicale (Inserm);
   Universite Cote d'Azur; Centre National de la Recherche Scientifique
   (CNRS); CNRS - National Institute for Biology (INSB); Institut National
   de la Sante et de la Recherche Medicale (Inserm); Universite Cote d'Azur
RP Peraldi, P (corresponding author), Univ Cote Azur, CNRS, INSERM, Fac Med,UMR7277,U1091,IBV, F-06107 Nice, France.
EM peraldi@unice.fr; Annie.LADOUX@univ-cotedazur.fr;
   Sophie.GIORGETTI-PERALDI@univ-cotedazur.fr;
   Christian.DANI@univ-cotedazur.fr
RI LADOUX, ANNIE/S-2077-2019; DANI, Christian/G-3639-2014; Peraldi,
   Pascal/O-4592-2016; LADOUX, ANNIE/O-4267-2016
OI Peraldi, Pascal/0000-0003-0205-9252; Dani,
   Christian/0000-0003-3228-0230; LADOUX, ANNIE/0000-0003-3857-2621;
   Giorgetti-Peraldi, Sophie/0000-0002-2751-2618
FU French Government INSERM; CNRS; French National Research Agency
   [ANR-18-CE18-0006-01]; Agence Nationale de la Recherche (ANR)
   [ANR-18-CE18-0006] Funding Source: Agence Nationale de la Recherche
   (ANR)
FX The French Government INSERM, CNRS, and the French National Research
   Agency (grant number ANR-18-CE18-0006-01) supported this work.
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NR 45
TC 4
Z9 4
U1 0
U2 9
PU MDPI
PI BASEL
PA ST ALBAN-ANLAGE 66, CH-4052 BASEL, SWITZERLAND
EI 2073-4409
J9 CELLS-BASEL
JI Cells
PD OCT
PY 2020
VL 9
IS 10
AR 2251
DI 10.3390/cells9102251
PG 17
WC Cell Biology
WE Science Citation Index Expanded (SCI-EXPANDED)
SC Cell Biology
GA OH5YA
UT WOS:000582660000001
PM 33049976
OA Green Published, gold
DA 2025-03-13
ER

PT J
AU Al-Tweigeri, T
   AlRaouji, NN
   Tulbah, A
   Arafah, M
   Aboussekhra, M
   Al-Mohanna, F
   Gad, AM
   Eldali, AM
   Elhassan, TA
   Aboussekhra, A
AF Al-Tweigeri, Taher
   AlRaouji, Noura N.
   Tulbah, Asma
   Arafah, Maria
   Aboussekhra, Mouad
   Al-Mohanna, Falah
   Gad, Ahmed Mostafa
   Eldali, Abdelmonneim M.
   Elhassan, Tusneem A.
   Aboussekhra, Abdelilah
TI High AUF1 level in stromal fibroblasts promotes carcinogenesis and
   chemoresistance and predicts unfavorable prognosis among locally
   advanced breast cancer patients
SO BREAST CANCER RESEARCH
LA English
DT Article
DE AUF1; Breast cancer; Cancer-associated fibroblasts; Prognosis
ID CARCINOMA
AB Background Locally advanced breast cancer (LABC), the most aggressive form of the disease, is a serious threat for women's health worldwide. The AU-rich RNA-binding factor 1 (AUF1) promotes the formation of chemo-resistant breast cancer stem cells. Thereby, we investigated the power of AUF1 expression, in both cancer cells and their stromal fibroblasts, as predictive biomarker for LABC patients' clinical outcome following neoadjuvant treatment. Methods We have used immunohistochemistry to assess the level of AUF1 on formalin-fixed paraffin-embedded tissues. Immunoblotting was utilized to show the effect of AUF1 ectopic expression in breast stromal fibroblasts on the expression of various genes both in vitro and in orthotopic tumor xenografts. Cytotoxicity was evaluated using the WST1 assay, while a label-free real-time setting using the xCELLigence RTCA technology was utilized to assess the proliferative, migratory and invasive abilities of cells. Results We have shown that high AUF1 immunostaining (>= 10%) in both cancer cells and their adjacent cancer-associated fibroblasts (CAFs) was significantly associated with higher tumor grade. Kaplan-Meier univariate analysis revealed a strong correlation between high AUF1 level in CAFs and poor patient's survival. This correlation was highly significant in patients with triple negative breast cancer, who showed poor disease-free survival (DFS) and overall survival (OS). High expression of AUF1 in CAFs was also associated with poor OS of ER+/Her2- patients. Similarly, AUF1-positive malignant cells tended to be associated with shorter DFS and OS of ER+/Her2+ patients. Interestingly, neoadjuvant therapy downregulated AUF1 to a level lower than 10% in malignant cells in a significant number of patients, which improved both DFS and OS. In addition, ectopic expression of AUF1 in breast fibroblasts activated these cells and enhanced their capacity to promote, in an IL-6-dependent manner, the epithelial-to-mesenchymal transition and stemness processes. Furthermore, these AUF1-expressing cells enhanced the chemoresistance of breast cancer cells and their growth in orthotopic tumor xenografts. Conclusions The present findings show that the CAF-activating factor AUF1 has prognostic/predictive value for breast cancer patients and could represent a great therapeutic target in order to improve the precision of cancer treatment.
C1 [Al-Tweigeri, Taher; Gad, Ahmed Mostafa; Elhassan, Tusneem A.] King Faisal Specialist Hosp & Res Ctr, Oncol Ctr, Riyadh 11211, Saudi Arabia.
   [AlRaouji, Noura N.; Aboussekhra, Mouad; Aboussekhra, Abdelilah] King Faisal Specialist Hosp & Res Ctr, Dept Mol Oncol, Canc Biol & Expt Therapeut Sect, MBC 03,POB 3354, Riyadh 11211, Saudi Arabia.
   [Tulbah, Asma] King Faisal Specialist Hosp & Res Ctr, Dept Pathol, Riyadh 11211, Saudi Arabia.
   [Arafah, Maria] King Saud Univ, Dept Pathol, POB 2925, Riyadh 11461, Saudi Arabia.
   [Al-Mohanna, Falah] King Faisal Specialist Hosp & Res Ctr, Dept Comparat Med, Riyadh 11211, Saudi Arabia.
   [Gad, Ahmed Mostafa] Ain Shams Univ, Fac Med, Clin Oncol & Nucl Med Dept, Cairo 11591, Egypt.
   [Eldali, Abdelmonneim M.] King Faisal Specialist Hosp & Res Ctr, Dept Biostat Epidemiol & Sci Comp, Riyadh 11211, Saudi Arabia.
C3 King Faisal Specialist Hospital & Research Center; King Faisal
   Specialist Hospital & Research Center; King Faisal Specialist Hospital &
   Research Center; King Saud University; King Faisal Specialist Hospital &
   Research Center; Egyptian Knowledge Bank (EKB); Ain Shams University;
   King Faisal Specialist Hospital & Research Center
RP Aboussekhra, A (corresponding author), King Faisal Specialist Hosp & Res Ctr, Dept Mol Oncol, Canc Biol & Expt Therapeut Sect, MBC 03,POB 3354, Riyadh 11211, Saudi Arabia.
EM aboussekhra@kfshrc.edu.sa
RI Alraouji, Noura/JGL-6423-2023; Aboussekhra, Abdelilah/JCD-8138-2023;
   Almohanna, Falah/IYJ-6603-2023; Gad, Ahmed/ACW-8124-2022; Arafah,
   Maria/ABH-3517-2020
OI Elhassan, Tusneem/0000-0002-1625-1168; Alraouji,
   Noura/0009-0008-4177-149X; Almohanna, Falah/0000-0002-2426-0945
FU King Faisal Specialist Hospital and Research Center, under RAC [2151051]
FX This work was supported in totality by King Faisal Specialist Hospital
   and Research Center, under RAC proposal #2151051.
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NR 26
TC 8
Z9 8
U1 0
U2 1
PU BMC
PI LONDON
PA CAMPUS, 4 CRINAN ST, LONDON N1 9XW, ENGLAND
SN 1465-5411
EI 1465-542X
J9 BREAST CANCER RES
JI Breast Cancer Res.
PD JUL 11
PY 2022
VL 24
IS 1
AR 46
DI 10.1186/s13058-022-01543-x
PG 15
WC Oncology
WE Science Citation Index Expanded (SCI-EXPANDED)
SC Oncology
GA 2X0CO
UT WOS:000824882300001
PM 35821051
OA gold, Green Published
DA 2025-03-13
ER

PT J
AU Huang, ML
   Fu, MR
   Wang, J
   Xia, CH
   Zhang, H
   Xiong, YQ
   He, JK
   Liu, JM
   Liu, BC
   Pan, SY
   Liu, FL
AF Huang, Minli
   Fu, Mengru
   Wang, Jia
   Xia, Chunhua
   Zhang, Hong
   Xiong, Yuqing
   He, Jiake
   Liu, Jianming
   Liu, Bingchen
   Pan, Siyi
   Liu, Fanglan
TI TGF-β1-activated cancer-associated fibroblasts promote breast cancer
   invasion, metastasis and epithelial-mesenchymal transition by autophagy
   or overexpression of FAP-α
SO BIOCHEMICAL PHARMACOLOGY
LA English
DT Article
DE Cancer-associated fibroblasts; TGF-beta 1; Epithelial-mesenchymal
   transition; Autophagy; FAP-alpha
ID ACTIVATION PROTEIN-ALPHA; TUMOR PROGRESSION; TGF-BETA; CELLS; CARCINOMA;
   INDUCE; GROWTH; MICROENVIRONMENT; CONTRIBUTE; RESISTANCE
AB Cancer-associated fibroblasts (CAFs) play an important role in the initiation, metastasis, and invasion of breast cancer. However, whether autophagy acts as a tumor promotion mechanism by inducing epithelial-mesenchymal transition (EMT) is still controversial and remains undefined at the mechanistic levels. In this study, we investigated whether autophagy or FAP-alpha is required for the invasion, pulmonary metastasis and EMT of breast cancer cells and underlying mechanism. We employed an in vitro model of NIH3T3 fibroblasts treated with H2O2 and confirmed that TGF-beta 1 could convert fibroblasts into CAFs through autophagy under oxidative stress in the tumor microenvironment. Modulation of autophagy by rapamycin, 3-methyladenine or ATG-5 knockdown regulated the expression of CAFs markers, suggesting a role of autophagy in the tumor promotion mechanism of TGF-beta 1-induced CAFs activation. Furthermore, we established an indirect co-culture model and a mixed xenograft as a corresponding in vivo model. We demonstrated that TGF-beta 1-activated CAFs promote tumor invasion, pulmonary metastasis and EMT, which act through autophagy and overexpression of FAP-alpha in both models, while autophagy inhibitor 3-methyladenine blocked these effects induced by TGF-beta 1-activated CAFs. Moreover, the colocalization of LC3 beta and EMT marker vimentin in mixed xenograft also revealed that TGF-beta 1-activated CAFs promote tumor growth, pulmonary metastasis, and EMT program partly through autophagy. In addition, knockdown of FAP-alpha resulted in reversed EMT and abolished tumor invasion and pulmonary metastasis induced by TGF-beta 1-activated CAFs. Taken together, we conclude that both autophagy and FAP-alpha are required for breast cancer cell invasion and metastasis. Targeting autophagy or FAP-alpha rather than both can serve as a potential approach to improve the prognosis for human breast cancer.
C1 [Huang, Minli; Fu, Mengru; Wang, Jia; Xia, Chunhua; Zhang, Hong; Xiong, Yuqing; Liu, Jianming; Liu, Bingchen; Pan, Siyi; Liu, Fanglan] Nanchang Univ, Clin Pharmacol Inst, Nanchang 330031, Jiangxi, Peoples R China.
   [He, Jiake] Nanchang Univ, Affiliated Hosp 2, Nanchang 330006, Jiangxi, Peoples R China.
C3 Nanchang University; Nanchang University
RP Liu, FL (corresponding author), Nanchang Univ, Clin Pharmacol Inst, Nanchang 330031, Jiangxi, Peoples R China.
EM liufanglan@ncu.edu.cn
RI Liu, Bingchen/KZU-7203-2024
OI Liu, Fanglan/0000-0002-5189-6658
FU National Natural Science Foundation of China [81703554, 81760672];
   Scientific Research Project of Jiangxi Education Department [GJJ160110];
   Young Teacher Research Funds of Nanchang University
FX This work was supported by National Natural Science Foundation of China
   (No. 81703554 and 81760672), Scientific Research Project of Jiangxi
   Education Department (No. GJJ160110) and the Young Teacher Research
   Funds of Nanchang University (No.4209-16100009PY201811).
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NR 57
TC 63
Z9 66
U1 4
U2 27
PU PERGAMON-ELSEVIER SCIENCE LTD
PI OXFORD
PA THE BOULEVARD, LANGFORD LANE, KIDLINGTON, OXFORD OX5 1GB, ENGLAND
SN 0006-2952
EI 1873-2968
J9 BIOCHEM PHARMACOL
JI Biochem. Pharmacol.
PD JUN
PY 2021
VL 188
AR 114527
DI 10.1016/j.bcp.2021.114527
EA MAR 2021
PG 16
WC Pharmacology & Pharmacy
WE Science Citation Index Expanded (SCI-EXPANDED)
SC Pharmacology & Pharmacy
GA SK4OE
UT WOS:000656196100003
PM 33741330
DA 2025-03-13
ER

PT J
AU Gao, MQ
   Kim, BG
   Kang, S
   Choi, YP
   Park, H
   Kang, KS
   Cho, NH
AF Gao, Ming-Qing
   Kim, Baek Gil
   Kang, Suki
   Choi, Yoon Pyo
   Park, Hangran
   Kang, Kyu Sub
   Cho, Nam Hoon
TI Stromal fibroblasts from the interface zone of human breast carcinomas
   induce an epithelial-mesenchymal transition-like state in breast cancer
   cells in vitro
SO JOURNAL OF CELL SCIENCE
LA English
DT Article
DE Breast carcinoma; Epithelial-mesenchymal transition; Stromal
   fibroblasts; Tumor zones; Tumor microenvironment; Interface fibroblasts
ID ACTIVATION PROTEIN; TUMOR-DEVELOPMENT; PROGRESSION; GROWTH; ERK;
   ANGIOGENESIS; KINASE; PROLIFERATION; APOPTOSIS; MIGRATION
AB Fibroblasts were extracted from tissue in tumor burden zones, distal normal zones and interface zones between tumor and normal tissue of human breast carcinomas, and the corresponding fibroblasts were designated as cancer-associated fibroblasts (CAFs), normal zone fibroblasts (NFs) and interface zone fibroblasts (INFs). The crosstalk between three types of fibroblasts and breast cancer cells was evaluated using an in vitro direct co-culture model. We found that INFs grew faster and expressed higher levels of fibroblast activation protein than did NFs and CAFs. Compared with CAFs and NFs, INFs grown with breast cancer cells were significantly more effective in inducing an epithelial-mesenchymal transition (EMT) in cancer cells, as indicated by induction of vimentin and N-cadherin and downregulation of E-cadherin. This EMT process was also accompanied by activation of extracellular signal-regulated kinase (ERK) and modulation of membrane-type 1 matrix metalloproteinase (MT1-MMP) expression. Additionally, INFs promoted breast cell migration to a larger extent compared with NFs and CAFs. Taken together, these findings indicate that INFs isolated from the tumor interface zone exhibited more robust biological modulatory activity than did NFs and CAFs isolated from normal and tumor zones of the same tumor tissue, suggesting that the interface zone of the tumor represents a dynamic region vital to tumor progression.
C1 [Gao, Ming-Qing; Kim, Baek Gil; Choi, Yoon Pyo; Park, Hangran; Kang, Kyu Sub; Cho, Nam Hoon] Yonsei Univ, Coll Med, Brain Korea Project Med Sci 21, Seoul 120752, South Korea.
   [Gao, Ming-Qing; Kim, Baek Gil; Kang, Suki; Choi, Yoon Pyo; Park, Hangran; Kang, Kyu Sub; Cho, Nam Hoon] Yonsei Univ, Coll Med, Dept Pathol, Seoul 120752, South Korea.
C3 Yonsei University; Yonsei University Health System; Yonsei University;
   Yonsei University Health System
RP Cho, NH (corresponding author), Yonsei Univ, Coll Med, Brain Korea Project Med Sci 21, Seoul 120752, South Korea.
EM cho1988@yuhs.ac
RI KIM, BAEK GIL/KCL-0984-2024
OI KANG, SUKI/0000-0002-9957-3479; KIM, BAEK GIL/0000-0001-6270-1433; jo,
   namhun/0000-0002-0045-6441
FU Korean government (MEST) [20090079165, 20090078398]
FX This work was supported by the National Research Foundation of Korea
   (NRF) grant funded by the Korean government (MEST) (No. 20090079165; No.
   20090078398; CNH).
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NR 29
TC 120
Z9 145
U1 0
U2 15
PU COMPANY OF BIOLOGISTS LTD
PI CAMBRIDGE
PA BIDDER BUILDING CAMBRIDGE COMMERCIAL PARK COWLEY RD, CAMBRIDGE CB4 4DL,
   CAMBS, ENGLAND
SN 0021-9533
J9 J CELL SCI
JI J. Cell Sci.
PD OCT 15
PY 2010
VL 123
IS 20
BP 3507
EP 3514
DI 10.1242/jcs.072900
PG 8
WC Cell Biology
WE Science Citation Index Expanded (SCI-EXPANDED)
SC Cell Biology
GA 660KZ
UT WOS:000282642900011
PM 20841377
DA 2025-03-13
ER

PT J
AU Liao, D
   Luo, YP
   Markowitz, D
   Xiang, R
   Reisfeld, RA
AF Liao, Debbie
   Luo, Yunping
   Markowitz, Dorothy
   Xiang, Rong
   Reisfeld, Ralph A.
TI Cancer Associated Fibroblasts Promote Tumor Growth and Metastasis by
   Modulating the Tumor Immune Microenvironment in a 4T1 Murine Breast
   Cancer Model
SO PLOS ONE
LA English
DT Article
ID DENDRITIC CELLS; SUPPRESSOR-CELLS; APOPTOTIC CELLS; MYELOID CELLS;
   INFLAMMATION; RECRUITMENT; PROTEASE; IMMUNOGENICITY; IMMUNOTHERAPY;
   CALRETICULIN
AB Background: Local inflammation associated with solid tumors commonly results from factors released by tumor cells and the tumor stroma, and promotes tumor progression. Cancer associated fibroblasts comprise a majority of the cells found in tumor stroma and are appealing targets for cancer therapy. Here, our aim was to determine the efficacy of targeting cancer associated fibroblasts for the treatment of metastatic breast cancer.
   Methodology/Principal Findings: We demonstrate that cancer associated fibroblasts are key modulators of immune polarization in the tumor microenvironment of a 4T1 murine model of metastatic breast cancer. Elimination of cancer associated fibroblasts in vivo by a DNA vaccine targeted to fibroblast activation protein results in a shift of the immune microenvironment from a Th2 to Th1 polarization. This shift is characterized by increased protein expression of IL-2 and IL-7, suppressed recruitment of tumor-associated macrophages, myeloid derived suppressor cells, T regulatory cells, and decreased tumor angiogenesis and lymphangiogenesis. Additionally, the vaccine improved anti-metastatic effects of doxorubicin chemotherapy and enhanced suppression of IL-6 and IL-4 protein expression while increasing recruitment of dendritic cells and CD8(+) T cells. Treatment with the combination therapy also reduced tumor-associated Vegf, Pdgfc, and GM-CSF mRNA and protein expression.
   Conclusions/Significance: Our findings demonstrate that cancer associated fibroblasts promote tumor growth and metastasis through their role as key modulators of immune polarization in the tumor microenvironment and are valid targets for therapy of metastatic breast cancer.
C1 [Liao, Debbie; Luo, Yunping; Markowitz, Dorothy; Xiang, Rong; Reisfeld, Ralph A.] Scripps Res Inst, Dept Immunol & Microbial Sci, La Jolla, CA 92037 USA.
   [Xiang, Rong] Nankai Univ, Sch Med, Dept Immunol, Tianjin, Peoples R China.
C3 Scripps Research Institute; Nankai University
RP Liao, D (corresponding author), Scripps Res Inst, Dept Immunol & Microbial Sci, La Jolla, CA 92037 USA.
EM reisfeld@scripps.edu
FU National Institutes of Health (NIH) [T32 HL007195-31]; DOD BCRP
   [BC050141]; National Science Foundation of China (NSFC) [30672389]; NSFC
   973 [2007CB914804]; NSFC 863 [2007AA021010]
FX This study was supported by National Institutes of Health (NIH) grant
   T32 HL007195-31 (to L. K. Curtiss, The Scripps Research Institute), DOD
   BCRP grant BC050141 (to R. A. R.), National Science Foundation of China
   (NSFC) grant 30672389 (to R. X.), NSFC 973 program grant 2007CB914804
   (to R. X.), and NSFC 863 program grant 2007AA021010 (to R. X.). This is
   TSRI manuscript number 20046-IMM. The funders had no role in study
   design, data collection and analysis, decision to publish, or
   preparation of the manuscript.
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NR 44
TC 353
Z9 426
U1 1
U2 74
PU PUBLIC LIBRARY SCIENCE
PI SAN FRANCISCO
PA 185 BERRY ST, STE 1300, SAN FRANCISCO, CA 94107 USA
SN 1932-6203
J9 PLOS ONE
JI PLoS One
PD NOV 23
PY 2009
VL 4
IS 11
AR e7965
DI 10.1371/journal.pone.0007965
PG 10
WC Multidisciplinary Sciences
WE Science Citation Index Expanded (SCI-EXPANDED)
SC Science & Technology - Other Topics
GA 533MF
UT WOS:000272827300020
PM 19956757
OA Green Published, Green Submitted, gold
DA 2025-03-13
ER

PT J
AU De Marco, P
   Lappano, R
   De Francesco, EM
   Cirillo, F
   Pupo, M
   Avino, S
   Vivacqua, A
   Abonante, S
   Picard, D
   Maggiolini, M
AF De Marco, Paola
   Lappano, Rosamaria
   De Francesco, Ernestina Marianna
   Cirillo, Francesca
   Pupo, Marco
   Avino, Silvia
   Vivacqua, Adele
   Abonante, Sergio
   Picard, Didier
   Maggiolini, Marcello
TI GPER signalling in both cancer-associated fibroblasts and breast cancer
   cells mediates a feedforward IL1β/IL1R1 response
SO SCIENTIFIC REPORTS
LA English
DT Article
ID ESTROGEN-RECEPTOR-ALPHA; GENE-EXPRESSION; CROSS-TALK; GPR30; IL-1-BETA;
   MIGRATION; GROWTH; METASTASIS; MEMBRANE; MCF-7
AB Cancer-associated fibroblasts (CAFs) contribute to the malignant aggressiveness through secreted factors like IL1 beta, which may drive pro-tumorigenic inflammatory phenotypes mainly acting via the cognate receptor named IL1R1. Here, we demonstrate that signalling mediated by the G protein estrogen receptor (GPER) triggers IL1 beta and IL1R1 expression in CAFs and breast cancer cells, respectively. Thereby, ligand-activation of GPER generates a feedforward loop coupling IL1 beta induction by CAFs to IL1R1 expression by cancer cells, promoting the up-regulation of IL1 beta/IL1R1 target genes such as PTGES, COX2, RAGE and ABCG2. This regulatory interaction between the two cell types induces migration and invasive features in breast cancer cells including fibroblastoid cytoarchitecture and F-actin reorganization. A better understanding of the mechanisms involved in the regulation of proinflammatory cytokines by GPER-integrated estrogen signals may be useful to target these stromacancer interactions.
C1 [De Marco, Paola; Lappano, Rosamaria; De Francesco, Ernestina Marianna; Cirillo, Francesca; Pupo, Marco; Avino, Silvia; Vivacqua, Adele; Maggiolini, Marcello] Univ Calabria, Dept Pharm & Hlth & Nutr Sci, I-87036 Arcavacata Di Rende, Italy.
   [Abonante, Sergio] Reg Hosp, Breast Canc Unit, I-87100 Cosenza, Italy.
   [Pupo, Marco; Picard, Didier] Univ Geneva, Fac Sci, Dept Cell Biol, Geneva, Switzerland.
   [Pupo, Marco; Picard, Didier] Univ Geneva, Inst Genet & Genom Geneva, Geneva, Switzerland.
C3 University of Calabria; University of Geneva; University of Geneva
RP Maggiolini, M (corresponding author), Univ Calabria, Dept Pharm & Hlth & Nutr Sci, I-87036 Arcavacata Di Rende, Italy.
EM marcellomaggiolini@yahoo.it
RI CIRILLO, FRANCESCA/K-2612-2018; Maggiolini, Marcello/Z-4729-2019; De
   Francesco, Ernestina Marianna/LQK-4482-2024; vivacqua, adele/I-2771-2015
OI De Francesco, Ernestina Marianna/0000-0002-2810-6128; vivacqua,
   adele/0000-0001-5333-8396; Lappano, Rosamaria/0000-0002-9374-9701
FU Associazione Italiana per la Ricerca sul Cancro [16719/2015]; Ministero
   della Salute [67/GR-2010-2319511]
FX This work was supported by Associazione Italiana per la Ricerca sul
   Cancro (grant n. 16719/2015) and Ministero della Salute (grant n.
   67/GR-2010-2319511).
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NR 60
TC 65
Z9 66
U1 1
U2 14
PU NATURE PORTFOLIO
PI BERLIN
PA HEIDELBERGER PLATZ 3, BERLIN, 14197, GERMANY
SN 2045-2322
J9 SCI REP-UK
JI Sci Rep
PD APR 13
PY 2016
VL 6
AR 24354
DI 10.1038/srep24354
PG 14
WC Multidisciplinary Sciences
WE Science Citation Index Expanded (SCI-EXPANDED)
SC Science & Technology - Other Topics
GA DJ0TA
UT WOS:000373916100002
PM 27072893
OA Green Published, gold
DA 2025-03-13
ER

PT J
AU Li, CH
   Wang, Z
   Zhang, YF
   Zhu, YQ
   Xu, MC
   Lei, H
   Zhang, D
AF Li, Chunhong
   Wang, Zhen
   Zhang, Yifeng
   Zhu, Yuqing
   Xu, Maochang
   Lei, Hui
   Zhang, Dan
TI Efficient Sequential Co-Delivery Nanosystem for Inhibition of Tumor and
   Tumor-Associated Fibroblast-Induced Resistance and Metastasis
SO INTERNATIONAL JOURNAL OF NANOMEDICINE
LA English
DT Article
DE liposomes; targeted delivery; triple-negative breast cancer; anti-tumor;
   combination therapy; sequential drug delivery
ID BREAST-CANCER; BETULINIC ACID; MICELLES; GROWTH; CELLS
AB Purpose: Triple -negative breast cancer (TNBC) is the most lethal subtype of breast cancer. However, the effect of current treatment strategies by inducing tumor cell apoptosis alone is not satisfactory. The growth, metastasis and treatment sensitivity of tumors can be strongly influenced by cancer -associated fibroblasts (CAFs) in the microenvironment. Effective cancer therapies may need to target not only the tumor cells directly but also the CAFs that protect them. Methods: Celastrol and small -sized micelles containing betulinic acid were co -encapsulated into liposomes using the thin-film hydration method (CL@BM). Folic acid was further introduced to modify liposomes as the targeting moiety (F/CL@BM). We established a novel NIH3T3+4T1 co -culture model to mimic the tumor microenvironment and assessed the nanocarrier's inhibitory effects on CAFs-induced drug resistance and migration in the co -culture model. The in vivo biological distribution, fluorescence imaging, biological safety evaluation, and combined therapeutic effect evaluation of the nanocarrier were carried out based on a triplenegative breast cancer model. Results: In the present study, a novel multifunctional nano -formulation was designed by combining the advantages of sequential release, co -loading of tretinoin and betulinic acid, and folic acid -mediated active targeting. As expected, the nano -formulation exhibited enhanced cytotoxicity in different cellular models and effectively increased drug accumulation at the tumor site by disrupting the cellular barrier composed of CAFs by tretinoin. Notably, the co -loaded nano -formulations proved to be more potent in inhibiting tumor growth in mice and also showed better anti -metastatic effects in lung metastasis models compared to the formulations with either drug alone. This novel drug delivery system has the potential to be used to develop more effective cancer therapies. Conclusion: Targeting CAFs with celastrol sensitizes tumor cells to chemotherapy, increasing the efficacy of betulinic acid. The combination of drugs targeting tumor cells and CAFs may lead to more effective therapies against various cancers.
C1 [Li, Chunhong; Wang, Zhen; Zhang, Yifeng; Zhu, Yuqing; Xu, Maochang; Lei, Hui; Zhang, Dan] Southwest Med Univ, Sch Pharm, Dept Pharmaceut Sci, Luzhou 646000, Sichuan, Peoples R China.
   [Zhang, Dan] Southwest Med Univ, Sch Pharm, Green Pharmaceut Technol Key Lab Luzhou, Luzhou 646000, Peoples R China.
   [Lei, Hui; Zhang, Dan] Southwest Med Univ, Sch Pharm, Dept Pharmaceut Sci, 1-1 Xianglin Rd, Luzhou 646000, Sichuan, Peoples R China.
C3 Southwest Medical University; Southwest Medical University; Southwest
   Medical University
RP Lei, H; Zhang, D (corresponding author), Southwest Med Univ, Sch Pharm, Dept Pharmaceut Sci, 1-1 Xianglin Rd, Luzhou 646000, Sichuan, Peoples R China.
EM huilei@swmu.edu.cn; zhangdan@swmu.edu.cn
RI zhu, yuqing/JCP-2481-2023; li, chunhong/ABD-9811-2020
FU Sichuan Science and Technology Program [22YFS0614, 23NSFSC0666]; Key
   research and development project fund of social development of [Luzhou
   Science and Technology Bureau] [2022-SYF-56]
FX This work was supported by the [Sichuan Science and Technology Program
   #1] under Grant [number 23NSFSC0666] ; [Sichuan Science and Technology
   Program #2] under Grant [number 22YFS0614] and [the key research and
   development project fund of social development of [Luzhou Science and
   Technology Bureau #3] under Grant (number 2022-SYF-56) .
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Z9 4
U1 6
U2 15
PU DOVE MEDICAL PRESS LTD
PI ALBANY
PA PO BOX 300-008, ALBANY, AUCKLAND 0752, NEW ZEALAND
SN 1178-2013
J9 INT J NANOMED
JI Int. J. Nanomed.
PY 2024
VL 19
BP 1749
EP 1766
DI 10.2147/IJN.S427783
PG 18
WC Nanoscience & Nanotechnology; Pharmacology & Pharmacy
WE Science Citation Index Expanded (SCI-EXPANDED)
SC Science & Technology - Other Topics; Pharmacology & Pharmacy
GA JE7T7
UT WOS:001171560500001
PM 38414527
OA Green Published, gold
DA 2025-03-13
ER

PT J
AU Lappano, R
   Rigiracciolo, DC
   Belfiore, A
   Maggiolini, M
   De Francesco, EM
AF Lappano, Rosamaria
   Rigiracciolo, Damiano Cosimo
   Belfiore, Antonino
   Maggiolini, Marcello
   De Francesco, Ernestina Marianna
TI Cancer associated fibroblasts: role in breast cancer and potential as
   therapeutic targets
SO EXPERT OPINION ON THERAPEUTIC TARGETS
LA English
DT Review
DE Cancer Associated Fibroblasts (CAFs); breast tumor microenvironment;
   breast cancer; targeted therapy; molecular targets; oncogenic signaling
ID CARCINOMA-ASSOCIATED FIBROBLASTS; ACTIVATION PROTEIN ALPHA;
   TUMOR-STROMAL INTERACTIONS; STEM-CELLS; EXTRACELLULAR-MATRIX; DNA
   VACCINE; GENE-EXPRESSION; LUNG METASTASIS; UP-REGULATION; CROSS-TALK
AB Introduction: Cancer associated fibroblasts (CAFs) are the largest population of stromal cells in breast tumors. Emerging evidence has suggested that CAFs are important players not only in fostering tumor growth and spread but also in altering the tumor response to therapeutic agents. On the basis of these observations, huge efforts have been made to exploit CAFs as potential targets for breast cancer therapy. Areas covered: The current understanding of the hallmarks and biology of CAFs, their multilayered interplay with various cell populations of breast tumor microenvironment toward cancer initiation, progression, metastasis and resistance to anticancer therapies are discussed. In addition, a comprehensive overview of the CAFs-based molecular druggable targets in breast tumors is provided. The most relevant literature, in particular the studies retrieved in Medline in the last 10 years, served for this purpose. Expert opinion: The interest on CAFs as a target to fight breast cancer has becoming a hot topic for drug discovery. Indeed, several CAFs-targeted approaches are emerging as appealing therapeutic strategies in breast cancer. At pre-clinical level, this research field is speedily advancing toward the assessment of successful tactics targeting CAFs in breast cancer. Therefore, anti-CAFs therapies may display an intriguing potential to be exploited in clinical studies.
C1 [Lappano, Rosamaria; Rigiracciolo, Damiano Cosimo; Maggiolini, Marcello] Univ Calabria, Dept Pharm Hlth & Nutr Sci, Arcavacata Di Rende, Italy.
   [Belfiore, Antonino; De Francesco, Ernestina Marianna] Univ Catania, Dept Clin & Expt Med, Endocrinol, Catania, Italy.
C3 University of Calabria; University of Catania
RP Maggiolini, M (corresponding author), Univ Calabria, Dept Pharm Hlth & Nutr Sci, Arcavacata Di Rende, Italy.; Belfiore, A (corresponding author), Univ Catania, Dept Clin & Expt Med, Endocrinol, Catania, Italy.
EM antonino.belfiore@unict.it; marcello.maggiolini@unical.it
RI Rigiracciolo, Damiano Cosimo/GRS-9234-2022; Maggiolini,
   Marcello/Z-4729-2019; De Francesco, Ernestina Marianna/LQK-4482-2024;
   BELFIORE, Antonino/B-4652-2011
OI De Francesco, Ernestina Marianna/0000-0002-2810-6128; Maggiolini,
   Marcello/0000-0002-7485-854X; BELFIORE, Antonino/0000-0002-6181-4193
FU Fondazione AIRC [23369, 21322, 21651]; Italian Minister of University
   and Research[MIUR] [3407/2018]
FX Fondazione AIRC supported A Belfiore (IG n. 23369), MM (IG n. 21322) and
   EMDF (Start-Up Grant 21651). DC Rigiracciolo was supported by Italian
   Minister of University and Research[MIUR, D.D. n. 3407/2018]-PON R&I
   2014-2020 `AIM Attrazione e Mobilita Internazionale'. R Lappano, DC
   Rigiracciolo and M Maggiolini acknowledge i) the special award namely
   `Department of Excellence 2018-2022' (Italian Law 232/2016) to the
   Department of Pharmacy, Health and Nutritional Sciences of the
   University of Calabria (Italy), ii) the `Sistema Integrato di Laboratori
   per L'Ambiente -(SILA) PONa3_00341'.
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NR 156
TC 47
Z9 50
U1 1
U2 26
PU TAYLOR & FRANCIS LTD
PI ABINGDON
PA 2-4 PARK SQUARE, MILTON PARK, ABINGDON OR14 4RN, OXON, ENGLAND
SN 1472-8222
EI 1744-7631
J9 EXPERT OPIN THER TAR
JI Expert Opin. Ther. Targets
PD JUN 2
PY 2020
VL 24
IS 6
BP 559
EP 572
DI 10.1080/14728222.2020.1751819
EA APR 2020
PG 14
WC Pharmacology & Pharmacy
WE Science Citation Index Expanded (SCI-EXPANDED)
SC Pharmacology & Pharmacy
GA LO8NB
UT WOS:000526304300001
PM 32249708
DA 2025-03-13
ER

PT J
AU Eiro, N
   Cid, S
   Fraile, M
   Cabrera, JR
   Gonzalez, LO
   Vizoso, FJ
AF Eiro, Noemi
   Cid, Sandra
   Fraile, Maria
   Cabrera, Jorge Ruben
   Gonzalez, Luis O.
   Vizoso, Francisco J.
TI Analysis of the Gene Expression Profile of Stromal Pro-Tumor Factors in
   Cancer-Associated Fibroblasts from Luminal Breast Carcinomas
SO DIAGNOSTICS
LA English
DT Article
DE cancer associated fibroblasts; tumor stroma; breast cancer; MMP11; IGF2
ID INTERNATIONAL EXPERT CONSENSUS; ENDOTHELIAL GROWTH-FACTOR; MATRIX
   METALLOPROTEINASES; CHEMOATTRACTANT PROTEIN-1; MOLECULAR PORTRAITS;
   PROGNOSTIC VALUE; PRIMARY THERAPY; SERUM-LEVELS; TGF-BETA; IN-VITRO
AB Luminal tumors are the most frequent type of breast carcinomas showing less tumor aggressiveness, although heterogeneity exists in their clinical outcomes. Cancer-associated fibroblasts (CAFs) are a key component of the tumor stroma which contribute to tumor progression. We investigated by real-time PCR the gene expression of 19 factors implicated in tumor progression. Those factors included the calcium-binding protein S100A4, several growth factors (FGF2, FGF7, HGF, PDGFA, PDGFB, TGF beta, VEGFA, and IGF2), and we also studied inflammatory cytokines (IL6 and IL8), chemokines (CCL2, CXCL12), important proteases (uPA, MMP2, MMP9 and MMP11), the nuclear factor NF kappa B, and the metalloprotease inhibitor TIMP1, from luminal A and luminal B breast carcinoma CAFs. We performed a similar analysis after co-culturing CAFs with MCF-7 and MDA-MB-231 breast cancer cell lines. MMP-9 and CCL2 gene expressions were higher in CAFs from luminal B tumors. We also found different patterns in the induction of pro-tumoral factors from different CAFs populations co-cultured with different cancer cell lines. Globally, CAFs from luminal B tumors showed a higher expression of pro-tumor factors compared to CAFs from luminal A tumors when co-cultured with breast cancer cell lines. Moreover, we found that CAFs from metastatic tumors had higher IGF-2 gene expression, and we detected the same after co-culture with cell lines. Our results show the variability in the capacities of CAFs from luminal breast carcinomas, which may contribute to a better biological and clinical characterization of these cancer subtypes.
C1 [Eiro, Noemi; Cid, Sandra; Fraile, Maria; Cabrera, Jorge Ruben; Vizoso, Francisco J.] Fdn Hosp Jove, Unit Res, Gijon 33290, Asturias, Spain.
   [Gonzalez, Luis O.] Fdn Hosp Jove, Dept Pathol Anat, Gijon 33290, Asturias, Spain.
RP Eiro, N; Vizoso, FJ (corresponding author), Fdn Hosp Jove, Unit Res, Gijon 33290, Asturias, Spain.
EM noemi.eiro@gmail.com; sandra.cid.89@gmail.com; maria.fraile82@gmail.com;
   jorge.ruben.cabrera@gmail.com; a.patologica2@hospitaldejove.com;
   investigacion@hospitaldejove.com
RI Eiro, Noemi/HNC-3166-2023; GONZALEZ, LUIS/AAT-9362-2021; Cabrera, Jorge
   Ruben/H-6310-2015; Eiro, Noemi/C-9510-2018
OI Fraile, Maria/0000-0002-0092-7805; Gonzalez, Luis O/0009-0009-2665-6458;
   Cabrera, Jorge Ruben/0000-0003-4481-0198; Eiro,
   Noemi/0000-0001-5840-4807; Vizoso, Francisco/0000-0002-2827-5511
FU Instituto de Salud Carlos III [PI17/02236]; European Union (ERDF/ESF,
   "Investing in your future"); Fundacion para la Investigacion en Celulas
   Madre Uterinas (FICEMU); Gobierno del Principado de Asturias "Severo
   Ochoa" PhD Program [BP14-128]
FX This study was supported by grants to F.J.V from Instituto de Salud
   Carlos III (PI17/02236) and co-funded by European Union (ERDF/ESF,
   "Investing in your future") and by Fundacion para la Investigacion en
   Celulas Madre Uterinas (FICEMU) to FV. SC was recipient of a fellowship
   financed by the Gobierno del Principado de Asturias "Severo Ochoa" PhD
   Program under Grant BP14-128.
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NR 79
TC 8
Z9 8
U1 0
U2 4
PU MDPI
PI BASEL
PA ST ALBAN-ANLAGE 66, CH-4052 BASEL, SWITZERLAND
EI 2075-4418
J9 DIAGNOSTICS
JI Diagnostics
PD NOV
PY 2020
VL 10
IS 11
AR 865
DI 10.3390/diagnostics10110865
PG 16
WC Medicine, General & Internal
WE Science Citation Index Expanded (SCI-EXPANDED)
SC General & Internal Medicine
GA OX5UG
UT WOS:000593628800001
PM 33114046
OA Green Published, gold
DA 2025-03-13
ER

PT J
AU Jalilian, E
   Abolhasani-Zadeh, F
   Afgar, A
   Samoudi, A
   Zeinalynezhad, H
   Langroudi, L
AF Jalilian, Elnaz
   Abolhasani-Zadeh, Firoozeh
   Afgar, Ali
   Samoudi, Arash
   Zeinalynezhad, Hamid
   Langroudi, Ladan
TI Neutralizing tumor-related inflammation and reprogramming of
   cancer-associated fibroblasts by Curcumin in breast cancer therapy
SO SCIENTIFIC REPORTS
LA English
DT Article
ID NF-KAPPA-B; CELLS; METASTASIS; COX-2; MICROENVIRONMENT; CHEMOTHERAPY;
   DOXORUBICIN; SUPPRESSES; PREVENTION; EXPRESSION
AB Tumor-associated inflammation plays a vital role in cancer progression. Among the various stromal cells, cancer-associated fibroblasts are promising targets for cancer therapy. Several reports have indicated potent anti-inflammatory effects attributed to Curcumin. This study aimed to investigate whether inhibiting the inflammatory function of cancer-associated fibroblasts (CAFs) with Curcumin can restore anticancer immune responses. CAFs were isolated from breast cancer tissues, treated with Curcumin, and co-cultured with patients' PBMCs to evaluate gene expression and cytokine production alterations. Blood and breast tumor tissue samples were obtained from 12 breast cancer patients with stage II/III invasive ductal carcinoma. Fibroblast Activation Protein (FAP) + CAFs were extracted from tumor tissue, treated with 10 mu M Curcumin, and co-cultured with corresponding PBMCs. The expression of smooth muscle actin-alpha (alpha-SMA), Cyclooxygenase-2(COX-2), production of PGE2, and immune cell cytokines were evaluated using Real-Time PCR and ELISA, respectively. Analyzes showed that treatment with Curcumin decreased the expression of genes alpha-SMA and COX-2 and the production of PGE2 in CAFs. In PBMCs co-cultured with Curcumin-treated CAFs, the expression of FoxP3 decreased along with the production of TGF-beta, IL-10, and IL-4. An increase in IFN-gamma production was observed that followed by increased T-bet expression. According to our results, Curcumin could reprogram the pro-tumor phenotype of CAFs and increase the anti-tumor phenotype in PBMCs. Thus, CAFs, as a component of the tumor microenvironment, are a suitable target for combination immunotherapies of breast cancer.
C1 [Jalilian, Elnaz; Samoudi, Arash; Langroudi, Ladan] Kerman Univ Med Sci, Sch Med, Dept Parasitol, Pajoohesh Sq, Kerman, Iran.
   [Abolhasani-Zadeh, Firoozeh; Zeinalynezhad, Hamid] Kerman Univ Med Sci, Sch Med, Dept Surg, Kerman, Iran.
   [Afgar, Ali] Kerman Univ Med Sci, Sch Med, Departmeny Parasitol & Mycol, Kerman, Iran.
C3 Kerman University of Medical Sciences; Kerman University of Medical
   Sciences; Kerman University of Medical Sciences
RP Langroudi, L (corresponding author), Kerman Univ Med Sci, Sch Med, Dept Parasitol, Pajoohesh Sq, Kerman, Iran.
EM l.langroudi@kmu.ac.ir
RI Afgar, Ali/C-4702-2019; Abolhasani Zadeh, Firouzeh/ABT-3721-2022
OI Abolhasani Zadeh, Firoozeh/0000-0002-7349-7498; Samoudi,
   Arash/0000-0001-9915-5704
FU Kerman University of Medical Sciences
FX No Statement Available
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NR 77
TC 8
Z9 8
U1 1
U2 8
PU NATURE PORTFOLIO
PI BERLIN
PA HEIDELBERGER PLATZ 3, BERLIN, 14197, GERMANY
SN 2045-2322
J9 SCI REP-UK
JI Sci Rep
PD NOV 26
PY 2023
VL 13
IS 1
AR 20770
DI 10.1038/s41598-023-48073-w
PG 13
WC Multidisciplinary Sciences
WE Science Citation Index Expanded (SCI-EXPANDED)
SC Science & Technology - Other Topics
GA CH1G8
UT WOS:001124265200008
PM 38008819
OA gold
DA 2025-03-13
ER

PT J
AU Yao, YY
   Guo, QL
   Cao, Y
   Qiu, YM
   Tan, RX
   Yu, Z
   Zhou, YX
   Lu, N
AF Yao, Yuyuan
   Guo, Qinglong
   Cao, Yue
   Qiu, Yangmin
   Tan, Renxiang
   Yu, Zhou
   Zhou, Yuxin
   Lu, Na
TI Artemisinin derivatives inactivate cancer-associated fibroblasts through
   suppressing TGF- signaling in breast cancer
SO JOURNAL OF EXPERIMENTAL & CLINICAL CANCER RESEARCH
LA English
DT Article
DE CAFs; TGF-1; ART; ARM; ARS; DHA
ID DOWN-REGULATION; ACTIVATION; CELLS; QINGHAOSU; MICROENVIRONMENT;
   MECHANISM; PROMOTES; BIOLOGY; STROMA
AB BackgroundCancer-associated fibroblasts (CAFs) are activated fibroblasts associated with cancer. They have an important role in tumor growth and metastasis. Artemisinin (ART) is a sesquiterpene lactone extracted from Chinese herb qinghao, and artemether (ARM), artesunate (ARS) and dihydroartemisinin (DHA) were synthesized derivatives of artemisinin, which also have anti-malarial and anti-cancer effects such as artemisinin.MethodsIn this study, we investigated the in-vitro and in-vivo effects of artemisinin derivatives on inactivating cancer-associated fibroblasts and uncovered its underlying mechanism.ResultsWe demonstrated that ARS and DHA could revert L-929-CAFs and CAFs from activated to inactivated state in vitro. Mechanically, ARS and DHA could suppress TGF- signaling to inhibit activation of L-929-CAFs and CAFs, and decreased interaction between tumor and tumor microenvironment. The results showed that ARS and DHA could suppress CAFs-induced breast cancer growth and metastasis in the orthotopic model. Conformably, ARS and DHA suppressed TGF- signaling to inactivate cancer-associated fibroblasts and inhibit cancer metastasis in vivo.ConclusionsArtemisinin derivatives are potential therapeutic agents for the treatment of breast cancer.
C1 [Yao, Yuyuan; Guo, Qinglong; Cao, Yue; Qiu, Yangmin; Yu, Zhou; Zhou, Yuxin; Lu, Na] China Pharmaceut Univ, State Key Lab Nat Med, Jiangsu Key Lab Carcinogenesis & Intervent, Sch Basic Med & Clin Pharm, 24 Tongjiaxiang, Nanjing 210009, Jiangsu, Peoples R China.
   [Tan, Renxiang] Nanjing Univ Chinese Med, State Key Lab Cultivat Base TCM Qual & Efficacy, 138 Xinlin Rd, Nanjing 210023, Jiangsu, Peoples R China.
C3 China Pharmaceutical University
RP Lu, N (corresponding author), China Pharmaceut Univ, State Key Lab Nat Med, Jiangsu Key Lab Carcinogenesis & Intervent, Sch Basic Med & Clin Pharm, 24 Tongjiaxiang, Nanjing 210009, Jiangsu, Peoples R China.
EM nalu@cpu.edu.cn
OI Qiu, Yangmin/0000-0001-6039-7909
FU National Natural Science Foundation of China [81830105, 81872899,
   81703550, 81673461]; National Science & Technology Major Project
   [2017ZX09101003-005-023, 2017ZX09101003-003-007, 2017ZX09301014];
   Project Program of State Key Laboratory of Natural Medicines, China
   Pharmaceutical University [SKLNMZZCX201823]; Program for Changjiang
   Scholars and Innovative Research Team in University [IRT1193]; Jiangsu
   provincial key R&D program (Social development) Project [BE2018711];
   Open Project of State Key Laboratory Cultivation Base for TCM Quality
   and Efficacy, Nanjing University of Chinese Medicine [TCMQE201704];
   Postgraduate Research & Practice Innovation Program of Jiangsu Province
   [3152080070]
FX This work was supported by the National Natural Science Foundation of
   China (No. 81830105, 81872899, 81703550, 81673461), the National Science
   & Technology Major Project (No. 2017ZX09101003-005-023,
   2017ZX09101003-003-007, 2017ZX09301014), the Project Program of State
   Key Laboratory of Natural Medicines, China Pharmaceutical University
   (SKLNMZZCX201823), Program for Changjiang Scholars and Innovative
   Research Team in University (IRT1193), Jiangsu provincial key R&D
   program (Social development) Project (BE2018711), the Open Project of
   State Key Laboratory Cultivation Base for TCM Quality and Efficacy,
   Nanjing University of Chinese Medicine (No. TCMQ&E201704), the
   Postgraduate Research & Practice Innovation Program of Jiangsu Province
   (No. 3152080070).
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NR 39
TC 66
Z9 82
U1 3
U2 41
PU BMC
PI LONDON
PA CAMPUS, 4 CRINAN ST, LONDON N1 9XW, ENGLAND
EI 1756-9966
J9 J EXP CLIN CANC RES
JI J. Exp. Clin. Cancer Res.
PD NOV 26
PY 2018
VL 37
AR 282
DI 10.1186/s13046-018-0960-7
PG 14
WC Oncology
WE Science Citation Index Expanded (SCI-EXPANDED)
SC Oncology
GA HB8GR
UT WOS:000451326300003
PM 30477536
OA gold, Green Published
DA 2025-03-13
ER

PT J
AU González, L
   Eiro, N
   Fernandez-Garcia, B
   González, LO
   Dominguez, F
   Vizoso, FJ
AF Gonzalez, Lucia
   Eiro, Noemi
   Fernandez-Garcia, Belen
   Gonzalez, Luis O.
   Dominguez, Francisco
   Vizoso, Francisco J.
TI Gene Expression Profile of Normal and Cancer-Associated Fibroblasts
   According to Intratumoral Inflammatory Cells Phenotype From Breast
   Cancer Tissue
SO MOLECULAR CARCINOGENESIS
LA English
DT Article
DE stroma; fibroblasts; NAF; CAF; breast cancer; cancer cell line; gene
   expression; inflammation; invasion; metastasis
ID GROWTH-FACTOR; MATRIX METALLOPROTEINASES; TUMOR MICROENVIRONMENT;
   STROMAL FIBROBLASTS; PROGNOSTIC VALUE; WOUND CLOSURE; STEM-CELLS;
   CROSS-TALK; TGF-BETA; METASTASIS
AB The biological heterogeneity of breast cancer leads to the need for finding new approaches to understand the mechanisms implicated in breast cancer progression. The tumor stroma appears as a key in the progression of solid tumors towards a malignant phenotype. Cancer associated fibroblasts (CAFs) may orchestrate a functional "corrupted" stroma which in turn helps metastatic spread. In this study, we investigated by real-time PCR, the expression of 19 factors by normal breast-associated fibroblasts (NAFs) and CAFs, which were implicated in several actions promoting tumor growth, such as extracellular matrix remodeling, inflammation and invasion. Also, we explored the influence of inflammatory cells phenotypes (MMP11 status) and breast cancer cell lines (MCF-7 and MDA-MB-231) on the molecular profile of CAFs. If we consider that one of the major sources of CAFs are resident NAFs, the transition of NAFs into CAFs is associated with molecular changes involving the overexpression of some molecular factors of biological importance in tumor progression. In addition, the characterization of the tumor stroma regarding to the MMP11 status by MICs reflects a type of fibroblasts which contribute even more to tumor progression. Moreover, different patterns in the induction of the expression of factors by CAFs were observed, depending on the tumor cell line which they were co-cultured with. Furthermore, CAFs influence TGF beta expression in both cancer cell lines. Therefore, this study can help to a better characterization of tumor stroma in order to improve the prognostic evaluation, as well as to define the different populations of CAFs as potential therapeutic targets in breast cancer. (C) 2015 Wiley Periodicals, Inc.
C1 [Gonzalez, Lucia; Eiro, Noemi; Fernandez-Garcia, Belen; Gonzalez, Luis O.; Vizoso, Francisco J.] Fdn Hosp Jove, Unidad Invest, Avda Eduardo Castro S-N, Gijon 33920, Asturias, Spain.
   [Gonzalez, Luis O.] Fdn Hosp Jove, Serv Anat Patol, Gijon, Asturias, Spain.
   [Dominguez, Francisco] Hosp Cabuenes, Serv Anat Patol, Gijon, Asturias, Spain.
   [Vizoso, Francisco J.] Fdn Hosp Jove, Serv Ciruga Gen, Gijon, Spain.
C3 Hospital Universitario de Cabuenes
RP Vizoso, FJ (corresponding author), Fdn Hosp Jove, Unidad Invest, Avda Eduardo Castro S-N, Gijon 33920, Asturias, Spain.
RI Eiro, Noemi/HNC-3166-2023; González, Lucía/F-2065-2016; GONZALEZ,
   LUIS/AAT-9362-2021; Dominguez, Francisco/AAA-7260-2020; Eiro,
   Noemi/C-9510-2018
OI Fernandez-Garcia, Belen/0000-0002-9950-2494; Gonzalez,
   Lucia/0000-0002-6732-8073; Vizoso, Francisco/0000-0002-2827-5511; Eiro,
   Noemi/0000-0001-5840-4807; Gonzalez, Luis O/0009-0009-2665-6458
FU Instituto de Salud Carlos III [PI13/02745]; Consejeria de Economia y
   Empleo del Principado de Asturias; FEDER [GRUPIN14-116]
FX Grant sponsor: Instituto de Salud Carlos III; Grant number: PI13/02745;
   Grant sponsor: Consejeria de Economia y Empleo del Principado de
   Asturias; Grant sponsor: FEDER; Grant number: GRUPIN14-116
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NR 62
TC 25
Z9 25
U1 0
U2 10
PU WILEY-BLACKWELL
PI HOBOKEN
PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA
SN 0899-1987
EI 1098-2744
J9 MOL CARCINOGEN
JI Mol. Carcinog.
PD NOV
PY 2016
VL 55
IS 11
BP 1489
EP 1502
DI 10.1002/mc.22403
PG 14
WC Biochemistry & Molecular Biology; Oncology
WE Science Citation Index Expanded (SCI-EXPANDED)
SC Biochemistry & Molecular Biology; Oncology
GA EC1GP
UT WOS:000387853200001
PM 26349857
DA 2025-03-13
ER

PT J
AU Aboussekhra, A
AF Aboussekhra, Abdelilah
TI Role of cancer-associated fibroblasts in breast cancer development and
   prognosis
SO INTERNATIONAL JOURNAL OF DEVELOPMENTAL BIOLOGY
LA English
DT Article
DE Cancer-associated fibroblasts; breast cancer; paracrine signaling;
   prognosis
ID MESENCHYMAL STEM-CELLS; STROMAL FIBROBLASTS; TUMOR-STROMA;
   GENE-EXPRESSION; GROWTH-FACTOR; MATRIX METALLOPROTEINASES; SKIN
   FIBROBLASTS; TGF-BETA; IN-VIVO; MOLECULAR CHARACTERIZATION
AB Since Paget's "Seed and Soil" hypothesis in 1889 on cancer growth and metastasis, several studies on various solid tumors have confirmed the active role of the tumor milieu on the onset, growth and spread of neoplastic cells. Fibroblasts constitute the major components of the tumor microenvironment (stroma), and are therefore the most studied cell type. Therefore, a large amount of data has emerged showing the cancer-promoting function of these cells through paracrine effects that escort tumor cells through all the carcinogenesis steps. This involves many signaling proteins that transmit the message in both directions, allowing cooperative crosstalk between cancer cells and their stroma. This prompted several researchers to investigate the potential use of the molecular and cellular features of active stromal fibroblasts to generate specific tools for prevention, prognosis and treatment of cancer. Herein, I review the cellular and molecular features of active cancer-associated fibroblasts and their origin. Additionally, I summarize our current understanding of the procarcinogenic actions of these cells and their potential prognostic value for breast cancer patients.
C1 King Faisal Specialist Hosp & Res Ctr, BMR, Riyadh 11211, Saudi Arabia.
C3 King Faisal Specialist Hospital & Research Center
RP Aboussekhra, A (corresponding author), King Faisal Specialist Hosp & Res Ctr, BMR, MBC 03-66,POB 3354, Riyadh 11211, Saudi Arabia.
EM aboussekhra@kfshrc.edu.sa
RI Aboussekhra, Abdelilah/JCD-8138-2023
FU KACST [AT-24-32/RAC, 2031091]
FX I'm grateful to Velasco Melvin for his great help in preparing the
   figures, and Dr. Coralie Poizat, Dr. Taher Al-Tweigeri and Dr. Hazem
   Ghebah for the critical reading of the manuscript, and their valuable
   comments. I'm also very thankful to King Abdulaziz City for Science and
   Technology (KACST) for their valuable help. This work was in part
   supported by a KACST grant # AT-24-32/RAC#2031091.
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NR 108
TC 92
Z9 114
U1 0
U2 12
PU UNIV BASQUE COUNTRY UPV-EHU PRESS
PI BILBAO
PA PO BOX 1397, BILBAO, BIZKAIA E-48080, SPAIN
SN 0214-6282
EI 1696-3547
J9 INT J DEV BIOL
JI Int. J. Dev. Biol.
PY 2011
VL 55
IS 7-9
SI SI
BP 841
EP 849
DI 10.1387/ijdb.113362aa
PG 9
WC Developmental Biology
WE Science Citation Index Expanded (SCI-EXPANDED)
SC Developmental Biology
GA 883ST
UT WOS:000299655900019
PM 22161840
OA Bronze
DA 2025-03-13
ER

PT J
AU Mori, N
   Jin, JF
   Krishnamachary, B
   Mironchik, Y
   Wildes, F
   Vesuna, F
   Barnett, JD
   Bhujwalla, ZM
AF Mori, Noriko
   Jin, Jiefu
   Krishnamachary, Balaji
   Mironchik, Yelena
   Wildes, Flonne
   Vesuna, Farhad
   Barnett, James D.
   Bhujwalla, Zaver M.
TI Functional roles of FAP-α in metabolism, migration and invasion of human
   cancer cells
SO FRONTIERS IN ONCOLOGY
LA English
DT Article
DE FAP-alpha; metabolism; migration; invasion; breast cancer; magnetic
   resonance spectroscopy; wound healing
ID MEMBRANE-BOUND PROTEASE; BREAST-CANCER; INOSITOL HEXAPHOSPHATE;
   TUMOR-GROWTH; MALIGNANT-TRANSFORMATION; FIBROBLASTS; EXPRESSION; SEPRASE
AB Fibroblast activation protein-alpha (FAP-alpha) is a transmembrane serine protease that is attracting significant interest as it is expressed by a subgroup of cancer-associated fibroblasts that play a role in immune suppression and cancer metastasis. FAP-alpha is also expressed by some cancer cells, such as melanoma, colorectal and breast cancer cells. Triple negative breast cancer (TNBC) is an aggressive cancer that urgently requires identification of novel targets for therapy. To expand our understanding of the functional roles of FAP-alpha in TNBC we engineered a human TNBC cell line, MDA-MB-231, to stably overexpress FAP-alpha and characterized changes in metabolism by H-1 magnetic resonance spectroscopy, cell proliferation, migration characterized by wound healing, and invasion. FAP-alpha overexpression resulted in significant alterations in myoinositol, choline metabolites, creatine, and taurine, as well as a significant increase of migration and invasion, although proliferation remained unaltered. The increase of migration and invasion are consistent with the known activities of FAP-alpha as an exopeptidase and endopeptidase/gelatinase/collagenase in tissue remodeling and repair, and in cell migration. We additionally determined the effects of FAP-alpha overexpression on the human fibrosarcoma HT1080 cell line that showed increased migration, accompanied by limited changes in metabolism that identified the dependency of the metabolic changes on cell type. These metabolic data identify a previously unknown role of FAP-alpha in modifying cancer cell metabolism in the TNBC cell line studied here that may provide new insights into its functional roles in cancer progression.
C1 [Mori, Noriko; Jin, Jiefu; Krishnamachary, Balaji; Mironchik, Yelena; Wildes, Flonne; Vesuna, Farhad; Barnett, James D.; Bhujwalla, Zaver M.] Johns Hopkins Univ, Russell H Morgan Dept Radiol & Radiol Sci, Div Canc Imaging Res, Sch Med, Baltimore, MD 21205 USA.
   [Bhujwalla, Zaver M.] Johns Hopkins Univ, Sidney Kimmel Comprehens Canc Ctr, Sch Med, Baltimore, MD 21205 USA.
   [Bhujwalla, Zaver M.] Johns Hopkins Univ, Dept Radiat Oncol & Mol Radiat Sci, Sch Med, Baltimore, MD 21205 USA.
C3 Johns Hopkins University; Johns Hopkins University; Johns Hopkins
   Medicine; Johns Hopkins University
RP Mori, N; Bhujwalla, ZM (corresponding author), Johns Hopkins Univ, Russell H Morgan Dept Radiol & Radiol Sci, Div Canc Imaging Res, Sch Med, Baltimore, MD 21205 USA.; Bhujwalla, ZM (corresponding author), Johns Hopkins Univ, Sidney Kimmel Comprehens Canc Ctr, Sch Med, Baltimore, MD 21205 USA.; Bhujwalla, ZM (corresponding author), Johns Hopkins Univ, Dept Radiat Oncol & Mol Radiat Sci, Sch Med, Baltimore, MD 21205 USA.
EM nmori3@jhmi.edu; zbhujwa1@jhmi.edu
RI Jin, Jiefu/H-5666-2019; Vesuna, Farhad/G-3179-2010
FU National Institutes of Health (NIH) [R01CA82337, R35CA209960]
FX Funding This work was funded by National Institutes of Health (NIH)
   R01CA82337 and R35CA209960.
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NR 42
TC 2
Z9 3
U1 2
U2 4
PU FRONTIERS MEDIA SA
PI LAUSANNE
PA AVENUE DU TRIBUNAL FEDERAL 34, LAUSANNE, CH-1015, SWITZERLAND
SN 2234-943X
J9 FRONT ONCOL
JI Front. Oncol.
PD MAR 1
PY 2023
VL 13
AR 1068405
DI 10.3389/fonc.2023.1068405
PG 9
WC Oncology
WE Science Citation Index Expanded (SCI-EXPANDED)
SC Oncology
GA 9W9NP
UT WOS:000949404100001
PM 36937451
OA gold, Green Published
DA 2025-03-13
ER

PT J
AU Corsa, CAS
   Brenot, A
   Grither, WR
   Van Hove, S
   Loza, AJ
   Zhang, K
   Ponik, SM
   Liu, YM
   DeNardo, DG
   Eliceiri, KW
   Keely, PJ
   Longmore, GD
AF Corsa, Callie A. S.
   Brenot, Audrey
   Grither, Whitney R.
   Van Hove, Samantha
   Loza, Andrew J.
   Zhang, Kun
   Ponik, Suzanne M.
   Liu, Yuming
   DeNardo, David G.
   Eliceiri, Kevin W.
   Keely, Patricia J.
   Longmore, Gregory D.
TI The Action of Discoidin Domain Receptor 2 in Basal Tumor Cells and
   Stromal Cancer-Associated Fibroblasts Is Critical for Breast Cancer
   Metastasis
SO CELL REPORTS
LA English
DT Article
ID DDR2; EXPRESSION; PROMOTES; GENE; ANGIOGENESIS; INITIATION; DENSITY;
   SNAIL1
AB High levels of collagen deposition in human and mouse breast tumors are associated with poor outcome due to increased local invasion and distant metastases. Using a genetic approach, we show that, in mice, the action of the fibrillar collagen receptor discoidin domain receptor 2 (DDR2) in both tumor and tumor-stromal cells is critical for breast cancer metastasis yet does not affect primary tumor growth. In tumor cells, DDR2 in basal epithelial cells regulates the collective invasion of tumor organoids. In stromal cancer-associated fibroblasts (CAFs), DDR2 is critical for extracellular matrix production and the organization of collagen fibers. The action of DDR2 in CAFs also enhances tumor cell collective invasion through a pathway distinct from the tumor-cellintrinsic function of DDR2. This work identifies DDR2 as a potential therapeutic target that controls breast cancer metastases through its action in both tumor cells and tumor-stromal cells at the primary tumor site.
C1 [Corsa, Callie A. S.; Brenot, Audrey; Grither, Whitney R.; Van Hove, Samantha; Loza, Andrew J.; Zhang, Kun; DeNardo, David G.; Longmore, Gregory D.] Washington Univ, ICCE Inst, St Louis, MO 63110 USA.
   [Corsa, Callie A. S.; Van Hove, Samantha; Longmore, Gregory D.] Washington Univ, Dept Cell Biol & Physiol, St Louis, MO 63110 USA.
   [Corsa, Callie A. S.; Brenot, Audrey; Grither, Whitney R.; Van Hove, Samantha; Loza, Andrew J.; Zhang, Kun; DeNardo, David G.; Longmore, Gregory D.] Washington Univ, Dept Med, St Louis, MO 63110 USA.
   [Grither, Whitney R.] Washington Univ, Dept Biochem, St Louis, MO 63110 USA.
   [Loza, Andrew J.] Washington Univ, Dept Computat & Mol Biophys, St Louis, MO 63110 USA.
   [Ponik, Suzanne M.; Keely, Patricia J.] Univ Wisconsin, Dept Cell & Regenerat Biol, Sch Med & Publ Hlth, Madison, WI 53706 USA.
   [Liu, Yuming; Eliceiri, Kevin W.; Keely, Patricia J.] Univ Wisconsin, Lab Opt & Computat Imaging, Sch Med & Publ Hlth, Madison, WI 53706 USA.
C3 Washington University (WUSTL); Washington University (WUSTL); Washington
   University (WUSTL); Washington University (WUSTL); Washington University
   (WUSTL); University of Wisconsin System; University of Wisconsin
   Madison; University of Wisconsin System; University of Wisconsin Madison
RP Longmore, GD (corresponding author), Washington Univ, ICCE Inst, St Louis, MO 63110 USA.; Longmore, GD (corresponding author), Washington Univ, Dept Cell Biol & Physiol, St Louis, MO 63110 USA.; Longmore, GD (corresponding author), Washington Univ, Dept Med, St Louis, MO 63110 USA.
EM glongmore@wustl.edu
RI Eliceiri, Kevin/ABD-4516-2020; Ponik, Suzanne/AAF-5572-2020; Eliceiri,
   Kevin/P-8339-2015
OI Eliceiri, Kevin/0000-0001-8678-670X; DeNardo, David/0000-0002-3655-5783;
   Ponik, Suzanne/0000-0003-1367-4349; Corsa, Callie/0000-0002-3169-0281
FU NIH [F31 CA165729, CA196205]; Komen Foundation [110889]; NIH T32
   training grant [CA113275]
FX This work was supported by the NIH grants F31 CA165729 (C.A.C.) and
   CA196205 (G.D.L.) and the Komen Foundation grant 110889 (G.D.L.). C.A.C.
   was also supported, in part, by NIH T32 training grant CA113275. We
   thank the Washington University Advanced Imaging and Tissue Analysis
   Core for tissue processing (NIH P30DK052574). We thank members of the
   G.D.L. lab for helpful discussions.
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NR 41
TC 77
Z9 89
U1 1
U2 22
PU CELL PRESS
PI CAMBRIDGE
PA 50 HAMPSHIRE ST, FLOOR 5, CAMBRIDGE, MA 02139 USA
SN 2211-1247
J9 CELL REP
JI Cell Reports
PD JUN 14
PY 2016
VL 15
IS 11
BP 2510
EP 2523
DI 10.1016/j.celrep.2016.05.033
PG 14
WC Cell Biology
WE Science Citation Index Expanded (SCI-EXPANDED)
SC Cell Biology
GA DO4TG
UT WOS:000377776400019
PM 27264173
OA gold, Green Accepted
DA 2025-03-13
ER

PT J
AU Venning, FA
   Zornhagen, KW
   Wullkopf, L
   Sjölund, J
   Rodriguez-Cupello, C
   Kjellman, P
   Morsing, M
   Hajkarim, MC
   Won, KJ
   Erler, JT
   Madsen, CD
AF Venning, Freja Albjerg
   Zornhagen, Kamilla Westarp
   Wullkopf, Lena
   Sjolund, Jonas
   Rodriguez-Cupello, Carmen
   Kjellman, Pontus
   Morsing, Mikkel
   Hajkarim, Morteza Chalabi
   Won, Kyoung Jae
   Erler, Janine Terra
   Madsen, Chris Denis
TI Deciphering the temporal heterogeneity of cancer-associated fibroblast
   subpopulations in breast cancer
SO JOURNAL OF EXPERIMENTAL & CLINICAL CANCER RESEARCH
LA English
DT Article
DE Cancer-associated fibroblast (CAF); CAF heterogeneity; CAF
   subpopulations; Flow cytometry analysis; Breast cancer progression
ID REVEALS; MYOFIBROBLASTS; INHIBITION; EXPRESSION; METASTASES; RECEPTORS;
   LINEAGES
AB Background Cancer-associated fibroblasts (CAFs) comprise a heterogeneous population of stromal cells within the tumour microenvironment. CAFs exhibit both tumour-promoting and tumour-suppressing functions, making them exciting targets for improving cancer treatments. Careful isolation, identification, and characterisation of CAF heterogeneity is thus necessary for ex vivo validation and future implementation of CAF-targeted strategies in cancer. Methods Murine 4T1 (metastatic) and 4T07 (poorly/non-metastatic) orthotopic triple negative breast cancer tumours were collected after 7, 14, or 21 days. The tumours were analysed via flow cytometry for the simultaneous expression of six CAF markers: alpha smooth muscle actin (alpha SMA), fibroblast activation protein alpha (FAP alpha), platelet derived growth factor receptor alpha and beta (PDGFR alpha and PDGFR beta), CD26/DPP4 and podoplanin (PDPN). All non-CAFs were excluded from the analysis using a lineage marker cocktail (CD24, CD31, CD45, CD49f, EpCAM, LYVE-1, and TER-119). In total 128 murine tumours and 12 healthy mammary fat pads were analysed. Results We have developed a multicolour flow cytometry strategy based on exclusion of non-CAFs and successfully employed this to explore the temporal heterogeneity of freshly isolated CAFs in the 4T1 and 4T07 mouse models of triple-negative breast cancer. Analysing 128 murine tumours, we identified 5-6 main CAF populations and numerous minor ones based on the analysis of alpha SMA, FAP alpha, PDGFR alpha, PDGFR beta, CD26, and PDPN. All markers showed temporal changes with a distinct switch from primarily PDGFR alpha+ fibroblasts in healthy mammary tissue to predominantly PDGFR beta+ CAFs in tumours. CD26+ CAFs emerged as a large novel subpopulation, only matched by FAP alpha+ CAFs in abundance. Conclusion We demonstrate that multiple subpopulations of CAFs co-exist in murine triple negative breast cancer, and that the abundance and dynamics for each marker differ depending on tumour type and time. Our results form the foundation needed to isolate and characterise specific CAF populations, and ultimately provide an opportunity to therapeutically target specific CAF subpopulations.
C1 [Venning, Freja Albjerg; Zornhagen, Kamilla Westarp; Wullkopf, Lena; Hajkarim, Morteza Chalabi; Won, Kyoung Jae; Erler, Janine Terra; Madsen, Chris Denis] Univ Copenhagen UCPH, Biotech Res & Innovat Ctr BRIC, Ole Maaloes Vej 5, DK-2200 Copenhagen N, Denmark.
   [Sjolund, Jonas; Rodriguez-Cupello, Carmen; Kjellman, Pontus; Morsing, Mikkel; Madsen, Chris Denis] Lund Univ, Dept Lab Med, Div Translat Canc Res, Scheelevagen 2, S-22381 Lund, Sweden.
   [Hajkarim, Morteza Chalabi; Won, Kyoung Jae] Univ Copenhagen, Novo Nordisk Fdn, Fac Hlth & Med Sci, DanStem,Ctr Stem Cell Biol, DK-2200 Copenhagen N, Denmark.
C3 Lund University; University of Copenhagen; Novo Nordisk Foundation
RP Erler, JT; Madsen, CD (corresponding author), Univ Copenhagen UCPH, Biotech Res & Innovat Ctr BRIC, Ole Maaloes Vej 5, DK-2200 Copenhagen N, Denmark.; Madsen, CD (corresponding author), Lund Univ, Dept Lab Med, Div Translat Canc Res, Scheelevagen 2, S-22381 Lund, Sweden.
EM janine.erler@bric.ku.dk; chris.madsen@med.lu.se
RI Venning, Freja/P-6762-2019; chalabi hajakrim, morteza/JTV-7442-2023;
   Venning, Freja Albjerg/Q-5082-2017
OI chalabi hajakrim, morteza/0000-0002-2039-2676; Venning, Freja
   Albjerg/0000-0001-5229-2023; Erler, Janine/0000-0001-8675-6527; Madsen,
   Chris D/0000-0001-6838-2103; Morsing, Mikkel/0000-0001-8322-8796
FU Danish Council for Independent Research YDUN grant [1084181001]; Dansk
   Kraeftforsknings Fond; European Research Council
   [ERC-2015-CoG-682881-MATRICAN]; Novo Nordisk Foundation
   [NNF17CC0027852]; Ragnar Soderberg Foundation, Sweden [N91/15]; Swedish
   Cancer Society [CAN 2016/783, 19 0632 Pj, 190007]; Swedish Research
   Council [2017-03389, 2020-02088]; Ollie and Elof Ericsson's Foundation;
   Crafoord Foundation [20171049, 20190798]; Ake Wiberg Foundation, Sweden
   [M16-0120, M17-0235]; Lund University; Swedish Research Council
   [2020-02088, 2017-03389] Funding Source: Swedish Research Council
FX This work was supported by the Danish Council for Independent Research
   YDUN grant (1084181001, F.A.V.), Dansk Kraeftforsknings Fond (F.A.V.),
   the European Research Council (ERC-2015-CoG-682881-MATRICAN; L.W.,
   J.T.E.), the Novo Nordisk Foundation Hallas Moller Stipend (C.D.M.,
   J.T.E.), the Novo Nordisk Foundation (NNF17CC0027852, K.J.W.), the
   Ragnar Soderberg Foundation, Sweden (N91/15, C.D.M.), Swedish Cancer
   Society (CAN 2016/783, 19 0632 Pj, and 190007, C.D.M), Swedish Research
   Council (2017-03389 and 2020-02088, C.D.M.), Ollie and Elof Ericsson's
   Foundation (2017, C.D.M.), Crafoord Foundation (20171049 and 20190798,
   C.D.M.), and Ake Wiberg Foundation, Sweden (M16-0120 and M17-0235,
   C.D.M.). Open Access funding provided by Lund University.
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NR 53
TC 33
Z9 36
U1 0
U2 39
PU BMC
PI LONDON
PA CAMPUS, 4 CRINAN ST, LONDON N1 9XW, ENGLAND
EI 1756-9966
J9 J EXP CLIN CANC RES
JI J. Exp. Clin. Cancer Res.
PD MAY 20
PY 2021
VL 40
IS 1
AR 175
DI 10.1186/s13046-021-01944-4
PG 21
WC Oncology
WE Science Citation Index Expanded (SCI-EXPANDED)
SC Oncology
GA SF2UM
UT WOS:000652616300001
PM 34016130
OA Green Published, gold
DA 2025-03-13
ER

PT J
AU Al-Jomah, N
   Al-Mohanna, FH
   Aboussekhra, A
AF Al-Jomah, Naif
   Al-Mohanna, Falah H.
   Aboussekhra, Abdelilah
TI Tocilizumab suppresses the pro-carcinogenic effects of breast
   cancer-associated fibroblasts through inhibition of the STAT3/AUF1
   pathway
SO CARCINOGENESIS
LA English
DT Article
ID INTERLEUKIN-6 RECEPTOR INHIBITION; ENDOTHELIAL GROWTH-FACTOR;
   RHEUMATOID-ARTHRITIS; STROMAL FIBROBLASTS; TARGETED THERAPY;
   TUMOR-GROWTH; DOUBLE-BLIND; IL-6; ANGIOGENESIS; CYTOKINE
AB Active breast cancer-associated fibroblasts (CAFs), the most influential cells in breast tumor microenvironment, express/secrete high levels of the proinvasive/metastatic interleukin-6 (IL-6). Therefore, we have tested here the effect of the IL-6 receptor (IL-6R) inhibitor tocilizumab (TCZ; Actemra) on different active breast CAFs. We have shown that TCZ potently and persistently suppresses the expression of various CAF biomarkers, namely alpha-SMA, SDF-1 as well as the STAT3 pathway and its downstream target AUF1. TCZ also inhibited the proliferation, migration and invasion abilities of active breast CAF cells. Additionally, TCZ repressed the ability of CAF cells in promoting epithelial-to-mesenchymal transition, and enhancing the migratory/invasive and proliferative capacities of breast cancer cells in vitro. Importantly, these findings were confirmed in orthotopic humanized breast tumors in mice. Furthermore, TCZ suppressed the expression of the pro-angiogenic factor VEGF-A and its transactivator HIF-1 alpha in CAF cells, and consequently inhibited the angiogenic-promoting effect of active CAFs both in vitro and in orthotopic tumor xenografts. These results indicate that inhibition of the IL-6/STAT3/AUF1 pathway by TCZ can normalize active breast CAFs and suppress their paracrine pro-carcinogenic effects, which paves the way toward development of specific CAF-targeting therapy, badly needed for more efficient breast cancer treatments.
C1 [Al-Jomah, Naif; Aboussekhra, Abdelilah] King Faisal Specialist Hosp & Res Ctr, Res Ctr, Mol Oncol Dept, POB 3354, Riyadh 11211, Saudi Arabia.
   [Al-Mohanna, Falah H.] King Faisal Specialist Hosp & Res Ctr, Dept Comparat Med, Riyadh 11211, Saudi Arabia.
C3 King Faisal Specialist Hospital & Research Center; King Faisal
   Specialist Hospital & Research Center
RP Aboussekhra, A (corresponding author), King Faisal Specialist Hosp & Res Ctr, Dept Mol Oncol, Canc Biol & Expt Therapeut Sect, MBC 03,POB 3354, Riyadh 11211, Saudi Arabia.
EM aboussekhra@kfshrc.edu.sa
RI Aboussekhra, Abdelilah/JCD-8138-2023; Binjumah, Naif/JCE-8161-2023;
   Almohanna, Falah/IYJ-6603-2023
OI Almohanna, Falah/0000-0002-2426-0945; Al-Jomah, Naif/0000-0001-6653-2403
FU King Faisal Specialist Hospital & Research Center [2170006]
FX This work was performed under RAC#2170006, and was supported in totality
   by the King Faisal Specialist Hospital & Research Center.
NR 0
TC 16
Z9 17
U1 0
U2 5
PU OXFORD UNIV PRESS
PI OXFORD
PA GREAT CLARENDON ST, OXFORD OX2 6DP, ENGLAND
SN 0143-3334
EI 1460-2180
J9 CARCINOGENESIS
JI Carcinogenesis
PD DEC
PY 2021
VL 42
IS 12
BP 1439
EP 1448
DI 10.1093/carcin/bgab102
EA OCT 2021
PG 10
WC Oncology
WE Science Citation Index Expanded (SCI-EXPANDED)
SC Oncology
GA YH4IY
UT WOS:000743133500004
PM 34718441
DA 2025-03-13
ER

PT J
AU Ishikawa, M
   Inoue, T
   Shirai, T
   Takamatsu, K
   Kunihiro, S
   Ishii, H
   Nishikata, T
AF Ishikawa, Mami
   Inoue, Takahiro
   Shirai, Takuma
   Takamatsu, Kazuhiko
   Kunihiro, Shiori
   Ishii, Hirokazu
   Nishikata, Takahito
TI Simultaneous Expression of Cancer Stem Cell-Like Properties and
   Cancer-Associated Fibroblast-Like Properties in a Primary Culture of
   Breast Cancer Cells
SO CANCERS
LA English
DT Article
DE cancer-associated fibroblast; cancer stem cell; epithelial-mesenchymal
   transition; HIF1A; glycolysis
ID EPITHELIAL-MESENCHYMAL TRANSITION; STROMAL FIBROBLASTS; INHIBITORS;
   HYPOXIA
AB The importance of cancer-associated fibroblasts (CAFs) in cancer biology has been recently highlighted owing to their critical roles in cancer growth, progression, metastasis, and therapeutic resistance. We have previously established a primary culture of breast cancer cells, which showed epithelial-mesenchymal transition and cancer stem cell-like properties. In this study, we found that the primary culture also showed CAF-like properties. For example, hypoxia inducible factor 1 alpha (HIF1A) and its downstream genes, nuclear factor-kappa B2 (NF-kappa B2) and BCL2/adenovirus E1B 19 kd-interacting protein 3 (BNIP3), and many enzymes involved in glycolysis, such as GAPDH, LDH, PGAM1, and PKM2, were highly overexpressed in the primary culture. Moreover, media conditioned with the primary culture cells enhanced the growth of breast cancer cells. Similar to previous CAF studies, this enhancement suggested to be occurred through fibroblast growth factor signaling. This MCKH primary culture cell, which showed simultaneous expression of tumorigenic and CAF properties, offers a unique experimental system for studying the biology of CAFs.
C1 [Ishikawa, Mami; Inoue, Takahiro; Shirai, Takuma; Takamatsu, Kazuhiko; Kunihiro, Shiori; Ishii, Hirokazu; Nishikata, Takahito] Konan Univ, FIRST, Kobe, Hyogo 6500047, Japan.
   [Nishikata, Takahito] Konan Univ, FIBER, Kobe, Hyogo 6500047, Japan.
C3 Konan University; Konan University
RP Nishikata, T (corresponding author), Konan Univ, FIRST, Kobe, Hyogo 6500047, Japan.
EM m1461001@center.konan-u.ac.jp; m1461002@center.konan-u.ac.jp;
   sp091023@center.konan-u.ac.jp; kazuhiko.takamatsu@jp.astellas.com;
   m1361007@center.konan-u.ac.jp; dp161001@center.konan-u.ac.jp;
   nisikata@konan-u.ac.jp
FU "Core Research" project from the Ministry of Education, Culture, Sports,
   Science and Technology (Japan)
FX This work was partly supported by Grants-in-Aid for Scientific Research
   and the "Core Research" project (2009-2014) from the Ministry of
   Education, Culture, Sports, Science and Technology (Japan).
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NR 18
TC 23
Z9 25
U1 0
U2 3
PU MDPI
PI BASEL
PA ST ALBAN-ANLAGE 66, CH-4052 BASEL, SWITZERLAND
SN 2072-6694
J9 CANCERS
JI Cancers
PD SEP
PY 2014
VL 6
IS 3
BP 1570
EP 1578
DI 10.3390/cancers6031570
PG 9
WC Oncology
WE Science Citation Index Expanded (SCI-EXPANDED)
SC Oncology
GA V47KM
UT WOS:000209950700018
PM 25089665
OA Green Published, Green Submitted, gold
DA 2025-03-13
ER

PT J
AU Bagger, MM
   Sjoelund, J
   Kim, J
   Kohler, KT
   Villadsen, R
   Jafari, A
   Kassem, M
   Pietras, K
   Ronnov-Jessen, L
   Petersen, OW
AF Bagger, Mikkel Morsing
   Sjoelund, Jonas
   Kim, Jiyoung
   Kohler, Katharina Theresa
   Villadsen, Rene
   Jafari, Abbas
   Kassem, Moustapha
   Pietras, Kristian
   Ronnov-Jessen, Lone
   Petersen, Ole William
TI Evidence of steady-state fibroblast subtypes in the normal human breast
   as cells-of-origin for perturbed-state fibroblasts in breast cancer
SO BREAST CANCER RESEARCH
LA English
DT Article
DE Breast cancer; Cancer-associated fibroblast; Fibroblast; iCAF; myCAF;
   Cell line; TDLU
ID COMPREHENSIVE MOLECULAR PORTRAITS; SINGLE-CELL; HELPER-FREE; STEM-CELLS;
   HIGH-TITER; MYOFIBROBLASTS; TRANSITION; ENVIRONMENT; GENERATION
AB BackgroundHuman breast cancer most frequently originates within a well-defined anatomical structure referred to as the terminal duct lobular unit (TDLU). This structure is endowed with its very own lobular fibroblasts representing one out of two steady-state fibroblast subtypes-the other being interlobular fibroblasts. While cancer-associated fibroblasts (CAFs) are increasingly appreciated as covering a spectrum of perturbed states, we lack a coherent understanding of their relationship-if any-with the steady-state fibroblast subtypes. To address this, we here established two autologous CAF lines representing inflammatory CAFs (iCAFs) and myofibroblast CAFs (myCAFs) and compared them with already established interlobular- and lobular fibroblasts with respect to their origin and impact on tumor formation.MethodsPrimary breast tumor-derived CAFs were transduced to express human telomerase reverse transcriptase (hTERT) and sorted into CD105low and CD105high populations using fluorescence-activated cell sorting (FACS). The two populations were tested for differentiation similarities to iCAF and myCAF states through transcriptome-wide RNA-Sequencing (RNA-Seq) including comparison to an available iCAF-myCAF cell state atlas. Inference of origin in interlobular and lobular fibroblasts relied on RNA-Seq profiles, immunocytochemistry and growth characteristics. Osteogenic differentiation and bone formation assays in culture and in vivo were employed to gauge for origin in bone marrow-derived mesenchymal stem cells (bMSCs). Functional characteristics were assessed with respect to contractility in culture and interaction with tumor cells in mouse xenografts. The cells' gene expression signatures were tested for association with clinical outcome of breast cancer patients using survival data from The Cancer Genome Atlas database.ResultsWe demonstrate that iCAFs have properties in common with interlobular fibroblasts while myCAFs and lobular fibroblasts are related. None of the CAFs qualify as bMSCs as revealed by lack of critical performance in bone formation assays. Functionally, myCAFs and lobular fibroblasts are almost equally tumor promoting as opposed to iCAFs and interlobular fibroblasts. A myCAF gene signature is found to associate with poor breast cancer-specific survival.ConclusionsWe propose that iCAFs and myCAFs originate in interlobular and lobular fibroblasts, respectively, and more importantly, that the tumor-promoting properties of lobular fibroblasts render the TDLU an epicenter for breast cancer evolution.
C1 [Bagger, Mikkel Morsing; Sjoelund, Jonas; Pietras, Kristian] Lund Univ, Lund Univ Canc Ctr, Div Translat Canc Res, Dept Lab Med, Lund, Sweden.
   [Bagger, Mikkel Morsing; Kim, Jiyoung; Kohler, Katharina Theresa; Villadsen, Rene; Jafari, Abbas; Kassem, Moustapha; Petersen, Ole William] Univ Copenhagen, Dept Cellular & Mol Med, Copenhagen, Denmark.
   [Kassem, Moustapha] Odense Univ Hosp, Dept Endocrinol, Lab Mol Endocrinol, KMEB, Odense, Denmark.
   [Kassem, Moustapha] Univ Southern Denmark, Odense, Denmark.
   [Ronnov-Jessen, Lone] Univ Copenhagen, Dept Biol, Sect Cell Biol & Physiol, Copenhagen, Denmark.
C3 Lund University; University of Copenhagen; University of Southern
   Denmark; Odense University Hospital; University of Southern Denmark;
   University of Copenhagen
RP Bagger, MM (corresponding author), Lund Univ, Lund Univ Canc Ctr, Div Translat Canc Res, Dept Lab Med, Lund, Sweden.; Bagger, MM (corresponding author), Univ Copenhagen, Dept Cellular & Mol Med, Copenhagen, Denmark.
EM mikkel.morsing@med.lu.se
RI Jafari, Abbas/AAF-6256-2019; Pietras, Kristian/ABE-8727-2020;
   Ronnovjessen, Lone/A-5981-2013; Jafari Kermani, Abbas/I-5074-2015;
   Kassem, Moustapha/J-7688-2013
OI Jafari Kermani, Abbas/0000-0003-2443-6231; Sjolund,
   Jonas/0000-0002-6992-3415; Pietras, Kristian/0000-0001-6738-4705;
   Petersen, Ole William/0000-0003-1691-749X; Kim,
   Jiyoung/0000-0002-0049-2039; Villadsen, Rene/0000-0002-5226-381X;
   Kassem, Moustapha/0000-0003-1557-0869; Morsing,
   Mikkel/0000-0001-8322-8796; Ronnov-Jessen, Lone/0000-0002-0472-9320;
   Kohler, Katharina/0000-0002-5417-2495
FU Dagmar Marshalls Fond
FX We gratefully acknowledge the technical expertise and assistance of Lena
   Kristensen, Tove Marianne Lund and Anita Sharma Friismose (UCPH), and we
   thank Nicholas Ditzel (SDU) for help with the in vivo bone formation
   assay. We are thankful to the donors and to Vera Timmermans-Wielenga at
   the Department of Pathology, Rigshospitalet, for providing the biopsy
   material.
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NR 71
TC 2
Z9 2
U1 0
U2 3
PU BMC
PI LONDON
PA CAMPUS, 4 CRINAN ST, LONDON N1 9XW, ENGLAND
SN 1465-5411
EI 1465-542X
J9 BREAST CANCER RES
JI Breast Cancer Res.
PD JAN 16
PY 2024
VL 26
IS 1
AR 11
DI 10.1186/s13058-024-01763-3
PG 19
WC Oncology
WE Science Citation Index Expanded (SCI-EXPANDED)
SC Oncology
GA FB4I3
UT WOS:001143272100001
PM 38229104
OA Green Published, gold
DA 2025-03-13
ER

PT J
AU Bonneaud, TL
   Lefebvre, CC
   Nocquet, L
   Basseville, A
   Roul, J
   Weber, H
   Campone, M
   Juin, PP
   Souazé, F
AF Bonneaud, Thomas L.
   Lefebvre, Chloe C.
   Nocquet, Lisa
   Basseville, Agnes
   Roul, Julie
   Weber, Hugo
   Campone, Mario
   Juin, Philippe P.
   Souaze, Frederique
TI Targeting of MCL-1 in breast cancer-associated fibroblasts reverses
   their myofibroblastic phenotype and pro-invasive properties
SO CELL DEATH & DISEASE
LA English
DT Article
ID MITOCHONDRIAL DYNAMICS; STROMAL MYOFIBROBLASTS; CELLS
AB Cancer-associated fibroblasts (CAF) are a major cellular component of epithelial tumors. In breast cancers in particular these stromal cells have numerous tumorigenic effects in part due to their acquisition of a myofibroblastic phenotype. Breast CAFs (bCAFs) typically express MCL-1. We show here that pharmacological inhibition or knock down of this regulator of mitochondrial integrity in primary bCAFs directly derived from human samples mitigates myofibroblastic features. This decreases expression of genes involved in actomyosin organization and contractility (associated with a cytoplasmic retention of the transcriptional regulator, yes-associated protein-YAP) and decreases bCAFs ability to promote cancer cells invasion in 3D coculture assays. Our findings underscore the usefulness of targeting MCL-1 in breast cancer ecosystems, not only to favor death of cancer cells but also to counteract the tumorigenic activation of fibroblasts with which they co-evolve. Mechanistically, pharmacological inhibition of MCL-1 with a specific BH3 mimetic promotes mitochondrial fragmentation in bCAFs. Inhibition of the mitochondrial fission activity of DRP-1, which interacts with MCL-1 upon BH3 mimetic treatment, allows the maintenance of the myofibroblastic phenotype of bCAFs.
C1 [Bonneaud, Thomas L.; Lefebvre, Chloe C.; Nocquet, Lisa; Roul, Julie; Weber, Hugo; Campone, Mario; Juin, Philippe P.; Souaze, Frederique] Univ Nantes, CRCI2NA, CNRS, INSERM, F-44000 Nantes, France.
   [Bonneaud, Thomas L.; Lefebvre, Chloe C.; Nocquet, Lisa; Roul, Julie; Weber, Hugo; Campone, Mario; Juin, Philippe P.; Souaze, Frederique] SIRIC ILIAD, Angers, France.
   [Basseville, Agnes] ICO, Omics Data Sci Unit, Angers, France.
   [Roul, Julie; Campone, Mario; Juin, Philippe P.] ICO Rene Gauducheau, St Herblain, France.
C3 Centre National de la Recherche Scientifique (CNRS); Nantes Universite;
   Institut National de la Sante et de la Recherche Medicale (Inserm);
   UNICANCER; Institut de Cancerologie de l'Ouest (ICO); UNICANCER;
   Institut de Cancerologie de l'Ouest (ICO)
RP Juin, PP; Souazé, F (corresponding author), Univ Nantes, CRCI2NA, CNRS, INSERM, F-44000 Nantes, France.; Juin, PP; Souazé, F (corresponding author), SIRIC ILIAD, Angers, France.; Juin, PP (corresponding author), ICO Rene Gauducheau, St Herblain, France.
EM philippe.juin@univ-nantes.fr
RI JUIN, Philippe/H-3636-2014; Souazé, Frédérique/K-7937-2015
OI basseville, agnes/0000-0002-9349-1819; Lefebvre,
   Chloe/0000-0002-1866-7853; Nocquet, Lisa/0000-0002-2371-209X;
   Frederique, Souaze/0000-0003-0476-2603
FU Ligue contre le cancer [CD44, CD53, CD36, CD22]; European Union
   [841313]; French ministry of Higher Education, Research and Innovation;
   INCa (SIRIC ILIAD) [INCa-DGOS Inserm-12558, INCa-PLBio 16086]; Run
   Odyssea to ICOGauducheau; Marie Curie Actions (MSCA) [841313] Funding
   Source: Marie Curie Actions (MSCA)
FX TLB was supported by a fellowship from Ligue contre le cancer (CD44 and
   CD36), AB received a funding from the European Union's Horizon 2020
   research and innovation program under the Marie Sklodowska-Curie grant
   agreement No. 841313, and LN was a recipient of French ministry of
   Higher Education, Research and Innovation. This work was supported by
   INCa (SIRIC ILIAD, INCa-DGOS Inserm-12558, and INCa-PLBio 16086), Ligue
   contre le cancer (CD44, CD53, and CD22) and Run Odyssea to
   ICOGauducheau.
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NR 48
TC 8
Z9 8
U1 0
U2 4
PU SPRINGERNATURE
PI LONDON
PA CAMPUS, 4 CRINAN ST, LONDON, N1 9XW, ENGLAND
SN 2041-4889
J9 CELL DEATH DIS
JI Cell Death Dis.
PD SEP 14
PY 2022
VL 13
IS 9
AR 787
DI 10.1038/s41419-022-05214-9
PG 11
WC Cell Biology
WE Science Citation Index Expanded (SCI-EXPANDED)
SC Cell Biology
GA 4P1FW
UT WOS:000855142500003
PM 36104324
OA Green Published, Green Submitted, gold
DA 2025-03-13
ER

PT J
AU Gui, YR
   Aguilar-Mahecha, A
   Krzemien, U
   Hosein, A
   Buchanan, M
   Lafleur, J
   Pollak, M
   Ferrario, C
   Basik, M
AF Gui, Yirui
   Aguilar-Mahecha, Adriana
   Krzemien, Urszula
   Hosein, Abdel
   Buchanan, Marguerite
   Lafleur, Josiane
   Pollak, Michael
   Ferrario, Cristiano
   Basik, Mark
TI Metastatic Breast Carcinoma-Associated Fibroblasts Have Enhanced
   Protumorigenic Properties Related to Increased IGF2 Expression
SO CLINICAL CANCER RESEARCH
LA English
DT Article
ID CANCER-ASSOCIATED FIBROBLASTS; DRUG-RESISTANCE; CELLS; BINDING; EMT
AB Purpose: The microenvironment of metastatic breast cancer is incompletely characterized, despite prior evidence that it plays a key role in the biology of metastasis. A major component of the tumor stroma is the carcinoma-associated fibroblast (CAF), which has been shown to communicate with other stromal and cancer cells to create a protumorigenic milieu. Our study was designed to characterize human CAFs from different metastatic sites.
   Experimental Design: We collected eight carcinoma-associated fibroblasts (mCAFs) from different metastatic sites and compared them with CAFs from primary tumors (pCAFs) and with normal breast fibroblasts (NFs). Molecular profiles and effects on breast cancer cell growth, on response to doxorubicin and on T-cell proliferation were compared.
   Results: We observed marked differences in mCAFs compared with pCAFs and NFs with respect to in vitro proliferation and effects on breast cancer cell migration, spheroid growth, invasion, response to doxorubicin, and in vivo tumor growth. We found marked transcriptomic differences between mCAFs and pCAFs, including increased expression of IFN-related genes and IGF2 in the former. Cluster analysis revealed two groups of mCAFs, with the liver mCAFs clustering together, with increased PDGFA expression. Treatment with an antibody against insulin-like growth factors (BI836845) inhibited growth of mixed mCAF-tumor cell xenografts in vivo. Also, mCAFs had a suppressive effect on T-cell proliferation.
   Conclusions: This is the first comparative analysis of a set of CAFs from metastatic sites in breast cancer. It revealed a marked protumorigenic effect in these mCAFs, which occurs in part through increased expression of IGF2.
C1 [Gui, Yirui; Aguilar-Mahecha, Adriana; Krzemien, Urszula; Hosein, Abdel; Buchanan, Marguerite; Lafleur, Josiane; Pollak, Michael; Ferrario, Cristiano; Basik, Mark] McGill Univ, Lady Davis Inst Med Res, Jewish Gen Hosp, Montreal, PQ, Canada.
   [Pollak, Michael] McGill Univ, Goodman Canc Res Ctr, Montreal, PQ, Canada.
   [Pollak, Michael; Basik, Mark] McGill Univ, Dept Expt Med, Montreal, PQ, Canada.
   [Pollak, Michael; Ferrario, Cristiano; Basik, Mark] McGill Univ, Dept Oncol, Montreal, PQ, Canada.
   [Pollak, Michael] McGill Univ, Dept Med, Montreal, PQ, Canada.
   [Basik, Mark] McGill Univ, Dept Surg, Montreal, PQ, Canada.
C3 Lady Davis Institute
RP Basik, M (corresponding author), Lady Davis Insitute, 3755 Cote Ste Catherine, Montreal, PQ H3T 1E2, Canada.; Basik, M (corresponding author), Jewish Gen Hosp, 3755 Cote Ste Catherine, Montreal, PQ H3T 1E2, Canada.
EM mark.basik@mcgill.ca
RI Aguilar, Adriana/GRF-2369-2022; Pollak, Michael/G-9094-2011; Hosein,
   Abdel/KGM-7325-2024
OI Hosein, Abdel/0000-0003-1567-6700; Pollak, Michael/0000-0003-3047-0604
FU Canadian Cancer Society [702159 (INNOV13-2)]; Quebec Breast Cancer
   Foundation; FRQS Reseau de Cancer Axe cancer sein/ovaire funding for
   biobanking; Fonds de la recherche du Quebec-Sante (FRQS); CIHR/FRQS
   training grant in cancer research of the McGill Integrated Cancer
   Research Training Program (MICRTP) [FRN 53888]
FX We would like to thank Boehringer Ingelheim Pharmaceuticals, Inc for
   providing the BI-836845 Drug. This work was supported by an Innovation
   grant No. 702159 (INNOV13-2) from the Canadian Cancer Society to Dr.
   Basik and by the Quebec Breast Cancer Foundation and the FRQS Reseau de
   Cancer Axe cancer sein/ovaire funding for biobanking, also to Dr. Basik.
   Y. Gui was a recipient of a postdoctoral fellowship from Fonds de la
   recherche du Quebec-Sante (FRQS) and supported by a CIHR/FRQS training
   grant in cancer research FRN 53888 of the McGill Integrated Cancer
   Research Training Program (MICRTP).
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NR 26
TC 31
Z9 35
U1 1
U2 13
PU AMER ASSOC CANCER RESEARCH
PI PHILADELPHIA
PA 615 CHESTNUT ST, 17TH FLOOR, PHILADELPHIA, PA 19106-4404 USA
SN 1078-0432
EI 1557-3265
J9 CLIN CANCER RES
JI Clin. Cancer Res.
PD DEC 1
PY 2019
VL 25
IS 23
BP 7229
EP 7242
DI 10.1158/1078-0432.CCR-19-1268
PG 14
WC Oncology
WE Science Citation Index Expanded (SCI-EXPANDED)
SC Oncology
GA JT4IA
UT WOS:000500953700036
PM 31515454
OA Green Submitted
DA 2025-03-13
ER

PT J
AU Ritter, A
   Kreis, NN
   Roth, S
   Friemel, A
   Safdar, BK
   Hoock, SC
   Wildner, JM
   Allert, R
   Louwen, F
   Solbach, C
   Yuan, JP
AF Ritter, Andreas
   Kreis, Nina-Naomi
   Roth, Susanne
   Friemel, Alexandra
   Safdar, Babek Kahn
   Hoock, Samira Catharina
   Wildner, Julia Maria
   Allert, Roman
   Louwen, Frank
   Solbach, Christine
   Yuan, Juping
TI Cancer-educated mammary adipose tissue-derived stromal/stem cells in
   obesity and breast cancer: spatial regulation and function
SO JOURNAL OF EXPERIMENTAL & CLINICAL CANCER RESEARCH
LA English
DT Article
DE Breast adipose tissue-derived mesenchymal stromal; stem cells;
   Cancer-associated fibroblasts; Obesity; Breast cancer;
   Epithelial-to-mesenchymal transition; Chemoresistance; Cancer stem
   cells; Tumor microenvironment
ID MESENCHYMAL STEM-CELLS; DOUBLE-EDGED-SWORD; PRIMARY CILIA; TUMOR;
   FIBROBLASTS; GROWTH
AB Background Breast cancer is the most frequently diagnosed cancer and a common cause of cancer-related death in women. It is well recognized that obesity is associated with an enhanced risk of more aggressive breast cancer as well as reduced patient survival. Breast adipose tissue-derived mesenchymal stromal/stem cells (bASCs) are crucial components of the tumor microenvironment. A key step initially involved in this process might be the de-differentiation of bASCs into tumor supporting phenotypes. Methods In the present work, we isolated bASCs from adipose tissues adjacent to the tumor (aT bASCs) from lean- (ln-aT bASCs, BMI <= 25) and breast cancer patients with obesity (ob-aT bASCs, BMI >= 35), and analyzed their phenotypes with functional assays and RNA sequencing, compared to their counterparts isolated from adipose tissues distant from the tumor (dT bASCs). Results We show that ln-aT bASCs are susceptible to be transformed into an inflammatory cancer-associated phenotype, whereas ob-aT bASCs are prone to be cancer-educated into a myofibroblastic phenotype. Both ln-aT- and ob-aT bASCs compromise their physiological differentiation capacity, and upregulate metastasis-promoting factors. While ln-aT bASCs stimulate proliferation, motility and chemoresistance by inducing epithelial-mesenchymal transition of low malignant breast cancer cells, ob-aT bASCs trigger more efficiently a cancer stem cell phenotype in highly malignant breast cancer cells. Conclusion Breast cancer-associated bASCs are able to foster malignancy of breast cancer cells by multiple mechanisms, especially, induction of epithelial-mesenchymal transition and activation of stemness-associated genes in breast cancer cells. Blocking the de-differentiation of bASCs in the tumor microenvironment could be a novel strategy to develop an effective intervention for breast cancer patients. Significance This study provides mechanistic insights into how obesity affects the phenotype of bASCs in the TME. Moreover, it highlights the molecular changes inside breast cancer cells upon cell-cell interaction with cancer-educated bASCs.
C1 [Ritter, Andreas; Kreis, Nina-Naomi; Roth, Susanne; Friemel, Alexandra; Safdar, Babek Kahn; Hoock, Samira Catharina; Wildner, Julia Maria; Allert, Roman; Louwen, Frank; Solbach, Christine; Yuan, Juping] Goethe Univ Frankfurt, Univ Hosp Frankfurt, Obstet & Prenatal Med, Gynecol & Obstet, Theodor Stern Kai 7, D-60590 Frankfurt, Germany.
C3 Goethe University Frankfurt; Goethe University Frankfurt Hospital
RP Ritter, A; Yuan, JP (corresponding author), Goethe Univ Frankfurt, Univ Hosp Frankfurt, Obstet & Prenatal Med, Gynecol & Obstet, Theodor Stern Kai 7, D-60590 Frankfurt, Germany.
EM Andreas.Ritter@kgu.de; yuan@em.uni-frankfurt.de
RI Ritter, Andreas/ABB-6348-2020; Kreis, Nina-Naomi/AAF-5407-2019
OI Solbach, Christine/0000-0001-8284-3199; Ritter,
   Andreas/0000-0002-5955-859X
FU Projekt DEAL; "Deutsche Forschungsgemeinschaft "(DFG, German Research
   Foundation) [413992926]
FX Open Access funding enabled and organized by Projekt DEAL. This project
   was funded by the "Deutsche Forschungsgemeinschaft "(DFG, German
   Research Foundation, project number 413992926).
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NR 99
TC 18
Z9 18
U1 2
U2 7
PU BMC
PI LONDON
PA CAMPUS, 4 CRINAN ST, LONDON N1 9XW, ENGLAND
EI 1756-9966
J9 J EXP CLIN CANC RES
JI J. Exp. Clin. Cancer Res.
PD JAN 30
PY 2023
VL 42
IS 1
AR 35
DI 10.1186/s13046-022-02592-y
PG 26
WC Oncology
WE Science Citation Index Expanded (SCI-EXPANDED)
SC Oncology
GA 8K9KD
UT WOS:000923410900002
PM 36710348
OA gold, Green Published
DA 2025-03-13
ER

PT J
AU Ueno, T
   Utsumi, J
   Toi, M
   Shimizu, K
AF Ueno, Takayuki
   Utsumi, Jun
   Toi, Masakazu
   Shimizu, Kazuharu
TI Characteristic Gene Expression Profiles of Human Fibroblasts and Breast
   Cancer Cells in a Newly Developed Bilateral Coculture System
SO BIOMED RESEARCH INTERNATIONAL
LA English
DT Article
AB The microenvironment of cancer cells has been implicated in cancer development and progression. Cancer-associated fibroblast constitutes a major stromal component of the microenvironment. To analyze interaction between cancer cells and fibroblasts, we have developed a new bilateral coculture system using a two-sided microporous collagen membrane. Human normal skin fibroblasts were cocultured with three different human breast cancer cell lines: MCF-7, SK-BR-3, and HCC1937. After coculture, mRNA was extracted separately from cancer cells and fibroblasts and applied to transcriptomic analysis with microarray. Top 500 commonly up-or downregulated genes were characterized by enrichment functional analysis using MetaCore Functional Analysis. Most of the genes upregulated in cancer cells were downregulated in fibroblasts while most of the genes downregulated in cancer cells were upregulated in fibroblasts, indicating that changing patterns of mRNA expression were reciprocal between cancer cells and fibroblasts. In coculture, breast cancer cells commonly increased genes related to mitotic response and TCA pathway while fibroblasts increased genes related to carbohydrate metabolism including glycolysis, glycogenesis, and glucose transport, indicating that fibroblasts support cancer cell proliferation by supplying energy sources. We propose that the bilateral coculture system using collagen membrane is useful to study interactions between cancer cells and stromal cells by mimicking in vivo tumor microenvironment.
C1 [Ueno, Takayuki; Toi, Masakazu] Kyoto Univ Hosp, Dept Breast Surg, Kyoto 6068507, Japan.
   [Ueno, Takayuki] Kyorin Univ Hosp, Dept Breast Surg, Tokyo 1818611, Japan.
   [Utsumi, Jun; Shimizu, Kazuharu] Kyoto Univ, Grad Sch Pharmaceut Sci, Kyoto 6068501, Japan.
   [Utsumi, Jun] Japanese Fdn Canc Res, Inst Canc, Tokyo 1358550, Japan.
C3 Kyoto University; Kyorin University; Kyoto University; Japanese
   Foundation for Cancer Research
RP Ueno, T (corresponding author), Kyoto Univ Hosp, Dept Breast Surg, Kyoto 6068507, Japan.
EM t-ueno@ks.kyorin-u.ac.jp
FU JSPS KAKENHI [24591900]; Grants-in-Aid for Scientific Research
   [15K10067, 24591900] Funding Source: KAKEN
FX This study was supported by JSPS KAKENHI Grant no. 24591900.
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NR 13
TC 18
Z9 19
U1 1
U2 5
PU HINDAWI LTD
PI LONDON
PA ADAM HOUSE, 3RD FLR, 1 FITZROY SQ, LONDON, W1T 5HF, ENGLAND
SN 2314-6133
EI 2314-6141
J9 BIOMED RES INT
JI Biomed Res. Int.
PY 2015
VL 2015
AR 960840
DI 10.1155/2015/960840
PG 11
WC Biotechnology & Applied Microbiology; Medicine, Research & Experimental
WE Science Citation Index Expanded (SCI-EXPANDED)
SC Biotechnology & Applied Microbiology; Research & Experimental Medicine
GA CL1OD
UT WOS:000356712400001
PM 26171396
OA Green Published, gold, Green Submitted
DA 2025-03-13
ER

PT J
AU Krishnamachary, B
   Stasinopoulos, I
   Kakkad, S
   Penet, MF
   Jacob, D
   Wildes, F
   Mironchik, Y
   Pathak, AP
   Solaiyappan, M
   Bhujwalla, ZM
AF Krishnamachary, Balaji
   Stasinopoulos, Ioannis
   Kakkad, Samata
   Penet, Marie-France
   Jacob, Desmond
   Wildes, Flonne
   Mironchik, Yelena
   Pathak, Arvind P.
   Solaiyappan, Meiyappan
   Bhujwalla, Zaver M.
TI Breast cancer cell cyclooxygenase-2 expression alters extracellular
   matrix structure and function and numbers of cancer associated
   fibroblasts
SO ONCOTARGET
LA English
DT Article
DE COX-2; cancer associated fibroblasts; collagen 1 fibers; macromolecular
   transport; metastasis
ID TUMOR-GROWTH; COX-2 INHIBITION; COLLAGEN; ANGIOGENESIS;
   MICROENVIRONMENT; INFLAMMATION; PROGRESSION; SIDE
AB Cyclooxygenase-2 (COX-2) is a critically important mediator of inflammation that significantly influences tumor angiogenesis, invasion, and metastasis. We investigated the role of COX-2 expressed by triple negative breast cancer cells in altering the structure and function of the extracellular matrix (ECM). COX-2 downregulation effects on ECM structure and function were investigated using magnetic resonance imaging (MRI) and second harmonic generation (SHG) microscopy of tumors derived from triple negative MDA-MB-231 breast cancer cells, and a derived clone stably expressing a short hairpin (shRNA) molecule downregulating COX-2. MRI of albumin-GdDTPA was used to characterize macromolecular fluid transport in vivo and SHG microscopy was used to quantify collagen 1 (Col1) fiber morphology. COX-2 downregulation decreased Col1 fiber density and altered macromolecular fluid transport. Immunohistochemistry identified significantly fewer activated cancer associated fibroblasts (CAFs) in low COX2 expressing tumors. Metastatic lung nodules established by COX-2 downregulated cells were infrequent, smaller, and contained fewer Col1 fibers.
   COX-2 overexpression studies were performed with tumors derived from triple negative SUM-149 breast cancer cells lentivirally transduced to overexpress COX-2. SHG microscopy identified significantly higher Col1 fiber density in COX-2 overexpressing tumors with an increase of CAFs. These data expand upon the roles of COX-2 in shaping the structure and function of the ECM in primary and metastatic tumors, and identify the potential role of COX-2 in modifying the number of CAFs in tumors that may have contributed to the altered ECM.
C1 [Krishnamachary, Balaji; Stasinopoulos, Ioannis; Kakkad, Samata; Penet, Marie-France; Jacob, Desmond; Wildes, Flonne; Mironchik, Yelena; Pathak, Arvind P.; Solaiyappan, Meiyappan; Bhujwalla, Zaver M.] Russell H Morgan Dept Radiol & Radiol Sci, Div Canc Imaging Res, JHU ICMIC Program, Baltimore, MD 21205 USA.
   [Penet, Marie-France; Pathak, Arvind P.; Bhujwalla, Zaver M.] Johns Hopkins Univ Sch Med, Sidney Kimmel Comprehens Canc Ctr, Baltimore, MD 21205 USA.
C3 Johns Hopkins University; Johns Hopkins Medicine
RP Bhujwalla, ZM (corresponding author), Russell H Morgan Dept Radiol & Radiol Sci, Div Canc Imaging Res, JHU ICMIC Program, Baltimore, MD 21205 USA.; Bhujwalla, ZM (corresponding author), Johns Hopkins Univ Sch Med, Sidney Kimmel Comprehens Canc Ctr, Baltimore, MD 21205 USA.
EM zaver@mri.jhu.edu
RI Penet, Marie-France/AGZ-6991-2022; Kakkad, Samata/B-9266-2017
OI Kakkad, Samata/0000-0002-2959-8320; Solaiyappan,
   Meiyappan/0000-0002-2911-3936
FU NIH [R01CA82337, P50CA103175, R01CA136576, R01CA138515, R01CA73850,
   P30CA006973]
FX This work was supported by NIH R01CA82337, P50CA103175, R01CA136576,
   R01CA138515, R01CA73850, and P30CA006973.
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NR 48
TC 42
Z9 49
U1 0
U2 11
PU IMPACT JOURNALS LLC
PI ORCHARD PARK
PA 6666 E QUAKER ST, STE 1, ORCHARD PARK, NY 14127 USA
EI 1949-2553
J9 ONCOTARGET
JI Oncotarget
PD MAR 14
PY 2017
VL 8
IS 11
BP 17981
EP 17994
DI 10.18632/oncotarget.14912
PG 14
WC Oncology; Cell Biology
WE Science Citation Index Expanded (SCI-EXPANDED)
SC Oncology; Cell Biology
GA EO7NN
UT WOS:000396877500047
PM 28152501
OA Green Submitted, gold, Green Published
DA 2025-03-13
ER

PT J
AU Ding, MJ
   Dai, XY
   Liu, XJ
   Zhang, L
   Cui, GZ
   Geng, CZ
AF Ding, Ming-jian
   Dai, Xin-ya
   Liu, Xiao-jun
   Zhang, Liang
   Cui, Guo-zhong
   Geng, Cui-zhi
TI Curcumin Improves Chemotherapy Resistance in Breast Cancer Cells via
   Inhibiting the Secretion of FGF2/FGFR2 from Cancer-Associated
   Fibroblasts
SO JOURNAL OF BIOLOGICAL REGULATORS AND HOMEOSTATIC AGENTS
LA English
DT Article
DE breast cancer; curcumin; cancer-associated fibroblasts; paclitaxel;
   FGF2/FGFR2
ID EPITHELIAL-MESENCHYMAL TRANSITION; EXPRESSION
AB Background: Curcumin is an active ingredient isolated from the turmeric with anti -tumor activity. Cancer -associated fibroblasts (CAFs) can promote the development of chemical resistance in tumor cells. The present study aimed to explore the effect and molecular mechanism of curcumin on the chemosensitivity of breast cancer (BC). Methods: BC cell lines (MCF-7 and MDA-231) and paclitaxel (PTX)-resistant cell lines (MCF-7/PTX and MDA-231/PTX) were initially subjected to treatment with either curcumin or PTX. The cell proliferation and apoptosis rates were subsequently evaluated using Cell Counting Kit -8 (CCK-8) and flow cytometry. Western blotting was employed to evaluate the protein expression of fibroblast growth factor 2 (FGF2) and specific receptor-FGF receptor 2 (FGFR2). Because of the involvement of certain factors secreted by CAFs in chemotherapy resistance, the BC cells were exposed to a conditioned medium derived from CAFs (CAFsCM). Subsequently, the changes in PTX resistance were monitored following interventions with both CAFs-CM and curcumin. Results: Curcumin blocked the proliferation (p < 0.01) and promoted apoptosis in BC cells (p < 0.01). Moreover, it reduced the proliferation (p < 0.01) and augmented the apoptosis (p < 0.01) in MCF-7/PTX and MDA-231/PTX cells after PTX intervention by inhibiting the expression of FGF2 and FGFR2. CAFs-CM enhanced PTX resistance in BC cells, while the phenomenon was reversed by curcumin. Moreover, CAFs-CM induced an increase in FGF2 and FGFR2 protein expression in BC cells (p < 0.01), and this effect was eliminated after curcumin treatment (p < 0.01). Conclusions: Curcumin increases BC cell sensitivity to PTX by inhibiting the secretion of FGF2/FGFR2 from CAFs.
C1 [Ding, Ming-jian; Geng, Cui-zhi] Hebei Med Univ, Hosp 4, Breast Ctr, Shijiazhuang 050011, Hebei, Peoples R China.
   [Ding, Ming-jian; Liu, Xiao-jun; Zhang, Liang; Cui, Guo-zhong] Cangzhou Cent Hosp, Dept Thyroid & Mammary Surg, Cangzhou 061001, Hebei, Peoples R China.
   [Dai, Xin-ya] Cangzhou Cent Hosp, Dept Pharm, Cangzhou 061001, Hebei, Peoples R China.
C3 Hebei Medical University
RP Geng, CZ (corresponding author), Hebei Med Univ, Hosp 4, Breast Ctr, Shijiazhuang 050011, Hebei, Peoples R China.
EM gengcuizhisci@163.com
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NR 34
TC 1
Z9 1
U1 4
U2 7
PU BIOLIFE SAS
PI SILVA MARINA (TE)
PA VIA S STEFANO 39 BIS, 64029 SILVA MARINA (TE), ITALY
SN 0393-974X
EI 1724-6083
J9 J BIOL REG HOMEOS AG
JI J. Biol. Regul. Homeost. Agents
PD FEB
PY 2024
VL 38
IS 2
BP 1545
EP 1554
DI 10.23812/j.biol.regul.homeost.agents.20243802.123
PG 10
WC Endocrinology & Metabolism; Immunology; Medicine, Research &
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WE Science Citation Index Expanded (SCI-EXPANDED)
SC Endocrinology & Metabolism; Immunology; Research & Experimental
   Medicine; Physiology
GA HK1R0
UT WOS:001159308300001
DA 2025-03-13
ER

PT J
AU Dvoránková, B
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AF Dvorankova, B.
   Szabo, P.
   Lacina, L.
   Kodet, O.
   Matouskova, E.
   Smetana, K., Jr.
TI Fibroblasts prepared from different types of malignant tumors stimulate
   expression of luminal marker keratin 8 in the EM-G3 breast cancer cell
   line
SO HISTOCHEMISTRY AND CELL BIOLOGY
LA English
DT Article
DE Epithelial-mesenchymal interaction; Keratin 8; Keratin 14;
   Cancer-associated fibroblasts; Tumor stroma; Cancer microenvironment
ID STROMAL FIBROBLASTS; CARCINOMA; GROWTH; BASAL; PHENOTYPE
AB It is widely recognized that stromal fibroblasts significantly influence biological properties of multiple tumors including breast cancer. However, these epithelial-mesenchymal interactions seem to be essential in tumor biology and it is not fully clear whether this interaction is tumor type-specific or has a more general non-specific character. To elucidate this question, we tested the effect of cancer-associated fibroblasts (CAFs) isolated from different types of tumors (breast cancer skin metastasis, cutaneous basal cell carcinoma and melanoma, squamous cell carcinoma arising from oral cavity mucous membrane) on the EM-G3 breast cancer cell line. The results were compared with control experiments using normal human dermal fibroblasts, 3T3 mouse fibroblasts, and 3T3 fibroblasts influenced by the fibroblasts prepared from the basal cell carcinoma. Our results demonstrated that expression of luminal marker keratin 8 was influenced only by CAFs prepared from any tested tumors. In contrast, all tested types of fibroblasts showed a strong stimulatory effect on the expression of basal/myoepithelial marker keratin 14. The CAFs also elevated the number of cells with positivity for both keratins 8 and 14 that are similar to ductal originated precursor cells. The expression of proliferation marker Ki67 was not influenced by any of the tested fibroblasts. In conclusion, our data indicate that CAFs are able to influence the phenotype of a breast cancer cell line and this effect is based on a tumor type-unspecific mechanism. Finally, a clear functional difference between normal and CAFs was demonstrated.
C1 [Dvorankova, B.; Szabo, P.; Lacina, L.; Kodet, O.; Smetana, K., Jr.] Charles Univ Prague, Fac Med 1, Inst Anat, Nemocnice 3, Prague 12800 2, Czech Republic.
   [Lacina, L.; Kodet, O.] Charles Univ Prague, Fac Med 1, Dept Dermatovenereol, Prague 12800 2, Czech Republic.
   [Matouskova, E.] Charles Univ Prague, Fac Med 3, Dept Burns Med, Prague 12800 2, Czech Republic.
   [Matouskova, E.] Charles Univ Prague, Fac Med 1, Inst Biochem & Expt Oncol, Prague 12800 2, Czech Republic.
C3 Charles University Prague; Charles University Prague; Charles University
   Prague; Charles University Prague
RP Smetana, K (corresponding author), Charles Univ Prague, Fac Med 1, Inst Anat, Nemocnice 3, Prague 12800 2, Czech Republic.
EM karel.smetana@lf1.cuni.cz
RI Lacina, Lukas/C-1149-2017; Smetana, Jr., Karel/D-7039-2017; Szabo,
   Pavol/R-5197-2016; Kodet, Ondrej/A-1267-2017; Dvorankova,
   Barbora/R-2316-2016
OI Lacina, Lukas/0000-0002-1750-9933; Smetana, Jr.,
   Karel/0000-0002-7878-8403; Szabo, Pavol/0000-0002-1944-1493; Kodet,
   Ondrej/0000-0002-1382-2535; Dvorankova, Barbora/0000-0002-3914-9668
FU Grant Agency of the Czech Republic [304/12/1333]; Charles University of
   University Center of Excellence;  [260510]
FX This study was supported by grant No. 304/12/1333 from the Grant Agency
   of the Czech Republic and by the Charles University project of
   University Center of Excellence and for support of Specific University
   Research No. 260510. Authors are grateful to Iva Burdova, Radana
   Kavkova, and Vit Hajduch for excellent technical assistance and to Dr.
   Sarka Takacova for English revision.
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NR 22
TC 27
Z9 27
U1 0
U2 9
PU SPRINGER
PI NEW YORK
PA 233 SPRING ST, NEW YORK, NY 10013 USA
SN 0948-6143
J9 HISTOCHEM CELL BIOL
JI Histochem. Cell Biol.
PD MAY
PY 2012
VL 137
IS 5
BP 679
EP 685
DI 10.1007/s00418-012-0918-3
PG 7
WC Cell Biology; Microscopy
WE Science Citation Index Expanded (SCI-EXPANDED)
SC Cell Biology; Microscopy
GA 925GD
UT WOS:000302748000010
PM 22270320
DA 2025-03-13
ER

PT J
AU Al-Rakan, MA
   Hendrayani, SF
   Aboussekhra, A
AF Al-Rakan, Maha A.
   Hendrayani, Siti-Faujiah
   Aboussekhra, Abdelilah
TI <i>CHEK</i>2 represses breast stromal fibroblasts and their paracrine
   tumor-promoting effects through suppressing SDF-1 and IL-6
SO BMC CANCER
LA English
DT Article
DE Breast cancer; Cancer-associated fibroblasts; CHEK2; IL-6; SDF-1
ID CANCER-ASSOCIATED FIBROBLASTS; CHK2 KINASE; EXPRESSION;
   MICROENVIRONMENT; SUSCEPTIBILITY; SECRETION; RISK
AB Background: Active fibroblasts, the predominant and the most active cells of breast cancer stroma, are responsible for tumor growth and spread. However, the molecular mediators and pathways responsible for stromal fibroblast activation, and their paracrine pro-carcinogenic effects are still not well defined. The CHEK2 tumor suppressor gene codes for a protein kinase, which plays important roles in the cellular response to various genotoxic stresses.
   Methods: Immunoblotting, quantitative RT-PCR and Immunofluorescence were used to assess the expression of CHEK2 in different primary breast fibroblasts and in tissues. The effect of CHEK2 on the expression and secretion of SDF-1 and IL-6 was evaluated by immunoblotting and ELISA. The WST-1 colorimetric assay was used to assess cell proliferation, while the BD BioCoat Matrigel invasion chambers were utilized to determine the effects of CHEK2 on the migratory and the invasiveness capacities of breast stromal fibroblasts as well as breast cancer cells.
   Results: We have shown that CHEK2 is down-regulated in most cancer-associated fibroblasts (CAFs) as compared to their corresponding tumor counterpart fibroblasts (TCFs) at both the mRNA and protein levels. Interestingly, CHEK2 down-regulation using specific siRNA increased the expression/secretion of both cancer-promoting cytokines SDF-1 and IL-6, and transdifferentiated stromal fibroblasts to myofibroblasts. These cells were able to enhance the proliferation of non-cancerous epithelial cells, and also boosted the migration/invasion abilities of breast cancer cells in a paracrine manner. The later effect was SDF-1/IL-6-dependent. Importantly, ectopic expression of CHEK2 in active CAFs converted these cells to a normal state, with lower migration/invasion capacities and reduced paracrine pro-carcinogenic effects.
   Conclusion: These results indicate that CHEK2 possesses non-cell-autonomous tumor suppressor functions, and present the Chk2 protein as an important mediator in the functional interplay between breast carcinomas and their stromal fibroblasts.
C1 [Al-Rakan, Maha A.; Hendrayani, Siti-Faujiah; Aboussekhra, Abdelilah] King Saud Univ, Dept Clin Lab Sci, Coll Appl Med Sci, Riyadh 11211, Saudi Arabia.
   [Al-Rakan, Maha A.; Hendrayani, Siti-Faujiah; Aboussekhra, Abdelilah] King Faisal Specialist Hosp & Res Ctr, Dept Mol Oncol, MBC 03,POB 3354, Riyadh 11211, Saudi Arabia.
C3 King Saud University; King Faisal Specialist Hospital & Research Center
RP Aboussekhra, A (corresponding author), King Saud Univ, Dept Clin Lab Sci, Coll Appl Med Sci, Riyadh 11211, Saudi Arabia.; Aboussekhra, A (corresponding author), King Faisal Specialist Hosp & Res Ctr, Dept Mol Oncol, MBC 03,POB 3354, Riyadh 11211, Saudi Arabia.
EM aboussekhra@kfshrc.edu.sa
RI Aboussekhra, Abdelilah/JCD-8138-2023
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NR 24
TC 8
Z9 8
U1 0
U2 3
PU BIOMED CENTRAL LTD
PI LONDON
PA 236 GRAYS INN RD, FLOOR 6, LONDON WC1X 8HL, ENGLAND
SN 1471-2407
J9 BMC CANCER
JI BMC Cancer
PD AUG 2
PY 2016
VL 16
AR 575
DI 10.1186/s12885-016-2614-5
PG 10
WC Oncology
WE Science Citation Index Expanded (SCI-EXPANDED)
SC Oncology
GA DT1BL
UT WOS:000381216600009
PM 27484185
OA Green Published, gold
DA 2025-03-13
ER

PT J
AU Aghakhani, S
   Silva-Saffar, SE
   Soliman, S
   Niarakis, A
AF Aghakhani, Sahar
   Silva-Saffar, Sacha E.
   Soliman, Sylvain
   Niarakis, Anna
TI Hybrid computational modeling highlights reverse warburg effect in
   breast cancer-associated fibroblasts
SO COMPUTATIONAL AND STRUCTURAL BIOTECHNOLOGY JOURNAL
LA English
DT Article
DE Hybrid modeling; Metabolic reprogramming; Breast cancer;
   Cancer-associated fibroblasts
ID GROWTH-FACTOR; CELLS; PROMOTER
AB Cancer-associated fibroblasts (CAFs) are amongst the key players of the tumor microenvironment (TME) and are involved in cancer initiation, progression, and resistance to therapy. They exhibit aggressive phenotypes affecting extracellular matrix remodeling, angiogenesis, immune system modulation, tumor growth, and proliferation. CAFs phenotypic changes appear to be associated with metabolic alterations, notably a reverse Warburg effect that may drive fibroblasts transformation. However, its precise molecular mechanisms and regulatory drivers are still under investigation. Deciphering the reverse Warburg effect in breast CAFs may contribute to a better understanding of the interplay between TME and tumor cells, leading to new treatment strategies. In this regard, dynamic modeling approaches able to span multiple biological layers are essential to capture the emergent properties of various biological entities when complex and intertwined pathways are involved. This work presents the first hybrid large-scale computational model for breast CAFs covering major cellular signaling, gene regulation, and metabolic processes. It was generated by combining a cell-and disease-specific asynchronous Boolean model with a generic core metabolic network leveraging both data-driven and manual curation approaches. This model reproduces the experimentally observed reverse Warburg effect in breast CAFs and further identifies Hypoxia-Inducible Factor 1 (HIF-1) as its key molecular driver. Targeting HIF-1 as part of a TME-centered therapeutic strategy may prove beneficial in the treatment of breast cancer by addressing the reverse Warburg effect. Such findings in CAFs, in light of our previously published results in rheumatoid arthritis synovial fibroblasts, point to a common HIF-1-driven metabolic reprogramming of fibro-blasts in breast cancer and rheumatoid arthritis.
C1 [Aghakhani, Sahar; Silva-Saffar, Sacha E.; Niarakis, Anna] Univ Paris Saclay, Univ Evry, GenHotel European Res Lab Rheumatoid Arthrit, Evry, France.
   [Aghakhani, Sahar; Soliman, Sylvain; Niarakis, Anna] Lifeware Grp, Inria Saclay Ile Defrance, Palaiseau, France.
C3 Universite Paris Saclay
RP Niarakis, A (corresponding author), Univ Paris Saclay, Univ Evry, GenHotel European Res Lab Rheumatoid Arthrit, Evry, France.
EM anna.niarakis@inria.fr
RI Niarakis, Anna/AAB-1389-2021; Soliman, Sylvain/B-7445-2009
OI Niarakis, Anna/0000-0002-9687-7426; Soliman,
   Sylvain/0000-0001-5525-7418; Aghakhani, Sahar/0000-0002-6392-4687
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NR 74
TC 4
Z9 4
U1 0
U2 4
PU ELSEVIER
PI AMSTERDAM
PA RADARWEG 29, 1043 NX AMSTERDAM, NETHERLANDS
SN 2001-0370
J9 COMPUT STRUCT BIOTEC
JI Comp. Struct. Biotechnol. J..
PY 2023
VL 21
BP 4196
EP 4206
DI 10.1016/j.csbj.2023.08.015
EA AUG 2023
PG 11
WC Biochemistry & Molecular Biology; Biotechnology & Applied Microbiology
WE Science Citation Index Expanded (SCI-EXPANDED)
SC Biochemistry & Molecular Biology; Biotechnology & Applied Microbiology
GA S8CY0
UT WOS:001073403500001
PM 37705596
OA Green Submitted, Green Published, gold
DA 2025-03-13
ER

PT J
AU Liu, L
   Liu, SC
   Luo, HJ
   Chen, CX
   Zhang, XL
   He, L
   Tu, G
AF Liu, Li
   Liu, Shengchun
   Luo, Haojun
   Chen, Chenxi
   Zhang, Xiaoling
   He, Lin
   Tu, Gang
TI GPR30-mediated HMGB1 upregulation in CAFs induces autophagy and
   tamoxifen resistance in ERα-positive breast cancer cells
SO AGING-US
LA English
DT Article
DE G-protein-coupled estrogen receptor; HMGB1; tamoxifen resistance;
   cancer-associated fibroblast; autophagy
ID ESTROGEN-RECEPTOR; ADJUVANT TAMOXIFEN; CROSS-TALK; GPER; FIBROBLASTS;
   EXPRESSION; PROGRESSION; GROWTH; PROLIFERATION; GPR30
AB Tamoxifen (TAM) resistance constitutes a challenge in managing estrogen receptor (ER)alpha+ breast cancer patients. G-protein-coupled estrogen receptor (GPR30/GPER), which reportedly initiates TAM resistance in ER alpha+/ GPR30+ breast cancers, is detected in the breast cancer microenvironment, especially cancer associated fibroblasts (CAFs). Herein, considering that GPR30 mediates transcriptional regulation in different cell backgrounds, a microarray strategy was applied in immortalized CAFs derived from primary breast cancer samples, resulting in the identification of 165 GPR30 target genes, among which HMGB1 was confirmed to be upregulated by 17-beta estradiol(E2)- and TAM-triggered GPR30 activation in CAFs. Activated GPR30 increased extracellular HMGB1 secretion by CAFs, which was reduced by blocking PI3K/AKT signaling using G15 or LY294002. GPR30-induced HMGB1 upregulation triggered MEK/ERK signaling, leading to increased autophagic behavior to protect cancer cells from TAM-induced apoptosis, mimicking the recombinant HMGB1-mediated increase in cancer cell resistance potential to TAM. MEK/ERK signaling blockage by U0126 decreased the autophagic behavior and resistance ability of cancer cells to TAM. CAF-expressed GPR30 induced TAM resistance via HMGB1 in vivo. Overall, TAM upregulated HMGB1 expression and secretion in CAFs via GPR30/PI3K/AKT signaling, and the secreted HMGB1 induced autophagy to enhance TAM resistance in MCF-7 cells in an ERK-dependent manner. Thus, targeting GPR30 and downstream cascades may be an effective strategy to attenuate the resistance of ER alpha-positive breast tumors to endocrine therapy.
C1 [Liu, Li; Liu, Shengchun; He, Lin; Tu, Gang] Chongqing Med Univ, Dept Endocrine & Breast Surg, Affiliated Hosp 1, Chongqing 400016, Peoples R China.
   [Luo, Haojun] Chongqing Med Univ, Dept Breast & Thyroid Surg, Affiliated Hosp 2, Chongqing 400010, Peoples R China.
   [Chen, Chenxi] Chongqing Med Univ, Dept Geriatr, Affiliated Hosp 1, Chongqing 400016, Peoples R China.
   [Zhang, Xiaoling] Maternal & Child Care Ctr Serv Kaizhou, Chongqing 405400, Peoples R China.
C3 Chongqing Medical University; Chongqing Medical University; Chongqing
   Medical University
RP Tu, G (corresponding author), Chongqing Med Univ, Dept Endocrine & Breast Surg, Affiliated Hosp 1, Chongqing 400016, Peoples R China.
EM tugang@cqmu.edu.cn
RI Chen, Chenxi/JXN-5581-2024
OI li, lu/0009-0009-8381-3093; liu, shengchun/0000-0002-9933-3643
FU National Natural Science Foundation of China [30872520, 81372398]
FX This work was supported by The National Natural Science Foundation of
   China (Grant. No 30872520, and 81372398) .
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NR 48
TC 40
Z9 46
U1 3
U2 26
PU IMPACT JOURNALS LLC
PI ORCHARD PARK
PA 6666 E QUAKER ST, STE 1, ORCHARD PARK, NY 14127 USA
SN 1945-4589
J9 AGING-US
JI Aging-US
PD JUN 30
PY 2021
VL 13
IS 12
BP 16178
EP 16197
PG 20
WC Cell Biology; Geriatrics & Gerontology
WE Science Citation Index Expanded (SCI-EXPANDED)
SC Cell Biology; Geriatrics & Gerontology
GA TD0CL
UT WOS:000669004100006
PM 34182538
OA Green Published, gold
DA 2025-03-13
ER

PT J
AU Xie, JD
   Zheng, SQ
   Zou, YT
   Tang, YH
   Tian, WW
   Wong, CW
   Wu, S
   Ou, XQ
   Zhao, WZ
   Cai, MB
   Xie, XM
AF Xie, Jindong
   Zheng, Shaoquan
   Zou, Yutian
   Tang, Yuhui
   Tian, Wenwen
   Wong, Chau-Wei
   Wu, Song
   Ou, Xueqi
   Zhao, Wanzhen
   Cai, Manbo
   Xie, Xiaoming
TI Turning up a new pattern: Identification of cancer-associated
   fibroblast-related clusters in TNBC
SO FRONTIERS IN IMMUNOLOGY
LA English
DT Article
DE triple-negative breast cancer; cancer-associated fibroblasts; tumor
   microenvironment; machine learning; prognostic model
ID IMMUNOTHERAPY; EXPRESSION
AB Growing evidence indicates a connection between cancer-associated fibroblasts (CAFs) and tumor microenvironment (TME) remodeling and tumor progression. Nevertheless, how patterns of CAFs impact TME and immunotherapy responsiveness in triple-negative breast cancer (TNBC) remains unclear. Here, we systematically investigate the relationship between TNBC progression and patterns of CAFs. By using unsupervised clustering methods in the Molecular Taxonomy of Breast Cancer International Consortium (METABRIC) dataset, we identified two distinct CAF-associated clusters that were related to clinical features, characteristics of TME, and prognosis of patients. Then, we established a CAF-related prognosis index (CPI) by the least absolute shrinkage and selection operator (LASSO)-Cox regression method. CPI showed prognostic accuracy in both training and validation cohorts (METABRIC, GSE96058, and GSE21653). Consequently, we constructed a nomogram with great predictive performance. Moreover, the CPI was verified to be correlated with the responsiveness of immunotherapy in three independent cohorts (GSE91061, GSE165252, and GSE173839). Taken together, the CPI might help us improve our recognition of the TME of TNBC, predict the prognosis of TNBC patients, and offer more immunotherapy strategies in the future.
C1 [Xie, Jindong; Zou, Yutian; Tang, Yuhui; Tian, Wenwen; Wong, Chau-Wei; Wu, Song; Ou, Xueqi; Xie, Xiaoming] Sun Yat Sen Univ, Canc Ctr, Collaborat Innovat Ctr Canc Med, Dept Breast Oncol,State Key Lab Oncol South China, Guangzhou, Peoples R China.
   [Zheng, Shaoquan] Sun Yat Sen Univ, Affiliated Hosp 1, Breast Dis Ctr, Guangzhou, Peoples R China.
   [Zhao, Wanzhen; Cai, Manbo] Univ South China, Affiliated Hosp 1, Hengyang Med Sch, Dept Radiotherapy, Hengyang, Hunan, Peoples R China.
C3 Sun Yat Sen University; State Key Lab Oncology South China; Sun Yat Sen
   University; University of South China
RP Xie, XM (corresponding author), Sun Yat Sen Univ, Canc Ctr, Collaborat Innovat Ctr Canc Med, Dept Breast Oncol,State Key Lab Oncol South China, Guangzhou, Peoples R China.; Cai, MB (corresponding author), Univ South China, Affiliated Hosp 1, Hengyang Med Sch, Dept Radiotherapy, Hengyang, Hunan, Peoples R China.
EM caimanbo@nhfyyy.com; xiexm@sysucc.org.cn
RI Tang, Yuhui/IWU-4174-2023; Xie, Jindong/AGL-8633-2022; Zheng,
   Shaoquan/GOK-1936-2022; Zou, Yutian/AAB-2820-2022
OI Zou, Yutian/0000-0002-5205-9923; Tang, Yuhui/0009-0001-2181-4068; Zheng,
   Shaoquan/0000-0003-1912-0216; Xie, Jindong/0000-0002-2482-7358
FU National Natural Science Foundation of China;  [81872152]
FX Funding This research was funded by the National Natural Science
   Foundation of China (81872152, XX).
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NR 43
TC 31
Z9 31
U1 1
U2 15
PU FRONTIERS MEDIA SA
PI LAUSANNE
PA AVENUE DU TRIBUNAL FEDERAL 34, LAUSANNE, CH-1015, SWITZERLAND
SN 1664-3224
J9 FRONT IMMUNOL
JI Front. Immunol.
PD OCT 6
PY 2022
VL 13
AR 1022147
DI 10.3389/fimmu.2022.1022147
PG 14
WC Immunology
WE Science Citation Index Expanded (SCI-EXPANDED)
SC Immunology
GA 5Q2BK
UT WOS:000873642100001
PM 36275659
OA Green Published, gold
DA 2025-03-13
ER

PT J
AU Drews-Elger, K
   Brinkman, JA
   Miller, P
   Shah, SH
   Harrell, JC
   da Silva, TG
   Ao, Z
   Schlater, A
   Azzam, DJ
   Diehl, K
   Thomas, D
   Slingerland, JM
   Perou, CM
   Lippman, ME
   El-Ashry, D
AF Drews-Elger, Katherine
   Brinkman, Joeli A.
   Miller, Philip
   Shah, Sanket H.
   Harrell, J. Chuck
   da Silva, Thiago G.
   Ao, Zheng
   Schlater, Amy
   Azzam, Diana J.
   Diehl, Kathleen
   Thomas, Dafydd
   Slingerland, Joyce M.
   Perou, Charles M.
   Lippman, Marc E.
   El-Ashry, Dorraya
TI Primary breast tumor-derived cellular models: characterization of
   tumorigenic, metastatic, and cancer-associated fibroblasts in
   dissociated tumor (DT) cultures
SO BREAST CANCER RESEARCH AND TREATMENT
LA English
DT Article
DE Primary cultures; Tumors; ER-negative breast cancer; Metastatic
   xenograft models
ID EPITHELIAL-MESENCHYMAL TRANSITION; STROMAL FIBROBLASTS; MOLECULAR
   PORTRAITS; MOUSE MODELS; CELLS; LINES; CARCINOMA; ANGIOGENESIS;
   PHENOTYPE; RECEPTOR
AB Our goal was to establish primary cultures from dissociation of breast tumors in order to provide cellular models that may better recapitulate breast cancer pathogenesis and the metastatic process. Here, we report the characterization of six cellular models derived from the dissociation of primary breast tumor specimens, referred to as "dissociated tumor (DT) cells." In vitro, DT cells were characterized by proliferation assays, colony formation assays, protein, and gene expression profiling, including PAM50 predictor analysis. In vivo, tumorigenic and metastatic potential of DT cultures was assessed in NOD/SCID and NSG mice. These cellular models differ from recently developed patient-derived xenograft models in that they can be used for both in vitro and in vivo studies. PAM50 predictor analysis showed DT cultures similar to their paired primary tumor and as belonging to the basal and Her2-enriched subtypes. In vivo, three DT cultures are tumorigenic in NOD/SCID and NSG mice, and one of these is metastatic to lymph nodes and lung after orthotopic inoculation into the mammary fat pad, without excision of the primary tumor. Three DT cultures comprised of cancer-associated fibroblasts (CAFs) were isolated from luminal A, Her2-enriched, and basal primary tumors. Among the DT cells are those that are tumorigenic and metastatic in immunosuppressed mice, offering novel cellular models of ER-negative breast cancer subtypes. A group of CAFs provide tumor subtype-specific components of the tumor microenvironment (TME). Altogether, these DT cultures provide closer-to-primary cellular models for the study of breast cancer pathogenesis, metastasis, and TME.
C1 [Drews-Elger, Katherine; Brinkman, Joeli A.; Miller, Philip; Shah, Sanket H.; da Silva, Thiago G.; Ao, Zheng; Azzam, Diana J.; Slingerland, Joyce M.; Lippman, Marc E.; El-Ashry, Dorraya] Univ Miami, Miller Sch Med, Sylvester Comprehens Canc Ctr, Dept Med, Miami, FL 33136 USA.
   [Miller, Philip; Shah, Sanket H.] Univ Miami, Miller Sch Med, Sheila & David Fuente Grad Program Canc Biol, Miami, FL 33136 USA.
   [Harrell, J. Chuck; Perou, Charles M.] Univ N Carolina, Dept Genet, Chapel Hill, NC 27599 USA.
   [da Silva, Thiago G.] Univ Miami, Miller Sch Med, Dept Surg, Miami, FL 33136 USA.
   [Schlater, Amy] Univ Michigan, Div Hematol Oncol, Dept Internal Med, Med Ctr, Ann Arbor, MI 48109 USA.
   [Diehl, Kathleen] Univ Michigan, Dept Surg, Med Ctr, Ann Arbor, MI 48109 USA.
   [Thomas, Dafydd] Univ Michigan, Dept Pathol, Med Ctr, Ann Arbor, MI 48109 USA.
C3 University of Miami; University of Miami; University of North Carolina;
   University of North Carolina Chapel Hill; University of Miami;
   University of Michigan System; University of Michigan; University of
   Michigan System; University of Michigan; University of Michigan System;
   University of Michigan
RP El-Ashry, D (corresponding author), Univ Miami, Miller Sch Med, Sylvester Comprehens Canc Ctr, Dept Med, Biomed Res Bldg,1501 NW 10th Ave, Miami, FL 33136 USA.
EM del-ashry@med.miami.edu
RI Thomas, Dafydd/KRP-5768-2024; Shah, Sanket/I-1665-2019; ao,
   zheng/A-7890-2018; Azzam, Diana/ABB-8342-2021; Perou,
   Charles/H-9934-2014
OI Harrell, J. Chuck/0000-0003-3541-8418; Azzam, Diana/0000-0002-2605-8855;
   Drews-Elger, Katherine/0000-0001-9540-0610; Perou,
   Charles/0000-0001-9827-2247
FU NIH [1R01 CA113674]; Bankhead Coley Cancer Research Program Pre SPORE
   Grant [09BW-04]; National Cancer Institute [T32CA119929]; BCRF funds
FX This project was supported by the NIH Grant 1R01 CA113674 and The
   Bankhead Coley Cancer Research Program Pre SPORE Grant 09BW-04 to DEA.
   Award Number T32CA119929 from the National Cancer Institute supported
   KDE. The content is solely the responsibility of the authors and does
   not necessarily represent the official views of the National Cancer
   Institute or the National Institute of Health. This project was also
   supported by the BCRF funds to MEL. The authors would like to thank Ms.
   Sonja Dean and Dr. Ayse Burcu Ergonul (University of Miami) and Dr.
   James Rae (University of Michigan) for valuable discussions.
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NR 60
TC 30
Z9 35
U1 0
U2 13
PU SPRINGER
PI NEW YORK
PA ONE NEW YORK PLAZA, SUITE 4600, NEW YORK, NY, UNITED STATES
SN 0167-6806
EI 1573-7217
J9 BREAST CANCER RES TR
JI Breast Cancer Res. Treat.
PD APR
PY 2014
VL 144
IS 3
BP 503
EP 517
DI 10.1007/s10549-014-2887-9
PG 15
WC Oncology
WE Science Citation Index Expanded (SCI-EXPANDED)
SC Oncology
GA AD6IF
UT WOS:000333360700005
PM 24567196
DA 2025-03-13
ER

PT J
AU Latocha, M
   Plonka, J
   Kusmierz, D
   Jurzak, M
   Polaniak, R
   Nowosad, A
AF Latocha, Malgorzata
   Plonka, Justyna
   Kusmierz, Dariusz
   Jurzak, Magdalena
   Polaniak, Renata
   Nowosad, Ada
TI TRANSCRIPIONAL ACTIVITY OF GENES ENCODING MMPs AND TIMPs IN BREAST
   CANCER CELLS TREATED BY GENISTEIN AND IN NORMAL CANCER -ASSOCIATED
   FIBROBLASTS - <i>IN VITRO</i> STUDIES
SO ACTA POLONIAE PHARMACEUTICA
LA English
DT Article
DE genistein; matrix metalloproteinases (MMPs); tissue inhibitors of
   metalloproteinases (TIMPs)
ID PROLIFERATION; ANGIOGENESIS; METASTASIS; EXPRESSION; APOPTOSIS; EXTRACT
C1 [Latocha, Malgorzata; Plonka, Justyna; Kusmierz, Dariusz; Nowosad, Ada] Med Univ Silesia, Sch Pharm, Div Lab Med, Dept Cell Biol, Jednosci 8, PL-41200 Sosnowiec, Poland.
   [Jurzak, Magdalena] Med Univ Silesia, Sch Pharm, Div Lab Med, Dept Cosmetol, PL-41200 Sosnowiec, Poland.
   [Polaniak, Renata] Med Univ Silesia, Sch Publ Hlth, Dept Nutr, PL-41808 Zabrze, Poland.
C3 Medical University Silesia; Medical University Silesia; Medical
   University Silesia
RP Latocha, M (corresponding author), Med Univ Silesia, Sch Pharm, Div Lab Med, Dept Cell Biol, Jednosci 8, PL-41200 Sosnowiec, Poland.
EM mlatocha@sutn.edu.pl
RI Nowosad, Ada/ABA-3024-2021
OI Nowosad, Ada/0000-0001-5008-7552
FU Medical University of Silesia in Katowice (Poland) [KNW-1-023/K/3/0]
FX This work was supported by grant KNW-1-023/K/3/0 from the Medical
   University of Silesia in Katowice (Poland).
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NR 29
TC 11
Z9 13
U1 0
U2 1
PU POLSKIE TOWARZYSTWO FARMACEUTYCZNE
PI WARSAW
PA DLUGA 16, 00-238 WARSAW, POLAND
SN 0001-6837
J9 ACTA POL PHARM
JI ACTA POL. PHARM.
PD NOV-DEC
PY 2014
VL 71
IS 6
BP 1095
EP 1102
PG 8
WC Pharmacology & Pharmacy
WE Science Citation Index Expanded (SCI-EXPANDED)
SC Pharmacology & Pharmacy
GA V46QS
UT WOS:000209899300028
PM 25745786
DA 2025-03-13
ER

PT J
AU Wan, XY
   Guan, SD
   Hou, YX
   Qin, YL
   Zeng, H
   Yang, LP
   Qiao, YN
   Liu, SQ
   Li, Q
   Jin, T
   Qiu, YX
   Liu, MR
AF Wan, Xueying
   Guan, Shengdong
   Hou, Yixuan
   Qin, Yilu
   Zeng, Huan
   Yang, Liping
   Qiao, Yina
   Liu, Shuiqing
   Li, Qiao
   Jin, Ting
   Qiu, Yuxiang
   Liu, Manran
TI FOSL2 promotes VEGF-independent angiogenesis by transcriptionnally
   activating Wnt5a in breast cancer-associated fibroblasts
SO THERANOSTICS
LA English
DT Article
DE cancer-associated fibroblasts; FOSL2; Wnt5a; VEGF-independent
   angiogenesis
AB Cancer-associated fibroblasts (CAFs), a predominant component of the tumor microenvironment, contribute to aggressive angiogenesis progression. In clinical practice, traditional anti-angiogenic therapy, mainly anti-VEGF, provides extremely limited beneficial effects to breast cancer. Here, we reveal that FOS-like 2 (FOSL2), a transcription factor in breast CAFs, plays a critical role in VEGF-independent angiogenesis in stromal fibroblasts.
   Methods: FOSL2 and Wnt5a expression was assessed by qRT-PCR, western blotting and immunohistochemistry in primary and immortalized CAFs and clinical samples. FOSL2- or Wnt5a-silenced CAFs and FOSL2-overexpressing NFs were established to explore their proangiogenic effects. Invasion, tubule formation, three-dimensional sprouting assays, and orthotopic xenografts were conducted as angiogenesis experiments. FZD5/NF-kappa B/ERK signaling activation was evaluated by western blotting after blocking VEGF/VEGFR with an anti-VEGF antibody and axitinib. Dual luciferase reporter assays and chromatin immunoprecipitation were performed to test the role of FOSL2 in regulating Wnt5a expression, and Wnt5a in the serum of the patients was measured to assess its clinical diagnostic value for breast cancer patients.
   Results: Enhanced FOSL2 in breast CAFs was significantly associated with angiogenesis and clinical progression in patients. The supernatant from CAFs highly expressing FOSL2 strongly promoted tube formation and sprouting of human umbilical vein endothelial cells (HUVECs) in a VEGF-independent manner and angiogenesis as well as tumor growth in vivo. Mechanistically, the enhanced FOSL2 in CAFs was regulated by estrogen/cAMP/PKA signaling. Wnt5a, a direct target of FOSL2, specifically activated FZD5/NF-kappa B/ERK signaling in HUVECs to promote VEGF-independent angiogenesis. In addition, a high level of Wnt5a was commonly detected in the serum of breast cancer patients and closely correlated with microvessel density in breast tumor tissues, suggesting a promising clinical value of Wnt5a for breast cancer diagnostics.
   Conclusion: FOSL2/Wnt5a signaling plays an essential role in breast cancer angiogenesis in a VEGF-independent manner, and targeting the FOSL2/Wnt5a signaling axis in CAFs may offer a potential option for antiangiogenesis therapy.
C1 [Wan, Xueying; Guan, Shengdong; Qin, Yilu; Zeng, Huan; Yang, Liping; Qiao, Yina; Liu, Shuiqing; Li, Qiao; Jin, Ting; Qiu, Yuxiang; Liu, Manran] Chongqing Med Univ, Key Lab Lab Med Diagnost, Chinese Minist Educ, 1 Yi Xue Yuan Rd, Chongqing 400016, Peoples R China.
   [Hou, Yixuan] Chongqing Med Univ, Expt Teaching Ctr Basic Med Sci, Chongqing 400016, Peoples R China.
C3 Chongqing Medical University; Chongqing Medical University
RP Liu, MR (corresponding author), Chongqing Med Univ, Key Lab Lab Med Diagnost, Chinese Minist Educ, 1 Yi Xue Yuan Rd, Chongqing 400016, Peoples R China.
EM manranliu@cqmu.edu.cn
RI Qiu, Yuxiang/LBB-2192-2024; YANG, LiPing/IST-6327-2023
FU National Natural Science Foundation of China (NSFC) [81773078, 81402180,
   31671481]; Chongqing Graduate Research and Innovation Project of the
   Chongqing Education Committee [CYS18204]; outstanding Postgraduate Fund
   of Chongqing Medical University (2018)
FX This work was supported in part by National Natural Science Foundation
   of China (NSFC 81773078, and NSFC 81402180) for Yixuan Hou; and partly
   supported by National Natural Science Foundation of China (NSFC
   31671481) for Manran Liu. And also supported in part by Chongqing
   Graduate Research and Innovation Project of the Chongqing Education
   Committee (2018) (CYS18204) and the outstanding Postgraduate Fund of
   Chongqing Medical University (2018) for Xueying Wan.
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PU IVYSPRING INT PUBL
PI LAKE HAVEN
PA PO BOX 4546, LAKE HAVEN, NSW 2263, AUSTRALIA
SN 1838-7640
J9 THERANOSTICS
JI Theranostics
PY 2021
VL 11
IS 10
BP 4975
EP 4991
DI 10.7150/thno.55074
PG 17
WC Medicine, Research & Experimental
WE Science Citation Index Expanded (SCI-EXPANDED)
SC Research & Experimental Medicine
GA QX0RP
UT WOS:000629058400026
PM 33754039
OA Green Published, gold
DA 2025-03-13
ER

PT J
AU Lawal, B
   Wu, ATH
   Chen, CH
   George, TA
   Wu, SY
AF Lawal, Bashir
   Wu, Alexander T. H.
   Chen, Chien-Hsin
   George, T. A.
   Wu, Szu-Yuan
TI Identification of INFG/STAT1/NOTCH3 as γ-Mangostin's potential targets
   for overcoming doxorubicin resistance and reducing cancer-associated
   fibroblasts in triple-negative breast cancer
SO BIOMEDICINE & PHARMACOTHERAPY
LA English
DT Article
DE Triple-negative breast cancer (TNBC); Cancer stem cells (CSCs); Gamma
   mangostin (gMG); Cancer-associated fibroblasts (CAFs); IFNG; STAT1;
   NOTCH signaling
ID GARCINIA-MANGOSTANA; STAT1; FRUIT
AB Triple-negative breast cancer (TNBC) is a very aggressive subtype of breast cancer characterized by drug resis-tance and distant metastasis. Cancer stem cells (CSCs) are considered a major contributor to TNBC's drug resistance. Thus targeting and eliminating CSCs have been vigorously researched. However, the precise target -able molecular networks responsible for CSC genesis remain unclear; this conundrum is mainly due to the high heterogeneity of the TNBC tumor microenvironment (TME). The cancer-associated fibroblasts (CAFs) are one of the most abundant cellular components of the TME. Emerging studies indicate that CAFs facilitate TNBC's progression by establishing a pro-tumor TME. Hence, identifying the molecular networks involved in CAF transformation and CAF-associated oncogenesis are essential areas to be explored. Through a bioinformatics approach, we identified INFG/STAT1/NOTCH3 as a molecular link between CSCs and CAF. DOX-resistant TNBC cell lines showed increased expression of INFG/STAT1/NOTCH3 and CD44 and were associated with increased self-renewal ability and CAF-transformative ability. Downregulation of STAT1 significantly reduced the tumorigenic properties of MDA-MB-231 and-468 cells and their CAF-transforming potential. Our molecular docking analysis suggested that gamma mangostin (gMG), a xanthone, formed complexes with INFG/STAT1/ NOTCH3 better than celecoxib. We then demonstrated that gMG treatment reduced the tumorigenic properties similarly observed in STAT1-knocked down conditions. Finally, we utilized a DOX-resistant TNBC tumoroid-bearing mouse model to demonstrate that gMG treatment significantly delayed tumor growth, reduced CAF generation, and improved DOX sensitivity. Further investigations are warranted for clinical translation.
C1 [Lawal, Bashir] Univ Pittsburgh, UPMC Hillman Canc Ctr, Pittsburgh, PA USA.
   [Lawal, Bashir] Univ Pittsburgh, Dept Pathol, Pittsburgh, PA USA.
   [Wu, Alexander T. H.] Taipei Med Univ, TMU Res Ctr Canc Translat Med, Taipei 11031, Taiwan.
   [Wu, Alexander T. H.] Taipei Med Univ, Coll Med Sci & Technol, PhD Program Translat Med, Taipei 11031, Taiwan.
   [Wu, Alexander T. H.] Taipei Med Univ, Taipei Med Univ Hosp, Clin Res Ctr, Taipei 11031, Taiwan.
   [Wu, Alexander T. H.] Natl Def Med Ctr, Grad Inst Med Sci, Taipei 114, Taiwan.
   [Chen, Chien-Hsin] Taipei Med Univ, Coll Med, Dept Surg, Taipei 11031, Taiwan.
   [Chen, Chien-Hsin] Taipei Med Univ, Wan Fang Hosp, Dept Colorectal Surg, Taipei 11031, Taiwan.
   [George, T. A.] Univ Sierra Leone, Coll Med & Allied Hlth Sci, Freetown, Sierra Leone.
   [Wu, Szu-Yuan] Asia Univ, Coll Med & Hlth Sci, Dept Food Nutr & Hlth Biotechnol, Taichung, Taiwan.
   [Wu, Szu-Yuan] Asia Univ, Coll Med & Hlth Sci, Dept Healthcare Adm, Taichung, Taiwan.
   [Wu, Szu-Yuan] Fu Jen Catholic Univ, Grad Inst Business Adm, Coll Management, Taipei, Taiwan.
   [Wu, Szu-Yuan] Fu Jen Catholic Univ, Artificial Intelligence Dev Ctr, Taipei, Taiwan.
   [Wu, Szu-Yuan] Taipei Med Univ, Wan Fang Hosp, Ctr Reg Anaesthesia & Pain Med, Taipei, Taiwan.
   [Wu, Szu-Yuan] Lo Hsu Med Fdn, Lotung Poh Ai Hosp, Big Data Ctr, Yilan, Taiwan.
   [Wu, Szu-Yuan] Lo Hsu Med Fdn, Lotung Poh Ai Hosp, Div Radiat Oncol, Yilan, Taiwan.
C3 Pennsylvania Commonwealth System of Higher Education (PCSHE); University
   of Pittsburgh; Pennsylvania Commonwealth System of Higher Education
   (PCSHE); University of Pittsburgh; Taipei Medical University; Taipei
   Medical University; Taipei Medical University; Taipei Medical University
   Hospital; National Defense Medical Center; Taipei Medical University;
   Taipei Municipal WanFang Hospital; Taipei Medical University; Asia
   University Taiwan; Asia University Taiwan; Fu Jen Catholic University;
   Fu Jen Catholic University; Taipei Medical University; Taipei Municipal
   WanFang Hospital
RP Wu, SY (corresponding author), Asia Univ, Coll Med & Hlth Sci, Dept Healthcare Adm, Taichung, Taiwan.
EM Szu.Yuan.Wu.md@gmail.com
RI Lawal, Bashir/X-3358-2018; Wu, Shawn/J-8611-2014; Wu,
   Alexander/AAD-8826-2022
FU Hillman Postdoctoral Fellowship for Innovative Cancer Research award;
   National Science and Technology Council [111-2314-B-038-098,
   111-2314-B-038-142]; National Sci- ence and Technology Council
   [111-2314-B-468-004]
FX Bashir Lawal is supported by the Hillman Postdoctoral Fellowship for
   Innovative Cancer Research award. Alexander TH Wu is supported by the
   National Science and Technology Council (111-2314-B-038-098 and
   111-2314-B-038-142) . Szu-Yuan Wu is also supported by National Sci-
   ence and Technology Council (111-2314-B-468-004) . We express our
   sincere gratitude to Mr. Po-Yang Huang for his invaluable technical
   support during the in vivo experiments.
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NR 46
TC 13
Z9 14
U1 1
U2 6
PU ELSEVIER FRANCE-EDITIONS SCIENTIFIQUES MEDICALES ELSEVIER
PI ISSY-LES-MOULINEAUX
PA 65 RUE CAMILLE DESMOULINS, CS50083, 92442 ISSY-LES-MOULINEAUX, FRANCE
SN 0753-3322
EI 1950-6007
J9 BIOMED PHARMACOTHER
JI Biomed. Pharmacother.
PD JUL
PY 2023
VL 163
AR 114800
DI 10.1016/j.biopha.2023.114800
EA MAY 2023
PG 12
WC Medicine, Research & Experimental; Pharmacology & Pharmacy
WE Science Citation Index Expanded (SCI-EXPANDED)
SC Research & Experimental Medicine; Pharmacology & Pharmacy
GA G9QN6
UT WOS:000992416400001
PM 37141739
OA gold
DA 2025-03-13
ER

PT J
AU Tanaka, Y
   Ohno, T
   Kadonaga, T
   Kidokoro, Y
   Wakahara, M
   Nosaka, K
   Sakabe, T
   Suzuki, Y
   Nakamura, H
   Umekita, Y
AF Tanaka, Yuko
   Ohno, Takashi
   Kadonaga, Taichi
   Kidokoro, Yoshiteru
   Wakahara, Makoto
   Nosaka, Kanae
   Sakabe, Tomohiko
   Suzuki, Yoshimasa
   Nakamura, Hiroshige
   Umekita, Yoshihisa
TI Podoplanin expression in cancer-associated fibroblasts predicts
   unfavorable prognosis in node-negative breast cancer patients with
   hormone receptor-positive/HER2-negative subtype
SO BREAST CANCER
LA English
DT Article
DE Podoplanin; Breast cancer; Immunohistochemistry
ID POOR-PROGNOSIS
AB Background Podoplanin expression in cancer-associated fibroblasts (CAFs) has been proposed as an indicator for poor prognosis in patients with invasive breast carcinomas, but little is known about its clinical significance in node-negative breast cancer patients with hormone receptor (HR) + /HER2 - subtype, who are expected to have a favorable prognosis. Methods Immunohistochemical analyses were performed on 169 resected specimens of node-negative invasive carcinoma of no special type with HR + /HER2 - subtype using antibodies for podoplanin. When more than 10% of CAFs showed immunoreactivity with podoplanin as strong as that of internal positive controls, the specimens were judged as podoplanin-positive. Results Podoplanin-positive status in CAFs was observed in 16.0% (27 of 169 cases) and it associated with high Ki67 labeling index (LI) (> 30%) (p = 0.03), higher stromal tumor-infiltrating lymphocytes (p < 0.001) and progesterone receptor-negative status (p = 0.045). Log-rank test showed that podoplanin-positive status in CAFs correlated with shorter disease-free survival (DFS) (p = 0.007) and disease-specific survival (DSS) (p < 0.001). Univariate analysis showed a significant correlation between shorter DFS and podoplanin-positive status in CAFs (hazard ratio [HR] = 3.380; p = 0.012), the presence of lymphatic invasion (HR = 5.621; p < 0.001), high Ki67 LI (HR = 5.217; p < 0.001), and histological grade III (HR = 3.748; p = 0.008). According to Cox multivariate analysis, podoplanin-positive status in CAFs had the most significant effect on shorter DSS (HR = 37.759; p = 0.003) followed by high Ki67LI (HR = 27.664; p = 0.007). Conclusion Podoplanin expression in CAFs could be an independent predictor for poor prognosis in node-negative breast cancer patients with HR + /HER2 - subtype.
C1 [Tanaka, Yuko; Kadonaga, Taichi; Nosaka, Kanae; Sakabe, Tomohiko; Umekita, Yoshihisa] Tottori Univ, Dept Pathol, Fac Med, 86 Nishicho, Yonago, Tottori 6838503, Japan.
   [Tanaka, Yuko; Ohno, Takashi; Kadonaga, Taichi; Kidokoro, Yoshiteru; Wakahara, Makoto; Suzuki, Yoshimasa; Nakamura, Hiroshige] Tottori Univ, Div Gen Thorac Surg & Breast & Endocrine Surg, Dept Surg, Fac Med, Tottori, Japan.
C3 Tottori University; Tottori University
RP Umekita, Y (corresponding author), Tottori Univ, Dept Pathol, Fac Med, 86 Nishicho, Yonago, Tottori 6838503, Japan.
EM yume@tottori-u.ac.jp
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NR 21
TC 12
Z9 12
U1 0
U2 9
PU SPRINGER JAPAN KK
PI TOKYO
PA SHIROYAMA TRUST TOWER 5F, 4-3-1 TORANOMON, MINATO-KU, TOKYO, 105-6005,
   JAPAN
SN 1340-6868
EI 1880-4233
J9 BREAST CANCER-TOKYO
JI Breast Cancer
PD JUL
PY 2021
VL 28
IS 4
BP 822
EP 828
DI 10.1007/s12282-021-01217-0
EA JAN 2021
PG 7
WC Oncology; Obstetrics & Gynecology
WE Science Citation Index Expanded (SCI-EXPANDED)
SC Oncology; Obstetrics & Gynecology
GA SU7YS
UT WOS:000609944500001
PM 33481184
DA 2025-03-13
ER

PT J
AU Goliwas, KF
   Libring, S
   Berestesky, E
   Gholizadeh, S
   Schwager, SC
   Frost, AR
   Gaborski, TR
   Zhang, J
   Reinhart-King, CA
AF Goliwas, Kayla F.
   Libring, Sarah
   Berestesky, Emily
   Gholizadeh, Shayan
   Schwager, Samantha C.
   Frost, Andra R.
   Gaborski, Thomas R.
   Zhang, Jian
   Reinhart-King, Cynthia A.
TI Mitochondrial transfer from cancer-associated fibroblasts increases
   migration in aggressive breast cancer
SO JOURNAL OF CELL SCIENCE
LA English
DT Article
DE Reverse Warburg effect; CAF; Tunneling nanotube; Tumor microenvironment;
   Bioenergetics; Tumor spheroid; ATP production
ID CELL-MIGRATION; INTERCELLULAR TRANSFER; TUNNELING NANOTUBES; METASTASIS;
   INVASION; METABOLISM; SWITCH
AB Cancer-associated fibroblasts (CAFs) have distinct roles within the tumor microenvironment, which can impact the mode and efficacy of tumor cell migration. CAFs are known to increase invasion of less aggressive breast cancer cells through matrix remodeling and leader- follower dynamics. Here, we demonstrate that CAFs communicate with breast cancer cells through the formation of contact-dependent tunneling nanotubes (TNTs), which allow for the exchange of cargo between cell types. CAF mitochondria are an integral cargo component and are sufficient to increase the 3D migration of cancer cells. This cargo transfer results in an increase in mitochondrial ATP production in cancer cells, whereas it has a negligible impact on glycolytic ATP production. Manually increasing mitochondrial oxidative phosphorylation (OXPHOS) by providing extra substrates for OXPHOS fails to enhance cancer cell migration unless glycolysis is maintained at a constant level. Together, these data indicate that tumor-stromal cell crosstalk via TNTs and the associated metabolic symbiosis is a finely controlled mechanism by which tumor cells co-opt their microenvironment to promote cancer progression and may become a potential therapeutic target.
C1 [Goliwas, Kayla F.; Libring, Sarah; Berestesky, Emily; Schwager, Samantha C.; Zhang, Jian; Reinhart-King, Cynthia A.] Vanderbilt Univ, Dept Biomed Engn, Nashville, TN 37235 USA.
   [Gholizadeh, Shayan; Gaborski, Thomas R.] Rochester Inst Alabama Birmingham, Dept Biomed Engn, Birmingham, AL 35233 USA.
   [Frost, Andra R.] Univ Alabama Birmingham, Dept Pathol, Birmingham, AL 35233 USA.
   [Zhang, Jian] Univ Arkansas, Dept Biomed Engn, Fayetteville, AR 72701 USA.
   [Goliwas, Kayla F.] Univ Alabama Birmingham, Dept Med, Birmingham, AL 35233 USA.
C3 Vanderbilt University; University of Alabama System; University of
   Alabama Birmingham; University of Arkansas System; University of
   Arkansas Fayetteville; University of Alabama System; University of
   Alabama Birmingham
RP Zhang, J; Reinhart-King, CA (corresponding author), Vanderbilt Univ, Dept Biomed Engn, Nashville, TN 37235 USA.; Zhang, J (corresponding author), Univ Arkansas, Dept Biomed Engn, Fayetteville, AR 72701 USA.
EM jianz@uark.edu; cynthia.reinhart-king@vanderbilt.edu
RI Zhang, Jian/AAP-8929-2020; Gholizadeh, Shayan/JEP-6024-2023; Libring,
   Sarah/ABA-7683-2020; Reinhart-King, Cynthia/A-9264-2016
OI Libring, Sarah/0000-0001-8336-5862; Reinhart-King,
   Cynthia/0000-0001-6959-3914; Gholizadeh, Shayan/0000-0001-5534-460X;
   Berestesky, Emily/0009-0005-2826-1266; Zhang, Jian/0000-0003-2887-6082;
   Gaborski, Thomas/0000-0002-3676-3208
FU National Science Foundation; National Institutes of Health (NSF-NIH)
   Physical and Engineering Sciences in Oncology (PESO) program [1740900];
   NIH [HL127499, GM131178]; National Cancer Institute [CA264734];
   Vanderbilt University
FX & nbsp;This work was supported by funding from the National Science
   Foundation and National Institutes of Health (NSF-NIH) Physical and
   Engineering Sciences in Oncology (PESO) program (award number 1740900)
   and NIH grants HL127499 and GM131178 to C.A.R.-K. and by the National
   Cancer Institute, grant CA264734, to S.L. Open access funding provided
   by Vanderbilt University. Deposited in PMC for immediate release.
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NR 66
TC 16
Z9 16
U1 4
U2 14
PU COMPANY BIOLOGISTS LTD
PI CAMBRIDGE
PA BIDDER BUILDING, STATION RD, HISTON, CAMBRIDGE CB24 9LF, ENGLAND
SN 0021-9533
EI 1477-9137
J9 J CELL SCI
JI J. Cell Sci.
PD JUL
PY 2023
VL 136
IS 14
AR jcs260419
DI 10.1242/jcs.260419
PG 16
WC Cell Biology
WE Science Citation Index Expanded (SCI-EXPANDED)
SC Cell Biology
GA P4FZ2
UT WOS:001050232800001
PM 37358264
OA Green Published, hybrid
DA 2025-03-13
ER

PT J
AU Jabbari, K
   Cheng, QS
   Winkelmaier, G
   Furuta, S
   Parvin, B
AF Jabbari, Kosar
   Cheng, Qingsu
   Winkelmaier, Garrett
   Furuta, Saori
   Parvin, Bahram
TI CD36<SUP>+</SUP> Fibroblasts Secrete Protein Ligands That
   Growth-Suppress Triple-Negative Breast Cancer Cells While Elevating
   Adipogenic Markers for a Model of Cancer-Associated Fibroblast
SO INTERNATIONAL JOURNAL OF MOLECULAR SCIENCES
LA English
DT Article
DE CD36(+) fibroblasts; tumor suppression; cancer-associated fibroblasts;
   stromal reprogramming
ID FACTOR RECEPTOR AXIS; EXPRESSION; OVEREXPRESSION; PROENKEPHALIN;
   CHEMOTHERAPY; INHIBITION; FIBULIN-1; SLIT2
AB Tumor and stroma coevolve to facilitate tumor growth. Hence, effective tumor therapeutics would not only induce growth suppression of tumor cells but also revert pro-tumor stroma into anti-tumoral type. Previously, we showed that coculturing triple-negative or luminal A breast cancer cells with CD36(+) fibroblasts (FBs) in a three-dimensional extracellular matrix induced their growth suppression or phenotypic reversion, respectively. Then, we identified SLIT3, FBLN-1, and PENK as active protein ligands secreted from CD36(+) FBs that induced growth suppression of MDA-MB-231 breast cancer cells and determined their minimum effective concentrations. Here, we have expanded our analyses to include additional triple-negative cancer cell lines, BT549 and Hs578T, as well as HCC1937 carrying a BRCA1 mutation. We show that the ectopic addition of each of the three ligands to cancer-associated fibroblasts (CAFs) elevates the expression of CD36, as well as the adipogenic marker FABP4. Lastly, we show that an agonist antibody for one of the PENK receptors induces growth suppression of all cancer cell lines tested but not for non-transformed MCF10A cells. These results clearly suggest that proteins secreted from CD36(+) FBs induce not only growth suppression of tumor cells through binding the cognate receptors but also increasing adipogenic markers of CAFs to reprogram tumor stroma.
C1 [Jabbari, Kosar; Cheng, Qingsu; Winkelmaier, Garrett; Parvin, Bahram] Univ Nevada, Dept BioMed Engn, Reno, NV 89557 USA.
   [Cheng, Qingsu] Univ Wisconsin Milwaukee, Dept BioMed Engn, Milwaukee, WI 53211 USA.
   [Furuta, Saori] Univ Toledo Hlth Sci Campus, Dept Canc Biol, Toledo, OH 43614 USA.
   [Parvin, Bahram] Renown Hlth, Pennington Canc Inst, Reno, NV 89502 USA.
C3 Nevada System of Higher Education (NSHE); University of Nevada Reno;
   University of Wisconsin System; University of Wisconsin Milwaukee;
   University System of Ohio; University of Toledo; University of Toledo
   Health Science Campus
RP Parvin, B (corresponding author), Univ Nevada, Dept BioMed Engn, Reno, NV 89557 USA.; Parvin, B (corresponding author), Renown Hlth, Pennington Canc Inst, Reno, NV 89502 USA.
EM bparvin@unr.edu
RI ; Furuta, Saori/P-9677-2018
OI Parvin, Bahram/0000-0002-6433-8006; Cheng, Qingsu/0000-0001-6127-4046;
   Furuta, Saori/0000-0003-1121-0487
FU Pennington Foundation; NIH [1R15CA23543]; PI's startup funds; National
   Cancer Institute [R01CA248304] Funding Source: NIH RePORTER
FX This research was supported in part by PI's startup funds, Pennington
   Foundation, and NIH grant no. 1R15CA23543.
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NR 51
TC 5
Z9 6
U1 0
U2 3
PU MDPI
PI BASEL
PA MDPI AG, Grosspeteranlage 5, CH-4052 BASEL, SWITZERLAND
SN 1661-6596
EI 1422-0067
J9 INT J MOL SCI
JI Int. J. Mol. Sci.
PD NOV
PY 2022
VL 23
IS 21
AR 12744
DI 10.3390/ijms232112744
PG 11
WC Biochemistry & Molecular Biology; Chemistry, Multidisciplinary
WE Science Citation Index Expanded (SCI-EXPANDED)
SC Biochemistry & Molecular Biology; Chemistry
GA 6C8TC
UT WOS:000882278200001
PM 36361532
OA Green Published, gold
DA 2025-03-13
ER

PT J
AU Jin, XY
   Chen, Y
   Wang, G
AF Jin, Xiaoyan
   Chen, Yong
   Wang, Gui
TI Cancer-associated fibroblasts affect breast cancer cell sensitivity to
   chemotherapeutic agents by regulating NRBP2
SO TOXICOLOGY RESEARCH
LA English
DT Article
DE Breast cancer (BC); Cancer-associated fibroblasts (CAFs); Nuclear
   receptor-binding protein 2 (NRBP2); TAM; Akt pathway
ID PATHWAY
AB Objective To uncover the role of nuclear receptor-binding protein 2 (NRBP2) in cancer-associated fibroblasts (CAFs), and CAFmediated TAM sensitivity in breast cancer (BC).Methods 10 pairs of matched tumor tissues and adjacent normal tissues were collected and CAFs and normal fibroblasts (NFs) were isolated. CCK-8 as well as colony formation assays showed the effects on cell growth. qPCR and Immunoblot showed the expression of NRBP2 in CAFs. FCM as well as Immunoblot assays exhibited the effects on cell apoptosis. Immunoblot further confirmed the mechanism.Results CAFs contributed to BC cell growth. In addition, the expression of NRBP2 is downregulated in CAFs. NRBP2 suppressed CAF-induced resistance in BC cells. Further, NRBP2 expression in CAF group increased TAM induced apoptosis. Mechanically, NRBP2 in CAFs inhibited Akt pathway, therefore suppressed resistance in BC cells.Conclusion CAFs affected BC cell sensitivity to TAM by regulating NRBP2.
C1 [Jin, Xiaoyan; Chen, Yong] Taizhou Municipal Hosp, Dept Surg Oncol, 381 Zhongshan East Rd, Taizhou 318000, Zhejiang, Peoples R China.
   [Wang, Gui] Longquan Peoples Hosp, Dept Gen Surg, 699 Dongcha Rd, Lishui 323700, Zhejiang, Peoples R China.
C3 Taizhou University
RP Wang, G (corresponding author), Longquan Peoples Hosp, Dept Gen Surg, 699 Dongcha Rd, Lishui 323700, Zhejiang, Peoples R China.
EM jinxiaoyanangel@163.com; 31947188@qq.com; b1818207@zju.edu.cn
FU Zhejiang Provincial Public Service and Application Research Foundation,
   China [LGF20H280008]; Technology Research Projects of the Science
   Technology Department of Taizhou City [20ywa38]; Technology Research
   Projects of the Science Technology Department of Taizhou City [23ywb62]
FX This work was supported by the Zhejiang Provincial Public Service and
   Application Research Foundation, China (Grant No. LGF20H280008),
   Technology Research Projects of the Science Technology Department of
   Taizhou City (Grant No. 20ywa38) and Technology Research Projects of the
   Science Technology Department of Taizhou City (Grant No. 23ywb62).
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NR 24
TC 0
Z9 0
U1 3
U2 3
PU OXFORD UNIV PRESS
PI OXFORD
PA GREAT CLARENDON ST, OXFORD OX2 6DP, ENGLAND
SN 2045-452X
EI 2045-4538
J9 TOXICOL RES-UK
JI Toxicol. Res.
PD DEC 8
PY 2024
VL 13
IS 6
AR tfae204
DI 10.1093/toxres/tfae204
PG 9
WC Toxicology
WE Science Citation Index Expanded (SCI-EXPANDED)
SC Toxicology
GA O8J2X
UT WOS:001373517800001
PM 39664500
DA 2025-03-13
ER

PT J
AU Meng, MY
   Wang, WJ
   Yan, J
   Tan, J
   Liao, LW
   Shi, JL
   Wei, CY
   Xie, YH
   Jin, XF
   Yang, L
   Jin, Q
   Zhu, HR
   Tan, WW
   Yang, F
   Hou, ZL
AF Meng, Mingyao
   Wang, Wenju
   Yan, Jun
   Tan, Jing
   Liao, Liwei
   Shi, Jianlin
   Wei, Chuanyu
   Xie, Yanhua
   Jin, Xingfang
   Yang, Li
   Jin, Qing
   Zhu, Huirong
   Tan, Weiwei
   Yang, Fang
   Hou, Zongliu
TI Immunization of stromal cell targeting fibroblast activation protein
   providing immunotherapy to breast cancer mouse model
SO TUMOR BIOLOGY
LA English
DT Article
DE Fibroblast activation protein; Cancer-associated fibroblast;
   Immunotherapy; Tumor microenvironment; Breast cancer model
ID TUMOR-ASSOCIATED FIBROBLASTS; MICROENVIRONMENTAL REGULATION;
   DOWN-REGULATION; METASTASIS; GROWTH; ANGIOGENESIS; IMMUNOSURVEILLANCE;
   SUPPRESSION; PROGRESSION; CARCINOMA
AB Unlike heterogeneous tumor cells, cancer-associated fibroblasts (CAF) are genetically more stable which serve as a reliable target for tumor immunotherapy. Fibroblast activation protein (FAP) which is restrictively expressed in tumor cells and CAF in vivo and plays a prominent role in tumor initiation, progression, and metastasis can function as a tumor rejection antigen. In the current study, we have constructed artificial FAP(+) stromal cells which mimicked the FAP(+) CAF in vivo. We immunized a breast cancer mouse model with FAP(+) stromal cells to perform immunotherapy against FAP(+) cells in the tumor microenvironment. By forced expression of FAP, we have obtained FAP(+) stromal cells whose phenotype was CD11b(+)/CD34(+)/Sca-1(+)/FSP-1(+)/MHC class I+. Interestingly, proliferation capacity of the fibroblasts was significantly enhanced by FAP. In the breast cancer-bearing mouse model, vaccination with FAP(+) stromal cells has significantly inhibited the growth of allograft tumor and reduced lung metastasis indeed. Depletion of T cell assays has suggested that both CD4(+) and CD8(+) T cells were involved in the tumor cytotoxic immune response. Furthermore, tumor tissue from FAP-immunized mice revealed that targeting FAP(+) CAF has induced apoptosis and decreased collagen type I and CD31 expression in the tumor microenvironment. These results implicated that immunization with FAP(+) stromal cells led to the disruption of the tumor microenvironment. Our study may provide a novel strategy for immunotherapy of a broad range of cancer.
C1 [Meng, Mingyao; Wang, Wenju; Yan, Jun; Tan, Jing; Liao, Liwei; Shi, Jianlin; Wei, Chuanyu; Xie, Yanhua; Jin, Xingfang; Yang, Li; Jin, Qing; Zhu, Huirong; Tan, Weiwei; Yang, Fang; Hou, Zongliu] Kunming Med Univ, Dept Cent Lab, Yanan Affiliated Hosp, 245 East Renmin Rd, Kunming 650051, Yunnan, Peoples R China.
   [Meng, Mingyao; Wang, Wenju; Shi, Jianlin; Wei, Chuanyu; Xie, Yanhua; Jin, Xingfang; Tan, Weiwei; Yang, Fang; Hou, Zongliu] Yunnan Cell Biol & Clin Translat Res Ctr, Kunming 650051, Yunnan, Peoples R China.
   [Yang, Fang] Kunming Med Univ, Kunming 650050, Yunnan, Peoples R China.
C3 Kunming Medical University; Kunming Medical University
RP Yang, F; Hou, ZL (corresponding author), Kunming Med Univ, Dept Cent Lab, Yanan Affiliated Hosp, 245 East Renmin Rd, Kunming 650051, Yunnan, Peoples R China.; Yang, F; Hou, ZL (corresponding author), Yunnan Cell Biol & Clin Translat Res Ctr, Kunming 650051, Yunnan, Peoples R China.; Yang, F (corresponding author), Kunming Med Univ, Kunming 650050, Yunnan, Peoples R China.
EM yangfangkm@126.com; hzl579@163.com
RI Wang, Wenju/E-4437-2012; Tan, Weiwei/HZI-1642-2023
FU National Natural Science Foundation of China [81160267, 81360245,
   81460436]; Yunnan Province Science and Technology Department and Kunming
   Medical University [2013FB110, 2015FA008]; Yunnan Province Science and
   Technology Department [2015IA034]
FX This work is supported by grants from the National Natural Science
   Foundation of China (nos. 81160267, 81360245, and 81460436) and grants
   from the "Special and Joint Program" of Yunnan Province Science and
   Technology Department and Kunming Medical University (nos. 2013FB110 and
   2015FA008). This study is also funded by "International Collaboration
   Program" from Yunnan Province Science and Technology Department
   (2015IA034).
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NR 35
TC 21
Z9 21
U1 1
U2 35
PU SAGE PUBLICATIONS LTD
PI LONDON
PA 1 OLIVERS YARD, 55 CITY ROAD, LONDON EC1Y 1SP, ENGLAND
SN 1010-4283
EI 1423-0380
J9 TUMOR BIOL
JI Tumor Biol.
PD AUG
PY 2016
VL 37
IS 8
BP 10317
EP 10327
DI 10.1007/s13277-016-4825-4
PG 11
WC Oncology
WE Science Citation Index Expanded (SCI-EXPANDED)
SC Oncology
GA DV1HW
UT WOS:000382672900031
PM 26842926
DA 2025-03-13
ER

PT J
AU Wang, D
   Wu, JL
   Qi, CP
   Dong, JP
   Ding, XY
   Yu, GH
   Liu, SZ
   Zhang, B
   Gao, ZQ
   Wei, XH
   Liu, HY
AF Wang, Di
   Wu, Jingliang
   Qi, Cuiping
   Dong, Jinping
   Ding, Xueying
   Yu, Guohua
   Liu, Shuzhen
   Zhang, Bo
   Gao, Zhiqin
   Wei, Xiuhong
   Liu, Hongying
TI pH-responsive Sulfated Hyaluronic Acid Nanoparticles Targeting Tumor
   Cells and CAFs for the Treatment of Breast Cancer
SO RECENT PATENTS ON ANTI-CANCER DRUG DISCOVERY
LA English
DT Article
DE Breast cancer; delivery; nanoparticles; combination; fibroblast; CAFs
ID ANTICANCER DRUG; OVARIAN-CANCER; DELIVERY; CHEMOTHERAPY; MICELLES;
   DOXORUBICIN
AB Background: Tumor metastasis is a main cause of death in patients with breast cancer. The cross-talk between cancer-associated fibroblasts (CAFs) and tumor cells plays an important role in promoting tumor invasion and metastasis. It is important to develop a novel delivery system to inhibit tumor development by simultaneously targeting both CAFs and tumor cells. Objectives: The main objective of this research was to prepare nanoparticles to inhibit tumor proliferation and migration by blocking the cross-talk of tumor-CAFs. Additionally, a novel "MCF-7+NIH/3T3" mixed cell model was established to mimic the tumor microenvironment (TME). Methods: In this study, the pH-responsive nanoparticles (MIF/DOX-sul-HA NPs) based on sulfated hyaluronic acid (sul-HA) polymers were prepared for co-delivery of doxorubicin (DOX) and mifepristone (MIF). The effects of anti-proliferation and anti-metastasis of MIF/DOX-sul-HA NPs were investigated both in vitro and in vivo. Results: The results showed that MIF/DOX-sul-HA NPs were nearly spherical in shape with narrow particle size distribution and pH-responsive drug release, and could be taken up by both MCF-7 and NIH/3T3 cells. Compared with MCF-7 cells alone, the anti-tumor effect of single DOX was weak in the "MCF-7+NIH/3T3" mixed cell model. MIF/DOX-sul-HA NPs exhibited strong effects of anti-proliferation and anti-metastasis than the free single drug. Conclusion: The sul-HA nanoparticles for co-delivery of DOX and MIF could be a promising combined therapy strategy for the treatment of breast cancer.
C1 [Wang, Di; Qi, Cuiping; Ding, Xueying; Wei, Xiuhong] Weifang Med Univ, Sch Nursing, Weifang 261053, Peoples R China.
   [Wang, Di; Wu, Jingliang; Dong, Jinping] Weifang Univ Sci & Technol, Sch Nursing, Weifang 262700, Peoples R China.
   [Yu, Guohua; Liu, Shuzhen] Weifang Peoples Hosp, Dept Oncol, Weifang 261000, Peoples R China.
   [Gao, Zhiqin; Liu, Hongying] Weifang Med Univ, Sch Life Sci & Technol, Weifang 261053, Peoples R China.
   [Zhang, Bo] Weifang Med Univ, Sch Pharm, Weifang 261053, Peoples R China.
C3 Shandong Second Medical University; Weifang University of Science &
   Technology; Shandong Second Medical University; Shandong Second Medical
   University
RP Wei, XH (corresponding author), Weifang Med Univ, Sch Nursing, Weifang 261053, Peoples R China.; Liu, HY (corresponding author), Weifang Med Univ, Sch Life Sci & Technol, Weifang 261053, Peoples R China.
EM hongyingwf@163.com; hongyingwf@163.com
RI Jinping, Dong/HDN-0142-2022
OI Wu, Jingliang/0000-0001-6962-2842
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NR 58
TC 5
Z9 5
U1 1
U2 19
PU BENTHAM SCIENCE PUBL LTD
PI SHARJAH
PA EXECUTIVE STE Y-2, PO BOX 7917, SAIF ZONE, 1200 BR SHARJAH, U ARAB
   EMIRATES
SN 1574-8928
EI 2212-3970
J9 RECENT PAT ANTI-CANC
JI Recent Patents Anti-Canc. Drug Discov.
PY 2023
VL 18
IS 2
BP 200
EP 210
DI 10.2174/1574892817666220510123820
PG 11
WC Oncology; Pharmacology & Pharmacy
WE Science Citation Index Expanded (SCI-EXPANDED)
SC Oncology; Pharmacology & Pharmacy
GA 8X7IR
UT WOS:000932183900010
PM 35538821
DA 2025-03-13
ER

PT J
AU Pelon, F
   Bourachot, B
   Kieffer, Y
   Magagna, I
   Mermet-Meillon, F
   Bonnet, I
   Costa, A
   Givel, AM
   Attieh, Y
   Barbazan, J
   Bonneau, C
   Fuhrmann, L
   Descroix, S
   Vignjevic, D
   Silberzan, P
   Parrini, MC
   Vincent-Salomon, A
   Mechta-Grigoriou, F
AF Pelon, Floriane
   Bourachot, Brigitte
   Kieffer, Yann
   Magagna, Ilaria
   Mermet-Meillon, Fanny
   Bonnet, Isabelle
   Costa, Ana
   Givel, Anne-Marie
   Attieh, Youmna
   Barbazan, Jorge
   Bonneau, Claire
   Fuhrmann, Laetitia
   Descroix, Stephanie
   Vignjevic, Danijela
   Silberzan, Pascal
   Parrini, Maria Carla
   Vincent-Salomon, Anne
   Mechta-Grigoriou, Fatima
TI Cancer-associated fibroblast heterogeneity in axillary lymph nodes
   drives metastases in breast cancer through complementary mechanisms
SO NATURE COMMUNICATIONS
LA English
DT Article
ID STROMAL FIBROBLASTS; TUMOR-GROWTH; CELLS; INVASION; MICROENVIRONMENT;
   ACTIVATION; MYOFIBROBLASTS; METABOLISM; TRANSITION; EXPRESSION
AB Although fibroblast heterogeneity is recognized in primary tumors, both its characterization in and its impact on metastases remain unknown. Here, combining flow cytometry, immunohistochemistry and RNA-sequencing on breast cancer samples, we identify four Cancer-Associated Fibroblast (CAF) subpopulations in metastatic lymph nodes (LN). Two myofibroblastic subsets, CAF-S1 and CAF-S4, accumulate in LN and correlate with cancer cell invasion. By developing functional assays on primary cultures, we demonstrate that these subsets promote metastasis through distinct functions. While CAF-S1 stimulate cancer cell migration and initiate an epithelial-to-mesenchymal transition through CXCL12 and TGF beta pathways, highly contractile CAF-S4 induce cancer cell invasion in 3-dimensions via NOTCH signaling. Patients with high levels of CAFs, particularly CAF-S4, in LN at diagnosis are prone to develop late distant metastases. Our findings suggest that CAF subset accumulation in LN is a prognostic marker, suggesting that CAF subsets could be examined in axillary LN at diagnosis.
C1 [Pelon, Floriane; Bourachot, Brigitte; Kieffer, Yann; Magagna, Ilaria; Costa, Ana; Givel, Anne-Marie; Bonneau, Claire; Mechta-Grigoriou, Fatima] PSL Res Univ, Stress & Canc Lab, Equipe Labelisee Ligue Natl Canc, Inst Curie, 26 Rue Ulm, F-75005 Paris, France.
   [Pelon, Floriane; Bourachot, Brigitte; Kieffer, Yann; Magagna, Ilaria; Costa, Ana; Givel, Anne-Marie; Bonneau, Claire; Mechta-Grigoriou, Fatima] INSERM, U830, 26 Rue Ulm, F-75005 Paris, France.
   [Mermet-Meillon, Fanny; Parrini, Maria Carla] PSL Res Univ, Anal Transduct Pathway, Inst Curie, Inserm,U830, 26 Rue Ulm, F-75005 Paris, France.
   [Bonnet, Isabelle; Silberzan, Pascal] Sorbonne Univ, Biol Inspired Phys MesoScales Lab, Equipe Labelisee Ligue Natl Canc, Inst Curie,CNRS,UMR168,PSL Res Univ, 26 Rue Ulm, F-75005 Paris, France.
   [Attieh, Youmna; Barbazan, Jorge; Vignjevic, Danijela] PSL Res Univ, Inst Curie, Cell Migrat & Invas, UMR144, 26 Rue Ulm, F-75005 Paris, France.
   [Fuhrmann, Laetitia; Vincent-Salomon, Anne] Inst Curie Hosp, Dept Pathol, 26 Rue Ulm, F-75248 Paris, France.
   [Descroix, Stephanie] Inst Pierre Gilles de Gennes, Lab Physicochim Curie, Inst Curie, CNRS,UMR168, F-75005 Paris, France.
C3 UNICANCER; Universite PSL; Institut Curie; Universite PSL; UNICANCER;
   Institut Curie; Institut National de la Sante et de la Recherche
   Medicale (Inserm); Universite PSL; UNICANCER; Institut Curie; Institut
   National de la Sante et de la Recherche Medicale (Inserm); Universite
   PSL; UNICANCER; Institut Curie; Centre National de la Recherche
   Scientifique (CNRS); Sorbonne Universite; CNRS - Institute of Chemistry
   (INC); Sorbonne Universite; Centre National de la Recherche Scientifique
   (CNRS); CNRS - National Institute for Biology (INSB); Universite PSL;
   UNICANCER; Institut Curie; UNICANCER; Universite PSL; Institut Curie;
   Centre National de la Recherche Scientifique (CNRS); CNRS - Institute of
   Chemistry (INC); Universite PSL; UNICANCER; Institut Curie; Sorbonne
   Universite
RP Mechta-Grigoriou, F (corresponding author), PSL Res Univ, Stress & Canc Lab, Equipe Labelisee Ligue Natl Canc, Inst Curie, 26 Rue Ulm, F-75005 Paris, France.; Mechta-Grigoriou, F (corresponding author), INSERM, U830, 26 Rue Ulm, F-75005 Paris, France.
EM fatima.mechta-grigoriou@curie.fr
RI Parrini, Maria/J-5390-2016; Vignjevic, Danijela/L-9721-2017; DESCROIX,
   Stephanie/AAN-8875-2021; Bonnet, Isabelle/JVZ-6507-2024; Barbazán,
   Jorge/AAM-3263-2020; Bonneau, Claire/GON-5289-2022; Mechta-Grigoriou,
   Fatima/C-5253-2017; silberzan, pascal/L-5934-2016
OI Bourachot, Brigitte/0000-0001-7816-0539; Mechta-Grigoriou,
   Fatima/0000-0002-3751-6989; Costa, Ana/0000-0002-0893-3388; KIEFFER,
   Yann/0000-0003-2722-3071; Mermet-Meillon, Fanny/0000-0002-5114-2354;
   Magagna, Ilaria/0000-0003-4092-5457; Atieh, Youmna/0000-0003-1110-4991;
   Barbazan, Jorge/0000-0002-7165-8497; silberzan,
   pascal/0000-0002-8554-882X; claire, bonneau/0000-0001-6251-286X; Matic
   vignjevic, Danijela/0000-0003-4250-703X; Bonnet,
   Isabelle/0000-0003-2343-3784
FU Ecole des Mines de Paris; Foundation ARC (Association pour la Recherche
   sur le Cancer); Institut National de la Sante et de la Recherche
   Medicale (Inserm); Foundation pour la Recherche Medicale (FRM); SIRIC
   [INCa-DGOS-4654]; INCa [INCa-DGOS-9963, INCa-2016-166, INCa-11692,
   INCa-DGOS-Inserm-12554]; FRM [ING20160435436]; Inserm [EQ2016-01]; Ligue
   Nationale Contre le Cancer (Labelisation); Inserm; Institut Curie (PIC
   TME/T-MEGA); Institut Curie (PIC3i CAFi); ICGex [ANR-10-EQPX-03]; ARCS
FX We thank Dr. V. Mieulet and G. Gentric for critical reading of the
   manuscript and all members of F.M.-G.'s laboratory for fruitful
   discussions. We are grateful to Dr. V. Becette, M. Toutain and A.
   Duchenne for providing access to some tumor samples. We thank Z.
   Maciorowski, S. Grondin and A. Viguier from the Flow cytometry platform
   at Institut Curie (IC). We also thank R. Leclere, E. Martel and A.
   Nicolas from the experimental pathology platform (IC); S. Baulande,
   S.Lameiras, V. Raynal, M. Bohec and P. Legoix from the NGS platform (IC)
   for their help and advice. We acknowledge the Cell and Tissue Imaging
   (PICT-IBiSA) and Nikon Imaging Centre (IC) member of the French National
   Research Infrastructure France-BioImaging (ANR10-INBS-04). In
   particular, we thank O. Renaud and O. Leroy (IC) for technical
   assistance with microscopy and IMARIS software. We thank K. Laud for her
   help with spheroids experiments. F.P. was supported by funding from
   Ecole des Mines de Paris and from the Foundation ARC (Association pour
   la Recherche sur le Cancer). F.M.-G. and C.B. are supported by Institut
   National de la Sante et de la Recherche Medicale (Inserm). Y.K. was
   funded by the Foundation pour la Recherche Medicale (FRM), SIRIC
   (INCa-DGOS-4654) and INCa (INCa-DGOS-9963). M.C.P. was supported by FRM
   (ING20160435436) and Inserm (EQ2016-01). The experimental work was
   supported by grants from Ligue Nationale Contre le Cancer
   (Labelisation), Inserm, Institut Curie (PIC TME/T-MEGA and PIC3i CAFi),
   ICGex (ANR-10-EQPX-03), SIRIC (INCa-DGOS-4654) and INCa (INCa-DGOS-9963,
   INCa-2016-166, INCa-11692, INCa-DGOS-Inserm-12554) and ARCS. F.M.-G.
   acknowledges both the Association Le cancer du sein, Parlons-en and the
   Simone and Cino del Duca Foundation for attribution of their "Grand
   Prix". F.M.-G. is very grateful to her funders for providing support
   these last years.
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NR 70
TC 258
Z9 273
U1 1
U2 77
PU NATURE PUBLISHING GROUP
PI LONDON
PA MACMILLAN BUILDING, 4 CRINAN ST, LONDON N1 9XW, ENGLAND
SN 2041-1723
J9 NAT COMMUN
JI Nat. Commun.
PD JAN 21
PY 2020
VL 11
IS 1
AR 404
DI 10.1038/s41467-019-14134-w
PG 20
WC Multidisciplinary Sciences
WE Science Citation Index Expanded (SCI-EXPANDED)
SC Science & Technology - Other Topics
GA KJ3ER
UT WOS:000511940400008
PM 31964880
OA Green Published, gold
DA 2025-03-13
ER

PT J
AU Wang, GG
   Zhang, H
   Shen, XW
   Jin, WZ
   Wang, XL
   Zhou, ZJ
AF Wang, Ganggang
   Zhang, Hao
   Shen, Xiaowei
   Jin, Wenzhi
   Wang, Xiaoliang
   Zhou, Zhijie
TI Characterization of cancer-associated fibroblasts (CAFs) and development
   of a CAF-based risk model for triple-negative breast cancer
SO CANCER CELL INTERNATIONAL
LA English
DT Article
DE Triple-negative breast cancer; Tumor microenvironment; Cancer-associated
   fibroblast; Prognosis; GPR34
ID CELLS; CHEMORESISTANCE; EXPRESSION; PROGNOSIS
AB Triple-negative breast Cancer (TNBC) is a highly malignant cancer with unclear pathogenesis. Within the tumor microenvironment (TME), cancer-associated fibroblasts (CAFs) vitally influence tumor onset and progression. Thus, this research aimed to identify distinct subgroups of CAF using single-cell and TNBC-related information from the GEO and TCGA databases, respectively. The primary aim was to establish a novel predictive model based on the CAF features and their clinical relevance. Moreover, the CAFs were analyzed for their immune characteristics, response to immunotherapy, and sensitivity to different drugs. The developed predictive model demonstrated significant effectiveness in determining the prognosis of patients with TNBC, TME, and the immune landscape of the tumor. Of note, the expression of GPR34 was significantly higher in TNBC tissues compared to that in other breast cancer (non-TNBC) tissues, indicating that GPR34 plays a crucial role in the onset and progression of TNBC. In summary, this research has yielded a novel predictive model for TNBC that holds promise for the accurate prediction of prognosis and response to immunotherapy in patients with TNBC.
C1 [Wang, Ganggang; Zhang, Hao; Jin, Wenzhi; Wang, Xiaoliang; Zhou, Zhijie] Fudan Univ, Shanghai Pudong Hosp, Dept Hepatobiliary Surg, Pudong Med Ctr, Shanghai 201399, Peoples R China.
   [Shen, Xiaowei] Fudan Univ, Zhongshan Hosp, Dept Gen Surg, Qingpu Branch, Shanghai, Peoples R China.
C3 Fudan University; Fudan University
RP Wang, XL; Zhou, ZJ (corresponding author), Fudan Univ, Shanghai Pudong Hosp, Dept Hepatobiliary Surg, Pudong Med Ctr, Shanghai 201399, Peoples R China.
EM Xiaoliangwang2018@163.com; zhijiezhou2022@163.com
FU Talent Training Program of Pudong Hospital affiliated to Fudan
   University [LJ202101]; Fudan Zhangjiang Clinical Medicine Innovation
   Fund Project [KP7202105]; Outstanding Leaders Training Program of Pudong
   Health Committee of Shanghai [PWRI2022-04]; Scientific Research
   Foundation provided by Pudong Hospital affiliated to Fudan University
   [Zdxk2020-01, Zdzk2020-09, YJYJRC202104]; Pudong New Area Clinical
   Characteristic Discipline Project [PWYts2021-11]
FX This study was funded by the Talent Training Program of Pudong Hospital
   affiliated to Fudan University (Project No.LJ202101), Fudan Zhangjiang
   Clinical Medicine Innovation Fund Project (KP7202105), Outstanding
   Leaders Training Program of Pudong Health Committee of Shanghai (Grant
   No. PWRI2022-04), the Scientific Research Foundation provided by Pudong
   Hospital affiliated to Fudan University (Project No. Zdxk2020-01,
   Zdzk2020-09, and YJYJRC202104), and the Pudong New Area Clinical
   Characteristic Discipline Project (Grant No. PWYts2021-11).
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NR 63
TC 5
Z9 5
U1 4
U2 12
PU BMC
PI LONDON
PA CAMPUS, 4 CRINAN ST, LONDON N1 9XW, ENGLAND
EI 1475-2867
J9 CANCER CELL INT
JI Cancer Cell Int.
PD NOV 25
PY 2023
VL 23
IS 1
AR 294
DI 10.1186/s12935-023-03152-w
PG 16
WC Oncology
WE Science Citation Index Expanded (SCI-EXPANDED)
SC Oncology
GA AK3W4
UT WOS:001118331000002
PM 38007443
OA gold
DA 2025-03-13
ER

PT J
AU Fernández-Nogueira, P
   Fuster, G
   Gutierrez-Uzquiza, A
   Gascón, P
   Carbó, N
   Bragado, P
AF Fernandez-Nogueira, Patricia
   Fuster, Gemma
   Gutierrez-Uzquiza, Alvaro
   Gascon, Pere
   Carbo, Neus
   Bragado, Paloma
TI Cancer-Associated Fibroblasts in Breast Cancer Treatment Response and
   Metastasis
SO CANCERS
LA English
DT Review
DE breast cancer; cancer-associated fibroblasts; therapy resistance;
   metastasis
ID TUMOR-STROMAL INTERACTIONS; CARCINOMA IN-SITU; ANTIESTROGEN RESISTANCE;
   EXTRACELLULAR-MATRIX; STEM-CELLS; PREMETASTATIC NICHE; BONE METASTASIS;
   UP-REGULATION; TGF-BETA; GROWTH
AB Simple Summary Breast cancer is a major public health problem with a large impact on the life of patients and their families. It is a highly curable disease when detected early, and an inevitably mortal disease when discovered too late. Therapy resistance and metastases are the most critical clinical issues faced by breast cancer oncologists nowadays. It has become evident that interactions between carcinoma cells and tumor microenvironment are an essential part of tumor growth and progression. Cells that support the function of epithelial cells, like cancer-associated fibroblasts (CAFs), contribute to therapy resistance and metastasis via the production of several secreted factors and direct interaction with cancer cells. Here we review the role of CAFs in radiotherapy, chemotherapy, endocrine and targeted therapies resistance. We also highlight the role of CAFs and fibroblasts from metastatic sites in metastasis progression. Finally, we discuss advances and potential therapeutic strategies to target CAFs for overcoming resistance and preventing metastases. Breast cancer (BrCa) is the leading cause of death among women worldwide, with about one million new cases diagnosed each year. In spite of the improvements in diagnosis, early detection and treatment, there is still a high incidence of mortality and failure to respond to current therapies. With the use of several well-established biomarkers, such as hormone receptors and human epidermal growth factor receptor-2 (HER2), as well as genetic analysis, BrCa patients can be categorized into multiple subgroups: Luminal A, Luminal B, HER2-enriched, and Basal-like, with specific treatment strategies. Although chemotherapy and targeted therapies have greatly improved the survival of patients with BrCa, there is still a large number of patients who relapse or who fail to respond. The role of the tumor microenvironment in BrCa progression is becoming increasingly understood. Cancer-associated fibroblasts (CAFs) are the principal population of stromal cells in breast tumors. In this review, we discuss the current understanding of CAFs' role in altering the tumor response to therapeutic agents as well as in fostering metastasis in BrCa. In addition, we also review the available CAFs-directed molecular therapies and their potential implications for BrCa management.
C1 [Fernandez-Nogueira, Patricia; Fuster, Gemma; Gascon, Pere; Carbo, Neus] Univ Barcelona IBUB, Inst Biomed, Dept Biochem & Mol Biomed, Barcelona 08028, Spain.
   [Fernandez-Nogueira, Patricia] Univ Barcelona, Sch Med, Dept Biomed, Barcelona 08028, Spain.
   [Fuster, Gemma] Univ Barcelona, Sch Pharm & Food Sci, Dept Biochem & Physiol, Barcelona 08028, Spain.
   [Fuster, Gemma] Univ Vic, Dept Biosci, Fac Sci & Technol, Vic 08500, Spain.
   [Gutierrez-Uzquiza, Alvaro; Bragado, Paloma] Univ Complutense Madrid, Dept Biochem & Mol Biol, Fac Pharm, Madrid 28040, Spain.
   [Gutierrez-Uzquiza, Alvaro; Bragado, Paloma] Hosp Clin San Carlos, Hlth Res Inst, Madrid 28040, Spain.
C3 University of Barcelona; University of Barcelona; University of
   Barcelona; Universitat de Vic - Universitat Central de Catalunya
   (UVic-UCC); Complutense University of Madrid; Hospital Clinico San
   Carlos
RP Fernández-Nogueira, P (corresponding author), Univ Barcelona IBUB, Inst Biomed, Dept Biochem & Mol Biomed, Barcelona 08028, Spain.; Fernández-Nogueira, P (corresponding author), Univ Barcelona, Sch Med, Dept Biomed, Barcelona 08028, Spain.; Bragado, P (corresponding author), Univ Complutense Madrid, Dept Biochem & Mol Biol, Fac Pharm, Madrid 28040, Spain.; Bragado, P (corresponding author), Hosp Clin San Carlos, Hlth Res Inst, Madrid 28040, Spain.
EM pfernandezn@ub.edu; gemmafuster@ub.edu; alguuz@ucm.es;
   peregascon@ub.edu; ncarbo@ub.edu; pbragado@ucm.es
RI Uzquiza, Alvaro/E-4073-2012; Fuster, Gemma/ACH-5814-2022; fernandez,
   patricia/KTI-2987-2024; Domingo, Paloma/A-8679-2015; Fuster Orellana,
   Gemma/B-5468-2019
OI CARBO CARBO/0000-0001-8208-6896; Fernandez Nogueira,
   Patricia/0000-0002-7246-490X; Gutierrez-Uzquiza,
   Alvaro/0000-0002-0446-4131; Fuster Orellana, Gemma/0000-0002-4501-2422
FU Spanish Ministry of Economy and Competitiveness [PID2019-104991RB-I00];
   European FEDER Program; Madrid Community Program for Talent Attraction
   [MRF 2017-T1/BMD-5468]; Juan de la Cierva contract from the Spanish
   Ministry of science, innovation and universities; Cellex Foundation; La
   Marato TV3 [201915-30-31]; Secretaria d'Universitats i Recerca del
   Departament d'Economia i Coneixement [2017_SGR_1305]
FX This work was supported by grants from the Spanish Ministry of Economy
   and Competitiveness (PID2019-104991RB-I00 to PB). All funding was
   cosponsored by the European FEDER Program. A.G.-U. is supported by the
   Madrid Community Program for Talent Attraction (MRF 2017-T1/BMD-5468).
   P.F.-N. is supported by a Juan de la Cierva contract from the Spanish
   Ministry of science, innovation and universities. P.F.-N. and G.F. are
   supported by Cellex Foundation, and P.F.-N., G.F., N.C., and P.G. are
   funded by La Marato TV3 (201915-30-31), and by Secretaria d'Universitats
   i Recerca del Departament d'Economia i Coneixement (2017_SGR_1305).
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NR 184
TC 36
Z9 39
U1 0
U2 21
PU MDPI
PI BASEL
PA ST ALBAN-ANLAGE 66, CH-4052 BASEL, SWITZERLAND
EI 2072-6694
J9 CANCERS
JI Cancers
PD JUL
PY 2021
VL 13
IS 13
AR 3146
DI 10.3390/cancers13133146
PG 22
WC Oncology
WE Science Citation Index Expanded (SCI-EXPANDED)
SC Oncology
GA TF9ML
UT WOS:000671038600001
PM 34201840
OA Green Published, gold
DA 2025-03-13
ER

PT J
AU Wu, HJ
   Hao, MG
   Yeo, SK
   Guan, JL
AF Wu, Hsin-Jung
   Hao, Mingang
   Yeo, Syn Kok
   Guan, Jun-Lin
TI FAK signaling in cancer-associated fibroblasts promotes breast cancer
   cell migration and metastasis by exosomal miRNAs-mediated intercellular
   communication
SO ONCOGENE
LA English
DT Article
ID FOCAL-ADHESION KINASE; EPITHELIAL-SPECIFIC DISRUPTION; STEM-CELLS;
   HETEROGENEITY; SURVIVAL; BIOLOGY; GENES
AB Cancer-associated fibroblasts (CAFs) are activated fibroblasts that constitute the major components of tumor microenvironment (TME) and play crucial roles in tumor development and metastasis. Here, we generated fibroblast-specific inducible focal adhesion kinase (FAK) knockout (cKO) mice in a breast cancer model to study potential role and mechanisms of FAK signaling in CAF to promote breast cancer metastasis in vivo. While not affecting primary tumor development and growth, FAK deletion significantly suppressed breast cancer metastasis in vivo. Analyses of CAFs derived from cKO mice as well as human CAFs showed that FAK is required for their activity to promote mammary tumor cell migration. We further showed that FAK ablation in CAFs decreased exosome functions to promote tumor cell migration and other activities, which could contribute to the reduced metastasis observed in cKO mice. Lastly, profiling of miRs from CAF exosomes showed alterations of several exosomal miRs in FAK-null CAFs, and further analysis suggested that miR-16 and miR-148a enriched in exosomes from FAK-null CAFs contribute to the reduced tumor cell activities and metastasis. Together, these results identify a new role for FAK signaling in CAFs that regulate their intercellular communication with tumor cells to promote breast cancer metastasis.
C1 [Wu, Hsin-Jung; Hao, Mingang; Yeo, Syn Kok; Guan, Jun-Lin] Univ Cincinnati, Coll Med, Dept Canc Biol, Cincinnati, OH 45267 USA.
C3 University System of Ohio; University of Cincinnati
RP Guan, JL (corresponding author), Univ Cincinnati, Coll Med, Dept Canc Biol, Cincinnati, OH 45267 USA.
EM guanjl@uc.edu
RI Yeo, Syn/I-1617-2019; Hao, Mingang/AAL-7254-2020
OI Yeo, Syn/0000-0002-4333-2510; Hao, Mingang/0000-0001-6456-1710
FU NIH [R01CA163493, R01NS094144, R01HL073394]
FX We would like to thank Glenn Doerman for his help in the preparation of
   figures. We are grateful to members of our laboratory for their critical
   comments and suggestions for the manuscript. The work in this study is
   funded by NIH grants R01CA163493, R01NS094144, and R01HL073394 to J-LG.
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NR 50
TC 123
Z9 135
U1 1
U2 33
PU SPRINGERNATURE
PI LONDON
PA CAMPUS, 4 CRINAN ST, LONDON, N1 9XW, ENGLAND
SN 0950-9232
EI 1476-5594
J9 ONCOGENE
JI Oncogene
PD MAR
PY 2020
VL 39
IS 12
BP 2539
EP 2549
DI 10.1038/s41388-020-1162-2
EA JAN 2020
PG 11
WC Biochemistry & Molecular Biology; Oncology; Cell Biology; Genetics &
   Heredity
WE Science Citation Index Expanded (SCI-EXPANDED)
SC Biochemistry & Molecular Biology; Oncology; Cell Biology; Genetics &
   Heredity
GA KW4HU
UT WOS:000509655100003
PM 31988451
OA Green Accepted
DA 2025-03-13
ER

PT J
AU Lappano, R
   Maggiolini, M
AF Lappano, Rosamaria
   Maggiolini, Marcello
TI GPER is involved in the functional liaison between breast tumor cells
   and cancer-associated fibroblasts (CAFs)
SO JOURNAL OF STEROID BIOCHEMISTRY AND MOLECULAR BIOLOGY
LA English
DT Review
DE Breast cancer; Cancer-associated fibroblasts; GPER; Signal transduction
ID COUPLED ESTROGEN-RECEPTOR; GROWTH-FACTOR RECEPTOR;
   EPITHELIAL-MESENCHYMAL TRANSITION; TAMOXIFEN RESISTANCE;
   NUCLEAR-LOCALIZATION; STROMAL FIBROBLASTS; SIGNALING PATHWAY;
   GENE-EXPRESSION; INDUCED ACTIVATION; PROTEIN
AB The aggressiveness of breast tumors is deeply influenced by the surrounding stroma. In this regard, the functional crosstalk between cancer cells and the tumor microenvironment has received considerable attention in recent years. Cancer-associated fibroblasts (CAFs) are active components of the tumor stroma as they play a main role in the initiation, progression, metastasis and recurrence of breast malignancy. Hence, a better understanding of the mechanisms through which host stroma may contribute to cancer development would lead to novel therapeutic approaches aimed to target both tumor cells and the adjacent microenvironment. The G protein estrogen receptor (GPER/GPR30) has been involved in estrogenic signaling in normal and malignant cells, including breast cancer. It is noteworthy that the potential of GPER to mediate stimulatory effects of estrogens has been also shown in CAFs derived from patients with breast tumors, suggesting that GPER may act at the cross-road between cancer cells and these important components of the tumor microenvironment. This review recapitulates recent findings underlying the breast tumor-promoting action of CAFs, in particular their functional liaison with breast cancer cells via GPER toward the occurrence of malignant features. (C) 2017 Elsevier Ltd. All rights reserved.
C1 [Lappano, Rosamaria; Maggiolini, Marcello] Univ Calabria, Dept Pharm Hlth & Nutr Sci, Arcavacata Di Rende, Italy.
C3 University of Calabria
RP Lappano, R (corresponding author), Univ Calabria, Dept Pharm Hlth & Nutr Sci, Arcavacata Di Rende, Italy.
EM lappanorosamaria@yahoo.it; marcellomaggiolini@yahoo.it
RI Maggiolini, Marcello/Z-4729-2019
OI Lappano, Rosamaria/0000-0002-9374-9701
FU Associazione Italiana per la Ricerca sul Cancro [IG 16719/2015]
FX This work was supported by Associazione Italiana per la Ricerca sul
   Cancro (IG 16719/2015).
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NR 138
TC 37
Z9 42
U1 0
U2 26
PU PERGAMON-ELSEVIER SCIENCE LTD
PI OXFORD
PA THE BOULEVARD, LANGFORD LANE, KIDLINGTON, OXFORD OX5 1GB, ENGLAND
SN 0960-0760
J9 J STEROID BIOCHEM
JI J. Steroid Biochem. Mol. Biol.
PD FEB
PY 2018
VL 176
SI SI
BP 49
EP 56
DI 10.1016/j.jsbmb.2017.02.019
PG 8
WC Biochemistry & Molecular Biology; Endocrinology & Metabolism
WE Science Citation Index Expanded (SCI-EXPANDED)
SC Biochemistry & Molecular Biology; Endocrinology & Metabolism
GA FV1IH
UT WOS:000424314300007
PM 28249728
DA 2025-03-13
ER

PT J
AU Broad, RV
   Jones, SJ
   Teske, MC
   Wastall, LM
   Hanby, AM
   Thorne, JL
   Hughes, TA
AF Broad, Robyn, V
   Jones, Stacey J.
   Teske, Melina C.
   Wastall, Laura M.
   Hanby, Andrew M.
   Thorne, James L.
   Hughes, Thomas A.
TI Inhibition of interferon-signalling halts cancer-associated
   fibroblast-dependent protection of breast cancer cells from chemotherapy
SO BRITISH JOURNAL OF CANCER
LA English
DT Article
ID GENE-EXPRESSION; MICROENVIRONMENT; SURVIVAL
AB Background Triple negative breast cancers (TNBC) have poor prognoses despite aggressive treatment with cytotoxic chemotherapy. Cancer-associated fibroblasts (CAFs) are prominent in tumour stroma. Our hypothesis was that CAFs modulate chemotherapy sensitivity. Methods TNBC cells and breast fibroblasts were cultured; survival after chemotherapeutics was assessed using luciferase or clonogenic assays. Signalling was investigated using transcriptomics, reporters, recombinant proteins and blocking antibodies. Clinical relevance was investigated using immunohistochemistry. Results Breast CAFs dose-dependently protected TNBC cell lines MDA-MB-231 and MDA-MB-157, but not MDA-MB-468s, from chemotherapy. CAF-induced protection was associated with interferon (IFN) activation. CAFs were induced to express IFN beta 1 by chemotherapy and TNBC co-culture, leading to paracrine activation in cancer cells. Recombinant IFNs were sufficient to protect MDA-MB-231 and MDA-MB-157 but not MDA-MB-468 cells. In TNBC patients, IFN beta 1 expression in CAFs correlated with cancer cell expression of MX1, a marker of activated IFN signalling. High expression of IFN beta 1 (CAFs) or MX1 (tumour cells) correlated with reduced survival after chemotherapy, especially in claudin-low tumours (which MDA-MB-231 and MDA-MB-157 cells represent). Antibodies that block IFN receptors reduced CAF-dependent chemoprotection. Conclusions CAF-induced activation of IFN signalling in claudin-low TNBCs results in chemoresistance. Inhibition of this pathway represents a novel method to improve breast cancer outcomes.
C1 [Broad, Robyn, V; Jones, Stacey J.; Teske, Melina C.; Hanby, Andrew M.; Hughes, Thomas A.] Univ Leeds, Sch Med, Leeds, W Yorkshire, England.
   [Jones, Stacey J.] Leeds Teaching Hosp NHS Trust, Dept Breast Surg, Leeds, W Yorkshire, England.
   [Wastall, Laura M.; Hanby, Andrew M.] St James Univ Hosp, Dept Histopathol, Leeds, W Yorkshire, England.
   [Thorne, James L.] Univ Leeds, Sch Food Sci & Nutr, Leeds, W Yorkshire, England.
C3 University of Leeds; University of Leeds; Saint James's University
   Hospital; University of Leeds
RP Hughes, TA (corresponding author), Univ Leeds, Sch Med, Leeds, W Yorkshire, England.
EM t.hughes@leeds.ac.uk
RI thorne, james/R-9878-2019; Hughes, Thomas/O-8031-2015
OI Thorne, James/0000-0002-3037-8528; Hughes, Thomas/0000-0003-1169-3386
FU Breast Cancer Action [1170369-9]; University of Leeds; Leeds CRUK Cancer
   Centre
FX R.V.B. was supported by Breast Cancer Action (charity #1170369-9) and a
   studentship from the University of Leeds. J.L.T. was supported by a
   University Academic Fellowship from the University of Leeds. L.M.W. was
   supported by a fellowship from the Leeds CRUK Cancer Centre.
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NR 44
TC 35
Z9 37
U1 3
U2 14
PU SPRINGERNATURE
PI LONDON
PA CAMPUS, 4 CRINAN ST, LONDON, N1 9XW, ENGLAND
SN 0007-0920
EI 1532-1827
J9 BRIT J CANCER
JI Br. J. Cancer
PD MAR 16
PY 2021
VL 124
IS 6
BP 1110
EP 1120
DI 10.1038/s41416-020-01226-4
EA JAN 2021
PG 11
WC Oncology
WE Science Citation Index Expanded (SCI-EXPANDED)
SC Oncology
GA QX2NO
UT WOS:000604795900002
PM 33398063
OA Green Accepted, hybrid, Green Published
DA 2025-03-13
ER

PT J
AU Houthuijzen, JM
   Jonkers, J
AF Houthuijzen, J. M.
   Jonkers, J.
TI Cancer-associated fibroblasts as key regulators of the breast cancer
   tumor microenvironment
SO CANCER AND METASTASIS REVIEWS
LA English
DT Review
DE Breast cancer; Fibroblasts; Microenvironment; ECM; Metastasis; Therapy
   resistance
ID GROWTH-FACTOR-BETA; EPITHELIAL-MESENCHYMAL TRANSITION;
   EXTRACELLULAR-MATRIX; STROMAL FIBROBLASTS; TENASCIN-C; TGF-BETA;
   STEM-CELLS; ACTIVATION PROTEIN; LYSYL OXIDASE; T-CELLS
AB Tumor cells exist in close proximity with non-malignant cells. Extensive and multilayered crosstalk between tumor cells and stromal cells tailors the tumor microenvironment (TME) to support survival, growth, and metastasis. Fibroblasts are one of the largest populations of non-malignant host cells that can be found within the TME of breast, pancreatic, and prostate tumors. Substantial scientific evidence has shown that these cancer-associated fibroblasts (CAFs) are not only associated with tumors by proximity but are also actively recruited to developing tumors where they can influence other cells of the TME as well as influencing tumor cell survival and metastasis. This review discusses the impact of CAFs on breast cancer biology and highlights their heterogeneity, origin and their role in tumor progression, ECM remodeling, therapy resistance, metastasis, and the challenges ahead of targeting CAFs to improve therapy response.
C1 [Houthuijzen, J. M.; Jonkers, J.] Netherlands Canc Inst, Dept Mol Pathol, Amsterdam, Netherlands.
C3 Netherlands Cancer Institute
RP Houthuijzen, JM (corresponding author), Netherlands Canc Inst, Dept Mol Pathol, Amsterdam, Netherlands.
EM j.houthuijzen@nki.nl
RI Jonkers, Jos/AAG-3246-2019
OI Houthuijzen, Julia/0000-0003-0404-1961; Jonkers, Jos/0000-0002-9264-9792
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NR 220
TC 162
Z9 176
U1 1
U2 34
PU SPRINGER
PI DORDRECHT
PA VAN GODEWIJCKSTRAAT 30, 3311 GZ DORDRECHT, NETHERLANDS
SN 0167-7659
EI 1573-7233
J9 CANCER METAST REV
JI Cancer Metastasis Rev.
PD DEC
PY 2018
VL 37
IS 4
SI SI
BP 577
EP 597
DI 10.1007/s10555-018-9768-3
PG 21
WC Oncology
WE Science Citation Index Expanded (SCI-EXPANDED)
SC Oncology
GA HJ8XF
UT WOS:000457482700003
PM 30465162
DA 2025-03-13
ER

PT J
AU Nagel, A
   Popeda, M
   Muchlinska, A
   Sadej, R
   Szade, J
   Zielinski, J
   Skokowski, J
   Niemira, M
   Kretowski, A
   Markiewicz, A
   Zaczek, AJ
AF Nagel, Anna
   Popeda, Marta
   Muchlinska, Anna
   Sadej, Rafal
   Szade, Jolanta
   Zielinski, Jacek
   Skokowski, Jaroslaw
   Niemira, Magdalena
   Kretowski, Adam
   Markiewicz, Aleksandra
   Zaczek, Anna J.
TI ERα36-High Cancer-Associated Fibroblasts as an Unfavorable Factor in
   Triple-Negative Breast Cancer
SO CANCERS
LA English
DT Article
DE cancer-associated fibroblasts; breast cancer; estrogen receptor alpha
   36; triple-negative breast cancer
ID ESTROGEN-RECEPTOR-ALPHA; TUMOR; EXPRESSION; CYTOKINES; MICROENVIRONMENT;
   MYOFIBROBLASTS; SURVIVAL; PROMOTE; GROWTH; ROLES
AB Simple Summary The tumor microenvironment, as an important constituent of neoplastic tissue, has been a promising target for cancer therapy. Triple-negative breast cancer accounts for around 10-20% of invasive breast cancers. This study describes a new cancer-associated fibroblast subtype characterized by high ER alpha 36 levels that secretes HGF, which can impact triple-negative breast cancer. The data enlighten the importance of the stromal effect on the disease course and underlines the significance of further research on the tumor microenvironment and its role in the progression of cancer. Background: Cancer-associated fibroblasts (CAFs) are the most abundant cell type in the tumor microenvironment (TME). Estrogen receptor alpha 36 (ER alpha 36), the alternatively spliced variant of ER alpha, is described as an unfavorable factor when expressed in cancer cells. ER alpha can be expressed also in CAFs; however, the role of ER alpha 36 in CAFs is unknown. Methods: Four CAF cultures were isolated from chemotherapy-naive BC patients and characterized for ER alpha 36 expression and the NanoString gene expression panel using isolated RNA. Conditioned media from CAF cultures were used to assess the influence of CAFs on triple-negative breast cancer (TNBC) cells using a matrigel 3D culture assay. Results: We found that ER alpha 36(high) CAFs significantly induced the branching of TNBC cells in vitro (p < 0.001). They also produced a set of pro-tumorigenic cytokines compared to ER alpha 36(low) CAFs, among which hepatocyte growth factor (HGF) was the main inducer of TNBC cell invasive phenotype in vitro (p < 0.001). Tumor stroma rich in ER alpha 36(high) CAFs was correlated with high Ki67 expression (p = 0.041) and tumor-associated macrophages markers (CD68 and CD163, p = 0.041 for both). HGF was found to be an unfavorable prognostic factor in TCGA database analysis (p = 0.03 for DFS and p = 0.04 for OS). Conclusions: Breast cancer-associated fibroblasts represent distinct subtypes based on ER alpha 36 expression. We propose that ER alpha 36(high) CAFs could account for an unfavorable prognosis for TNBC patients.
C1 [Nagel, Anna; Popeda, Marta; Muchlinska, Anna; Markiewicz, Aleksandra; Zaczek, Anna J.] Med Univ Gdansk, Intercollegiate Fac Biotechnol, Lab Translat Oncol, PL-80211 Gdansk, Poland.
   [Sadej, Rafal] Med Univ Gdansk, Intercollegiate Fac Biotechnol, Lab Mol Enzymol & Oncol, PL-80211 Gdansk, Poland.
   [Szade, Jolanta] Med Univ Gdansk, Dept Pathomorphol, PL-80211 Gdansk, Poland.
   [Zielinski, Jacek; Skokowski, Jaroslaw] Med Univ Gdansk, Dept Surg Oncol, PL-80211 Gdansk, Poland.
   [Skokowski, Jaroslaw] Med Univ Gdansk, Dept Med Lab Diagnost Biobank Fahrenheit BBMRI Pl, Debinki St 7, PL-80211 Gdansk, Poland.
   [Niemira, Magdalena; Kretowski, Adam] Med Univ Bialystok, Clin Res Ctr, PL-15276 Bialystok, Poland.
C3 Fahrenheit Universities; Medical University Gdansk; Fahrenheit
   Universities; Medical University Gdansk; Fahrenheit Universities;
   Medical University Gdansk; Fahrenheit Universities; Medical University
   Gdansk; Fahrenheit Universities; Medical University Gdansk; Medical
   University of Bialystok
RP Zaczek, AJ (corresponding author), Med Univ Gdansk, Intercollegiate Fac Biotechnol, Lab Translat Oncol, PL-80211 Gdansk, Poland.
EM anna.nagel@gumed.edu.pl; marta.popeda@gumed.edu.pl;
   anna.jurek@gumed.edu.pl; rafal.sadej@gumed.edu.pl; jszade@gumed.edu.pl;
   jacek.zielinski@gumed.edu.pl; jskokowski@gumed.edu.pl;
   magdalena.niemira@umb.edu.pl; adamkretowski@wp.pl;
   aleksandra.markiewicz@gumed.edu.pl; azaczek@gumed.edu.pl
RI Zaczek, Anna/T-8894-2017; Muchlińska, Anna/JPY-0033-2023; Markiewic,
   Aleksandra/C-1493-2013; Popęda, Marta/JXM-4301-2024; Skokowski,
   Jaroslaw/C-6906-2011; Zieliński, Jacek/O-9716-2019; Kretowski,
   Adam/U-6299-2018; Niemira, Magdalena/T-8076-2019; Niemira,
   Magdalena/T-9091-2018
OI Muchlinska, Anna/0000-0001-5886-4854; Popeda, Marta/0000-0002-4596-4837;
   Niemira, Magdalena/0000-0002-0701-4961; Nagel, Anna/0000-0002-8575-0470;
   Sadej, Rafal/0000-0003-2583-7299; Skokowski,
   Jaroslaw/0000-0002-3079-3502
FU Ministry of Science and Higher Education program "Iuventus Plus" [IP
   2014 028473]; National Science Centre (Poland) [2016/22/E/NZ4/00664]
FX This research was funded by the Ministry of Science and Higher Education
   program "Iuventus Plus" No. IP 2014 028473 and by the National Science
   Centre (Poland), grant number 2016/22/E/NZ4/00664.
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NR 50
TC 2
Z9 2
U1 0
U2 8
PU MDPI
PI BASEL
PA ST ALBAN-ANLAGE 66, CH-4052 BASEL, SWITZERLAND
EI 2072-6694
J9 CANCERS
JI Cancers
PD APR
PY 2022
VL 14
IS 8
AR 2005
DI 10.3390/cancers14082005
PG 17
WC Oncology
WE Science Citation Index Expanded (SCI-EXPANDED)
SC Oncology
GA 0S6FO
UT WOS:000786367400001
PM 35454913
OA gold, Green Published
DA 2025-03-13
ER

PT J
AU Tang, X
   Tu, G
   Yang, GL
   Wang, X
   Kang, LM
   Yang, LP
   Zeng, H
   Wan, XY
   Qiao, YN
   Cui, XJ
   Liu, MR
   Hou, YX
AF Tang, Xi
   Tu, Gang
   Yang, Guanglun
   Wang, Xing
   Kang, Linmin
   Yang, Liping
   Zeng, Huan
   Wan, Xueying
   Qiao, Yina
   Cui, Xiaojiang
   Liu, Manran
   Hou, Yixuan
TI Autocrine TGF-β1/miR-200s/miR-221/DNMT3B regulatory loop maintains CAF
   status to fuel breast cancer cell proliferation
SO CANCER LETTERS
LA English
DT Article
DE CAFs; Autocrine TGF-beta 1; DNMT3B; miR-200s; miR-221
ID CARCINOMA-ASSOCIATED FIBROBLASTS; TGF-BETA; PANCREATIC-CANCER; DNA
   METHYLATION; GENOMIC DNA; STEM-CELLS; TUMOR; HYPOMETHYLATION;
   DIFFERENTIATION; EXPRESSION
AB Cancer-associated fibroblasts (CAFs) remain active even in the absence of cancer cells. However, the molecular mechanism underlying the sustained active status of CAFs is largely unrevealed. We found that in CAFs, DNMT3B was not only a target of miR-200b, miR-200c and miR-221, but was able to induce DNA methylation of miR-200s promoters. DNMT3B eventually reached a stably high level by the counteracting effect of decreasing miR-200b/c and increasing miR-221 in normal fibroblasts (NFs) with long-term exogenous TGF-beta 1 treatment, and DNMT3B further led to a low level of miR-200s which established CAF activation. Meanwhile, miR-200s/miR-221/DNMT3B signaling sustained autocrine TGF-beta 1 maintaining active CAF status. Destruction of the autocrine TGF-beta 1/miR-200s/miR-221/DNMT3B signaling led to demethylation of miR-200s promoters and further restored the NF phenotypes. Moreover, we confirmed that TCF12, the target of miR-141, stimulated c-Myc/Cyclin D1 axis in breast cancer cells to promote cancer growth by enhancing CXCL12 of CAFs. The current study reveals that the TGF-beta 1/miR-200s/miR-221/DNMT3B regulatory loop is responsible for the maintenance of CAFs status and is also necessary for CAF function in promoting malignance of breast cancer, which provides a potential target for CAF-driven therapeutic strategy.
C1 [Tang, Xi] Chongqing Med Univ, Affiliated Hosp 1, Dept Lab Med, Chongqing 400016, Peoples R China.
   [Tang, Xi; Yang, Liping; Zeng, Huan; Wan, Xueying; Qiao, Yina; Liu, Manran] Chongqing Med Univ, Key Lab Lab Med Diagnost, Chinese Minist Educ, Chongqing 400016, Peoples R China.
   [Tu, Gang; Yang, Guanglun] Chongqing Med Univ, Affiliated Hosp 1, Dept Endocrine & Breast Surg, Chongqing 400016, Peoples R China.
   [Wang, Xing] Sun Yat Sen Univ, Affiliated Hosp 7, Dept Surg, Shenzhen 518107, Peoples R China.
   [Kang, Linmin] Univ Pittsburgh, Dept Commun Sci & Disorders, Pittsburgh, PA 15206 USA.
   [Cui, Xiaojiang] Cedars Sinai Med Ctr, Samuel Oschin Comprehens Canc Inst, Dept Obstet & Gynecol, Dept Surg, Los Angeles, CA 91006 USA.
   [Hou, Yixuan] Chongqing Med Univ, Expt Teaching Ctr Basic Med Sci, 1 Yi Xue Yuan Rd, Chongqing 400016, Peoples R China.
C3 Chongqing Medical University; Chongqing Medical University; Chongqing
   Medical University; Sun Yat Sen University; Pennsylvania Commonwealth
   System of Higher Education (PCSHE); University of Pittsburgh; Cedars
   Sinai Medical Center; Chongqing Medical University
RP Liu, MR (corresponding author), Chongqing Med Univ, Key Lab Lab Med Diagnost, Chinese Minist Educ, Chongqing 400016, Peoples R China.; Hou, YX (corresponding author), Chongqing Med Univ, Expt Teaching Ctr Basic Med Sci, 1 Yi Xue Yuan Rd, Chongqing 400016, Peoples R China.
EM manranliu@cqmu.edu.cn; yixuan_hou@cqmu.edu.cn
RI YANG, LiPing/IST-6327-2023
OI Kang, Linmin/0000-0002-8374-9257
FU National Natural Science Foundation of China [NSFC 81773078, NSFC
   81402180, NSFC 81472476, NSFC 31671481, NSFC 81802653]; First Affiliated
   Hospital of Chongqing Medical University [PYJJ2018-04]
FX This work was supported by National Natural Science Foundation of China
   [grant numbers NSFC 81773078, NSFC 81402180 for Yixuan Hou; NSFC
   81472476, NSFC 31671481 for Manran Liu; NSFC 81802653 for Xi Tang], and
   also partly supported the First Affiliated Hospital of Chongqing Medical
   University [PYJJ2018-04].
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NR 43
TC 60
Z9 69
U1 0
U2 16
PU ELSEVIER IRELAND LTD
PI CLARE
PA ELSEVIER HOUSE, BROOKVALE PLAZA, EAST PARK SHANNON, CO, CLARE, 00000,
   IRELAND
SN 0304-3835
EI 1872-7980
J9 CANCER LETT
JI Cancer Lett.
PY 2019
VL 452
BP 79
EP 89
DI 10.1016/j.canlet.2019.02.044
PG 11
WC Oncology
WE Science Citation Index Expanded (SCI-EXPANDED)
SC Oncology
GA HW1PF
UT WOS:000466454100009
PM 30851420
OA Green Accepted
DA 2025-03-13
ER

PT J
AU Muchlinska, A
   Nagel, A
   Popeda, M
   Szade, J
   Niemira, M
   Zielinski, J
   Skokowski, J
   Bednarz-Knoll, N
   Zaczek, AJ
AF Muchlinska, Anna
   Nagel, Anna
   Popeda, Marta
   Szade, Jolanta
   Niemira, Magdalena
   Zielinski, Jacek
   Skokowski, Jaroslaw
   Bednarz-Knoll, Natalia
   Zaczek, Anna J.
TI Alpha-smooth muscle actin-positive cancer-associated fibroblasts
   secreting osteopontin promote growth of luminal breast cancer
SO CELLULAR & MOLECULAR BIOLOGY LETTERS
LA English
DT Article
DE Cancer-associated fibroblast; Luminal breast cancer; Alpha-smooth muscle
   actin; Osteopontin
ID EPITHELIAL-MESENCHYMAL TRANSITION; STROMAL MYOFIBROBLASTS; TUMOR
   MICROENVIRONMENT; EPCAM EXPRESSION; PROGNOSIS; CARCINOMA; CELLS
AB Background Cancer-associated fibroblasts (CAFs) have been shown to support tumor development in a variety of cancers. Different markers were applied to classify CAFs in order to elucidate their impact on tumor progression. However, the exact mechanism by which CAFs enhance cancer development and metastasis is yet unknown. Methods Alpha-smooth muscle actin (alpha-SMA) was examined immunohistochemically in intratumoral CAFs of nonmetastatic breast cancers and correlated with clinicopathological data. Four CAF cell lines were isolated from patients with luminal breast cancer (lumBC) and classified according to the presence of alpha-SMA protein. Conditioned medium (CM) from CAF cultures was used to assess the influence of CAFs on lumBC cell lines: MCF7 and T47D cells using Matrigel 3D culture assay. To identify potential factors accounting for promotion of tumor growth by alpha-SMA(high) CAFs, nCounter PanCancer Immune Profiling Panel (NanoString) was used. Results In luminal breast cancer, presence of intratumoral CAFs expressing high level of alpha-SMA (13% of lumBC group) correlated with poor prognosis (p = 0.019). In in vitro conditions, conditioned medium obtained from primary cultures of alpha-SMA-positive CAFs isolated from luminal tumors was observed to enhance growth of lumBC cell line colonies in 3D Matrigel, in contrast to CM derived from alpha-SMA-negative CAFs. Multigene expression analysis indicated that osteopontin (OPN) was overexpressed in alpha-SMA-positive CAFs in both clinical samples and in vitro models. OPN expression was associated with higher percentage of Ki67-positive cells in clinical material (p = 0.012), while OPN blocking in alpha-SMA-positive CAF-derived CM attenuated growth of lumBC cell line colonies in 3D Matrigel. Conclusions Our findings demonstrate that alpha-SMA-positive CAFs might enhance tumor growth via secretion of OPN.
C1 [Muchlinska, Anna; Nagel, Anna; Popeda, Marta; Bednarz-Knoll, Natalia; Zaczek, Anna J.] Med Univ Gdansk, Intercoll Fac Biotechnol, Lab Translat Oncol, PL-80211 Gdansk, Poland.
   [Szade, Jolanta] Med Univ Gdansk, Dept Pathomorphol, PL-80214 Gdansk, Poland.
   [Niemira, Magdalena] Med Univ Bialystok, Clin Res Ctr, PL-15276 Bialystok, Poland.
   [Zielinski, Jacek; Skokowski, Jaroslaw] Med Univ Gdansk, Dept Surg Oncol, PL-80214 Gdansk, Poland.
   [Skokowski, Jaroslaw] Biobanking & Biomol Resources Res Infrastruct Pol, PL-80211 Gdansk, Poland.
C3 Fahrenheit Universities; Medical University Gdansk; Fahrenheit
   Universities; Medical University Gdansk; Medical University of
   Bialystok; Fahrenheit Universities; Medical University Gdansk
RP Zaczek, AJ (corresponding author), Med Univ Gdansk, Intercoll Fac Biotechnol, Lab Translat Oncol, PL-80211 Gdansk, Poland.
EM azaczek@gumed.edu.pl
RI Skokowski, Jaroslaw/C-6906-2011; Zieliński, Jacek/O-9716-2019;
   Bednarz-Knoll, Natalia/D-3663-2011; Muchlińska, Anna/JPY-0033-2023;
   Popęda, Marta/JXM-4301-2024; Zaczek, Anna/T-8894-2017; Niemira,
   Magdalena/T-8076-2019
OI Muchlinska, Anna/0000-0001-5886-4854; Zaczek, Anna
   J/0000-0003-1482-6068; Bednarz-Knoll, Natalia/0000-0001-9506-942X
FU National Science Centre (Poland) [2016/22/E/NZ4/00664]
FX This research was funded by the National Science Centre (Poland), grant
   number 2016/22/E/NZ4/00664.
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NR 40
TC 41
Z9 44
U1 1
U2 11
PU BMC
PI LONDON
PA CAMPUS, 4 CRINAN ST, LONDON N1 9XW, ENGLAND
SN 1425-8153
EI 1689-1392
J9 CELL MOL BIOL LETT
JI Cell. Mol. Biol. Lett.
PD DEC
PY 2022
VL 27
IS 1
AR 45
DI 10.1186/s11658-022-00351-7
PG 14
WC Biochemistry & Molecular Biology; Cell Biology
WE Science Citation Index Expanded (SCI-EXPANDED)
SC Biochemistry & Molecular Biology; Cell Biology
GA 2A5VC
UT WOS:000809568300002
PM 35690734
OA gold, Green Published
DA 2025-03-13
ER

PT J
AU Yuan, J
   Liu, MR
   Yang, L
   Tu, G
   Zhu, Q
   Chen, MS
   Cheng, H
   Luo, HJ
   Fu, WJ
   Li, ZH
   Yang, GL
AF Yuan, Jie
   Liu, Manran
   Yang, Li
   Tu, Gang
   Zhu, Qing
   Chen, Maoshan
   Cheng, Hong
   Luo, Haojun
   Fu, Weijie
   Li, Zhenhua
   Yang, Guanglun
TI Acquisition of epithelial-mesenchymal transition phenotype in the
   tamoxifen-resistant breast cancer cell: a new role for G protein-coupled
   estrogen receptor in mediating tamoxifen resistance through
   cancer-associated fibroblast-derived fibronectin and β1-integrin
   signaling pathway in tumor cells
SO BREAST CANCER RESEARCH
LA English
DT Article
ID EXTRACELLULAR-MATRIX; GENE-EXPRESSION; ER-ALPHA; GROWTH; EMT; INTEGRIN;
   MICROENVIRONMENT; INVASIVENESS; ANGIOGENESIS; MODULATION
AB Introduction: Acquired tamoxifen resistance remains the major obstacle to breast cancer endocrine therapy. beta 1-integrin was identified as one of the target genes of G protein-coupled estrogen receptor (GPER), a novel estrogen receptor recognized as an initiator of tamoxifen resistance. Here, we investigated the role of beta 1-integrin in GPER-mediated tamoxifen resistance in breast cancer.
   Methods: The expression of beta 1-integrin and biomarkers of epithelial-mesenchymal transition were evaluated immunohistochemically in 53 specimens of metastases and paired primary tumors. The function of beta 1-integrin was investigated in tamoxifen-resistant (MCF-7R) subclones, derived from parental MCF-7 cells, and MCF-7R beta 1-integrin-silenced subclones in MTT and Transwell assays. Involved signaling pathways were identified using specific inhibitors and Western blotting analysis.
   Results: GPER, beta 1-integrin and mesenchymal biomarkers (vimentin and fibronectin) expression in metastases increased compared to the corresponding primary tumors; a close expression pattern of beta 1-integrin and GPER were in metastases. Increased beta 1-integrin expression was also confirmed in MCF-7R cells compared with MCF-7 cells. This upregulation of beta 1-integrin was induced by agonists of GPER and blocked by both antagonist and knockdown of it in MCF-7R cells. Moreover, the epidermal growth factor receptor/extracellular regulated protein kinase (EGFR/ERK) signaling pathway was involved in this transcriptional regulation since specific inhibitors of these kinases also reduced the GPER-induced upregulation of beta 1-integrin. Interestingly, silencing of beta 1-integrin partially rescued the sensitivity of MCF-7R cells to tamoxifen and the alpha 5 beta 1-integrin subunit is probably responsible for this phenomenon. Importantly, the cell migration and epithelial-mesenchymal transition induced by cancer-associated fibroblasts, or the product of cancer-associated fibroblasts, fibronectin, were reduced by knockdown of beta 1-integrin in MCF-7R cells. In addition, the downstream kinases of beta 1-integrin including focal adhesion kinase, Src and AKT were activated in MCF-7R cells and may be involved in the interaction between cancer cells and cancer-associated fibroblasts.
   Conclusions: GPER/EGFR/ERK signaling upregulates beta 1-integrin expression and activates downstream kinases, which contributes to cancer-associated fibroblast-induced cell migration and epithelial-mesenchymal transition, in MCF-7R cells. GPER probably contributes to tamoxifen resistance via interaction with the tumor microenvironment in a beta 1-integrin-dependent pattern. Thus, beta 1-integrin may be a potential target to improve anti-hormone therapy responses in breast cancer patients.
C1 [Yuan, Jie; Tu, Gang; Zhu, Qing; Chen, Maoshan; Cheng, Hong; Luo, Haojun; Fu, Weijie; Li, Zhenhua; Yang, Guanglun] Chongqing Med Univ, Affiliated Hosp 1, Dept Endocrine & Breast Surg, Chongqing 400016, Peoples R China.
   [Liu, Manran; Yang, Li] Chongqing Med Univ, Key Lab Lab Med Diagnost, Chinese Minist Educ, Chongqing 400016, Peoples R China.
C3 Chongqing Medical University; Chongqing Medical University
RP Yang, GL (corresponding author), Chongqing Med Univ, Affiliated Hosp 1, Dept Endocrine & Breast Surg, 1 You Yi Rd, Chongqing 400016, Peoples R China.
EM guanglunyang@163.com
RI Fu, Wei-jie/G-8472-2015
OI YUAN, JIE/0009-0008-5209-3874; li, lu/0009-0009-8381-3093; CHEN,
   MAOSHAN/0000-0002-3827-4969; Chen, Maoshan/0000-0002-6554-6210
FU National Natural Science Foundation of China (NSFC) [81072149]
FX This work was supported by the National Natural Science Foundation of
   China (NSFC 81072149). The funding agencies have no role in study
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NR 49
TC 97
Z9 109
U1 0
U2 29
PU BMC
PI LONDON
PA CAMPUS, 4 CRINAN ST, LONDON N1 9XW, ENGLAND
SN 1465-542X
EI 1465-5411
J9 BREAST CANCER RES
JI Breast Cancer Res.
PD MAY 21
PY 2015
VL 17
AR 69
DI 10.1186/s13058-015-0579-y
PG 18
WC Oncology
WE Science Citation Index Expanded (SCI-EXPANDED)
SC Oncology
GA CJ3SW
UT WOS:000355405300001
PM 25990368
OA Green Published, gold
DA 2025-03-13
ER

PT J
AU Wang, M
   Li, XZ
   Zhang, MX
   Ye, QY
   Chen, YX
   Chang, X
AF Wang, Meng
   Li, Xue-Zhen
   Zhang, Ming-Xing
   Ye, Qian-Yu
   Chen, Ying-Xia
   Chang, Xu
TI Atractylenolide-I Sensitizes Triple-Negative Breast Cancer Cells to
   Paclitaxel by Blocking CTGF Expression and Fibroblast Activation
SO FRONTIERS IN ONCOLOGY
LA English
DT Article
DE CTGF; fibroblast; chemoresistance; microenvironment; paclitaxel;
   triple-negative breast cancer; atractylenolide-I
ID TISSUE GROWTH-FACTOR; EPITHELIAL-MESENCHYMAL TRANSITION; GASTRIC-CANCER;
   DRUG-RESISTANCE; UP-REGULATION; MIGRATION; CHEMORESISTANCE; PROMOTE;
   PATHWAY; PROLIFERATION
AB This investigation was conducted to elucidate whether atractylenolide-I (ATL-1), which is the main component of Atractylodes macrocephala Koidz, can sensitize triple-negative breast cancer (TNBC) cells to paclitaxel and investigate the possible mechanism involved. We discovered that ATL-1 could inhibit tumor cell migration and increase the sensitivity of tumor cells to paclitaxel. ATL-1 downregulated the expression and secretion of CTGF in TNBC cells. Apart from inhibiting TNBC cell migration via CTGF, ATL-1 downregulated the expression of CTGF in fibroblasts and decreased the ability of breast cancer cells to transform fibroblasts into cancer-associated fibroblasts (CAFs), which in turn increased the sensitivity of TNBC cells to paclitaxel. In a mouse model, we found that ATL-1 treatments could enhance the chemotherapeutic effect of paclitaxel on tumors and reduce tumor metastasis to the lungs and liver. Primary cultured fibroblasts derived from inoculated tumors in mice treated with ATL-1 combined with paclitaxel expressed relatively low levels of CAF markers. Collectively, our data indicate that ATL-1 can sensitize TNBC cells to paclitaxel by blocking CTGF expression and fibroblast activation and could be helpful in future research to determine the value of ATL-1 in the clinical setting.
C1 [Wang, Meng] Panyu Hosp Chinese Med, Dept Surg 1, Guangzhou, Peoples R China.
   [Li, Xue-Zhen] Guangzhou Univ Chinese Med, Affiliated Hosp, Guangdong Hosp Tradit Chinese Med 2, Dept Breast Surg, Guangzhou, Peoples R China.
   [Zhang, Ming-Xing; Ye, Qian-Yu; Chen, Ying-Xia; Chang, Xu] Panyu Hosp Chinese Med, Dept Mammary Dis, Guangzhou, Peoples R China.
C3 Guangzhou University of Chinese Medicine
RP Chang, X (corresponding author), Panyu Hosp Chinese Med, Dept Mammary Dis, Guangzhou, Peoples R China.
EM changxu020@163.com
FU Scientific Research Project of Traditional Chinese Medicine Bureau of
   Guangdong Province of China [20201280]
FX This work was supported by grants to XC. from the Scientific Research
   Project of Traditional Chinese Medicine Bureau of Guangdong Province of
   China (No. 20201280).
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NR 61
TC 18
Z9 20
U1 4
U2 17
PU FRONTIERS MEDIA SA
PI LAUSANNE
PA AVENUE DU TRIBUNAL FEDERAL 34, LAUSANNE, CH-1015, SWITZERLAND
SN 2234-943X
J9 FRONT ONCOL
JI Front. Oncol.
PD OCT 6
PY 2021
VL 11
AR 738534
DI 10.3389/fonc.2021.738534
PG 15
WC Oncology
WE Science Citation Index Expanded (SCI-EXPANDED)
SC Oncology
GA WJ5WS
UT WOS:000709115900001
PM 34692516
OA Green Published, gold
DA 2025-03-13
ER

PT J
AU Busch, S
   Rydén, L
   Stål, O
   Jirström, K
   Landberg, G
AF Busch, Susann
   Ryden, Lisa
   Stal, Olle
   Jirstrom, Karin
   Landberg, Goran
TI Low ERK Phosphorylation in Cancer-Associated Fibroblasts Is Associated
   with Tamoxifen Resistance in Pre-Menopausal Breast Cancer
SO PLOS ONE
LA English
DT Article
ID ACTIVATED PROTEIN-KINASE; ENDOTHELIAL GROWTH-FACTOR; TUMOR
   MICROENVIRONMENT; KNOCKOUT MICE; LUNG-CANCER; EXPRESSION; SIGNATURE;
   ESTROGEN; CELLS; PATHWAY
AB Purpose: The aim of this study was to evaluate ERK phosphorylation as a stromal biomarker for breast cancer prognosis and tamoxifen treatment prediction within a randomized tamoxifen trial.
   Patients and Methods: Tissue microarrays of two breast cancer cohorts including in total 743 invasive breast cancer samples were analyzed for ERK phosphorylation (pERK) and smooth muscle actin-alpha expression (SMA alpha) in cancer-associated fibroblasts (CAFs) and links to clinico-pathological data and treatment-predictive values were delineated.
   Results: By analyzing a unique randomized tamoxifen trial including breast cancer patients receiving no adjuvant treatment we show for the first time that patients low in ERK phosphorylation in CAFs did not respond to tamoxifen treatment despite having estrogen-receptor alpha (ER alpha-positive tumors compared to patients with high pERK levels in CAFs (P = 0.015, multivariate Cox regression interaction analysis). In both clinical materials we further show a significant association between pERK and SMA alpha, a characteristic marker for activated fibroblasts. SMA alpha expression however was not linked to treatment-predictive information but instead had prognostic qualities.
   Conclusion: The data suggests that the presence of a subpopulation of CAFs, defined by minimal activated ERK signaling, is linked to an impaired tamoxifen response. Thus, this report illustrates the importance of the stroma for monitoring treatment effects in pre-menopausal breast cancer.
C1 [Busch, Susann; Landberg, Goran] Univ Manchester, Breakthrough Breast Canc Res Unit, Sch Canc Enabling Sci & Technol,Christie NHS Fdn, Manchester Acad Hlth Sci Ctr,Paterson Inst Canc R, Manchester, Lancs, England.
   [Ryden, Lisa] Univ Lund Hosp, Dept Surg, Inst Clin Sci, S-22185 Lund, Sweden.
   [Stal, Olle] Linkoping Univ, Dept Clin & Expt Med, Div Oncol, Linkoping, Sweden.
   [Jirstrom, Karin; Landberg, Goran] Lund Univ, Skane Univ Hosp Malmo, Dept Lab Med, Ctr Mol Pathol, Malmo, Sweden.
   [Landberg, Goran] Gothenburg Univ, Sahlgrenska Canc Ctr, Gothenburg, Sweden.
C3 Christie NHS Foundation Trust; University of Manchester; Lund
   University; Skane University Hospital; Linkoping University; Lund
   University; Skane University Hospital; University of Gothenburg
RP Landberg, G (corresponding author), Univ Manchester, Breakthrough Breast Canc Res Unit, Sch Canc Enabling Sci & Technol,Christie NHS Fdn, Manchester Acad Hlth Sci Ctr,Paterson Inst Canc R, Manchester, Lancs, England.
EM glandberg@picr.man.ac.uk
OI Jirstrom, Karin/0000-0003-2257-5000; Ryden, Lisa/0000-0001-7515-3130
FU Swedish Cancer Society and Breakthrough Breast Cancer UK
FX This study was supported by the Swedish Cancer Society and Breakthrough
   Breast Cancer UK. The funders had no role in study design, data
   collection and analysis, decision to publish, or preparation of the
   manuscript.
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NR 46
TC 22
Z9 28
U1 0
U2 3
PU PUBLIC LIBRARY SCIENCE
PI SAN FRANCISCO
PA 1160 BATTERY STREET, STE 100, SAN FRANCISCO, CA 94111 USA
SN 1932-6203
J9 PLOS ONE
JI PLoS One
PD SEP 24
PY 2012
VL 7
IS 9
AR e45669
DI 10.1371/journal.pone.0045669
PG 8
WC Multidisciplinary Sciences
WE Science Citation Index Expanded (SCI-EXPANDED)
SC Science & Technology - Other Topics
GA 016YB
UT WOS:000309554700056
PM 23029174
OA Green Published, gold, Green Submitted
DA 2025-03-13
ER

PT J
AU Ning, LW
   Quan, CT
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   Yuan, PX
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AF Ning, Lvwen
   Quan, Chuntao
   Wang, Yue
   Wu, Zhijie
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TI scRNA-seq characterizing the heterogeneity of fibroblasts in breast
   cancer reveals a novel subtype SFRP4<SUP>+</SUP> CAF that inhibits
   migration and predicts prognosis
SO FRONTIERS IN ONCOLOGY
LA English
DT Article
DE breast cancer; cancer-associated fibroblast; SFRP4+CAF; prognosis;
   heterogeneity; WNT; migration
ID PROTEIN 4 SFRP4; SINGLE-CELL; CHEMOTHERAPY; ACTIVATION; ATLAS
AB Introduction: Cancer-associated fibroblasts (CAFs) are a diverse group of cells that significantly impact the tumor microenvironment and therapeutic responses in breast cancer (BC). Despite their importance, the comprehensive profile of CAFs in BC remains to be fully elucidated. Methods: To address this gap, we utilized single-cell RNA sequencing (scRNA-seq) to delineate the CAF landscape within 14 BC normal-tumor paired samples. We further corroborated our findings by analyzing several public datasets, thereby validating the newly identified CAF subtype. Additionally, we conducted coculture experiments with BC cells to assess the functional implications of this CAF subtype. Results: Our scRNA-seq analysis unveiled eight distinct CAF subtypes across five tumor and six adjacent normal tissue samples. Notably, we discovered a novel subtype, designated as SFRP4+ CAFs, which was predominantly observed in normal tissues. The presence of SFRP4+ CAFs was substantiated by two independent scRNA-seq datasets and a spatial transcriptomics dataset. Functionally, SFRP4+ CAFs were found to impede BC cell migration and the epithelial-mesenchymal transition (EMT) process by secreting SFRP4, thereby modulating the WNT signaling pathway. Furthermore, we established that elevated expression levels of SFRP4+ CAF markers correlate with improved survival outcomes in BC patients, yet paradoxically, they predict a diminished response to neoadjuvant chemotherapy in cases of triple-negative breast cancer. Conclusion: This investigation sheds light on the heterogeneity of CAFs in BC and introduces a novel SFRP4+ CAF subtype that hinders BC cell migration. This discovery holds promise as a potential biomarker for refined prognostic assessment and therapeutic intervention in BC.
C1 [Ning, Lvwen; Quan, Chuntao; Wang, Yue; Wu, Zhijie; Xie, Ni] First Affiliated Hosp Shenzhen Univ, Affiliated Hosp 1, Shenzhen Peoples Hosp 2, Hlth Sci Ctr,Biobank, Shenzhen, Peoples R China.
   [Ning, Lvwen] Shenzhen Inst Adv Technol, Chinese Acad Sci, Shenzhen, Peoples R China.
   [Yuan, Peixiu] South China Agr Univ, Coll Mat & Energy, Guangzhou, Peoples R China.
C3 Chinese Academy of Sciences; Shenzhen Institute of Advanced Technology,
   CAS; South China Agricultural University
RP Xie, N (corresponding author), First Affiliated Hosp Shenzhen Univ, Affiliated Hosp 1, Shenzhen Peoples Hosp 2, Hlth Sci Ctr,Biobank, Shenzhen, Peoples R China.
EM xn100@szu.edu.cn
RI Wu, Zhijie/L-9795-2019; bones, bones/KHV-3721-2024
FU National Natural Science Foundation of China, China [82172356, 81972003,
   82203559]; Natural Science Foundation of Guangdong, China
   [2021A1515012144]; Guangdong Basic and Applied Basic Research
   Foundation, China [2020A1515111165, 2023A1515220238]; Natural Science
   Foundation of Shenzhen, China [JCYJ20230807115112024]
FX The author(s) declare financial support was received for the research,
   authorship, and/or publication of this article. This project was
   supported by the National Natural Science Foundation of China, China
   (No. 82172356, No. 81972003, No. 82203559), the Natural Science
   Foundation of Guangdong, China (No. 2021A1515012144), Guangdong Basic
   and Applied Basic Research Foundation, China (2020A1515111165 and
   2023A1515220238), the Natural Science Foundation of Shenzhen, China
   (JCYJ20230807115112024).
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NR 60
TC 1
Z9 1
U1 1
U2 1
PU FRONTIERS MEDIA SA
PI LAUSANNE
PA AVENUE DU TRIBUNAL FEDERAL 34, LAUSANNE, CH-1015, SWITZERLAND
SN 2234-943X
J9 FRONT ONCOL
JI Front. Oncol.
PD APR 15
PY 2024
VL 14
AR 1348299
DI 10.3389/fonc.2024.1348299
PG 14
WC Oncology
WE Science Citation Index Expanded (SCI-EXPANDED)
SC Oncology
GA WY1A5
UT WOS:001258330700001
PM 38686196
OA Green Published, gold
DA 2025-03-13
ER

PT J
AU Cirillo, F
   Pellegrino, M
   Talia, M
   Perrotta, ID
   Rigiracciolo, DC
   Spinelli, A
   Scordamaglia, D
   Muglia, L
   Guzzi, R
   Miglietta, AM
   De Francesco, EM
   Belfiore, A
   Maggiolini, M
   Lappano, R
AF Cirillo, Francesca
   Pellegrino, Michele
   Talia, Marianna
   Perrotta, Ida Daniela
   Rigiracciolo, Damiano Cosimo
   Spinelli, Asia
   Scordamaglia, Domenica
   Muglia, Lucia
   Guzzi, Rita
   Miglietta, Anna Maria
   De Francesco, Ernestina Marianna
   Belfiore, Antonino
   Maggiolini, Marcello
   Lappano, Rosamaria
TI Estrogen receptor variant ERα46 and insulin receptor drive in primary
   breast cancer cells growth effects and interleukin 11 induction
   prompting the motility of cancer-associated fibroblasts
SO CLINICAL AND TRANSLATIONAL MEDICINE
LA English
DT Article
DE breast cancer; ER alpha 46; estrogens; insulin; insulin receptor
ID EXTRACELLULAR-MATRIX; GENE-EXPRESSION; ALPHA; PROGRESSION;
   IDENTIFICATION; MECHANISMS; SUBTYPES; ISOFORM; DISEASE; ROLES
AB Among the prognostic and predictive biomarkers of breast cancer (BC), the role of estrogen receptor (ER)alpha wild-type has been acknowledged, although the action of certain ER alpha splice variants has not been elucidated. Insulin/insulin receptor (IR) axis has also been involved in the progression and metastasis of BC. For instance, hyperinsulinemia, which is often associated with obesity and type 2 diabetes, may be a risk factor for BC. Similarly, an aberrant expression of IR or its hyperactivation may correlate with aggressive BC phenotypes. In the present study, we have shown that a novel naturally immortalized BC cell line (named BCAHC-1) is characterized by a unique expression of 46 kDa ER alpha splice variant (ER alpha 46) along with IR. Moreover, we have shown that a multifaceted crosstalk between ER alpha 46 and IR occurs in BCAHC-1 cells upon estrogen and insulin exposure for growth and pulmonary metastasis. Through high-throughput RNA sequencing analysis, we have also found that the cytokine interleukin-11 (IL11) is the main factor linking BCAHC-1 cells to breast cancer-associated fibroblasts (CAFs). In particular, we have found that IL11 induced by estrogens and insulin in BCAHC-1 cells regulates pro-tumorigenic genes of the "extracellular matrix organization" signaling pathway, such as ICAM-1 and ITGA5, and promotes both migratory and invasive features in breast CAFs. Overall, our results may open a new scientific avenue to identify additional prognostic and therapeutic targets in BC.
C1 [Cirillo, Francesca; Guzzi, Rita] Univ Calabria, Dept Phys, Arcavacata Di Rende, Italy.
   [Cirillo, Francesca; Pellegrino, Michele; Talia, Marianna; Rigiracciolo, Damiano Cosimo; Spinelli, Asia; Scordamaglia, Domenica; Muglia, Lucia; Maggiolini, Marcello; Lappano, Rosamaria] Univ Calabria, Dept Pharm Hlth & Nutr Sci, I-87036 Arcavacata Di Rende, Italy.
   [Perrotta, Ida Daniela] Univ Calabria, Ctr Microscopy & Microanal, Transmiss Electron Microscopy Lab, Arcavacata Di Rende, Italy.
   [Perrotta, Ida Daniela] Univ Calabria, Dept Biol Ecol & Earth Sci, Arcavacata Di Rende, Italy.
   [Miglietta, Anna Maria] Reg Hosp Cosenza, Breast Unit, Cosenza, Italy.
   [De Francesco, Ernestina Marianna; Belfiore, Antonino] Univ Catania, Garibaldi Nesima Hosp, Dept Clin & Expt Med, Catania, Italy.
C3 University of Calabria; University of Calabria; University of Calabria;
   University of Calabria; Presidio Ospedaliero Garibaldi-Nesima;
   University of Catania
RP Maggiolini, M; Lappano, R (corresponding author), Univ Calabria, Dept Pharm Hlth & Nutr Sci, I-87036 Arcavacata Di Rende, Italy.
EM marcello.maggiolini@unical.it; rosamaria.lappano@unical.it
RI CIRILLO, FRANCESCA/K-2612-2018; Rigiracciolo, Damiano
   Cosimo/GRS-9234-2022; Belfiore, Antonino/B-4652-2011; Maggiolini,
   Marcello/Z-4729-2019; Guzzi, Rita/M-7654-2015; De Francesco, Ernestina
   Marianna/LQK-4482-2024; Muglia, Lucia/LRT-2748-2024
OI Talia, Marianna/0000-0002-3440-5618; Guzzi, Rita/0000-0001-6769-3399; De
   Francesco, Ernestina Marianna/0000-0002-2810-6128; Scordamaglia,
   Domenica/0000-0001-8384-4230; Muglia, Lucia/0009-0006-4112-3340
FU Fondazione AIRC [21651, 23369, 21322]; MIUR [3407/2018]
FX Fondazione AIRC supported Ernestina Marianna De Francesco (Start-Up
   Grant 21651), Antonino Belfiore (IG n. 23369) and Marcello Maggiolini
   (IG n. 21322). Damiano Cosimo Rigiracciolo was supported by Italian
   Minister of University and Research (MIUR, D.D. n. 3407/2018)-PON R&I
   2014-2020 l 'AIMAttrazione eMobilita Internazionale'.
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NR 52
TC 6
Z9 6
U1 0
U2 7
PU JOHN WILEY & SONS LTD
PI CHICHESTER
PA THE ATRIUM, SOUTHERN GATE, CHICHESTER PO19 8SQ, W SUSSEX, ENGLAND
SN 2001-1326
J9 CLIN TRANSL MED
JI Clin. Transl. Med.
PD NOV
PY 2021
VL 11
IS 11
AR e516
DI 10.1002/ctm2.516
PG 19
WC Oncology; Medicine, Research & Experimental
WE Science Citation Index Expanded (SCI-EXPANDED)
SC Oncology; Research & Experimental Medicine
GA XE8WY
UT WOS:000723664600024
PM 34841688
OA Green Published
DA 2025-03-13
ER

PT J
AU Jovanovic, B
   Pickup, MW
   Chytil, A
   Gorska, AE
   Johnson, KC
   Moses, HL
   Owens, P
AF Jovanovic, Bojana
   Pickup, Michael W.
   Chytil, Anna
   Gorska, Agnieszka E.
   Johnson, Kimberly C.
   Moses, Harold L.
   Owens, Philip
TI TβRIII Expression in Human Breast Cancer Stroma and the Role of Soluble
   TβRIII in Breast Cancer Associated Fibroblasts
SO CANCERS
LA English
DT Article
DE TGFBR3; T beta RIII; Cancer-Associated-Fibroblasts (CAFs); tumor
   microenvironment; cancer stroma; Betaglycan
ID RECEPTOR DOWN-REGULATION; TGF-BETA; MESENCHYMAL TRANSITION;
   TUMOR-SUPPRESSOR; GROWTH; METASTASIS; CELLS; GENE; PROGRESSION; INVASION
AB The TGF-beta pathway plays a major role in tumor progression through regulation of epithelial and stromal cell signaling. Dysfunction of the pathway can lead to carcinoma progression and metastasis. To gain insight into the stromal role of the TGF-beta pathway in breast cancer, we performed laser capture microdissection (LCM) from breast cancer patients and reduction mammoplasty patients. Microdissected tumor stroma and normal breast stroma were examined for gene expression. Expression of the TGF-beta type III receptor (TGFBR3) was greatly decreased in the tumor stroma compared to control healthy breast tissue. These results demonstrated a 44-fold decrease in TGFBR3 mRNA in tumor stroma in comparison to control tissue. We investigated publicly available databases, and have identified that TGFBR3 mRNA levels are decreased in tumor stroma. We next investigated fibroblast cell lines derived from cancerous and normal breast tissue and found that in addition to mRNA levels, T beta RIII protein levels were significantly reduced. Having previously identified that cancer-associated fibroblasts secrete greater levels of tumor promoting cytokines, we investigated the consequences of soluble-T beta RIII (sT beta RIII) on fibroblasts. Fibroblast conditioned medium was analyzed for 102 human secreted cytokines and distinct changes in response to sT beta RIII were observed. Next, we used the fibroblast-conditioned medium to stimulate human monocyte cell line THP-1. These results indicate a distinct transcriptional response depending on sT beta RIII treatment and whether it was derived from normal or cancerous breast tissue. We conclude that the effect of T beta RIII has distinct roles not only in cancer-associated fibroblasts but that sT beta RIII has distinct paracrine functions in the tumor microenvironment.
C1 [Jovanovic, Bojana] Harvard Med Sch, Dana Farber Canc Inst, Dept Med Oncol, Boston, MA 02215 USA.
   [Pickup, Michael W.] Univ Calif San Francisco, Dept Bioengn, San Francisco, CA 94117 USA.
   [Chytil, Anna; Gorska, Agnieszka E.; Moses, Harold L.; Owens, Philip] Vanderbilt Univ, Dept Canc Biol, Nashville, TN 37232 USA.
   [Johnson, Kimberly C.] Vanderbilt Univ, Dept Biochem, Nashville, TN 37232 USA.
   [Owens, Philip] Tennessee Valley Healthcare Syst, Res Med Vet Affairs, Nashville, TN 37232 USA.
C3 Harvard University; Harvard University Medical Affiliates; Dana-Farber
   Cancer Institute; Harvard Medical School; University of California
   System; University of California San Francisco; Vanderbilt University;
   Vanderbilt University; US Department of Veterans Affairs; Veterans
   Health Administration (VHA); VA Tennessee Valley Healthcare System
RP Owens, P (corresponding author), Vanderbilt Univ, Dept Canc Biol, Nashville, TN 37232 USA.; Owens, P (corresponding author), Tennessee Valley Healthcare Syst, Res Med Vet Affairs, Nashville, TN 37232 USA.
EM bojana_jovanovic@dfci.harvard.edu; michael.pickup@ucsfmedctr.org;
   anna.chytil@vanderbilt.edu; agnes.gorska@vanderbilt.edu;
   kimberly.n.johnson@vanderbilt.edu; hal.moses@vanderbilt.edu;
   Philip.owens@vanderbilt.edu
FU Department of Defense-Breast Cancer Res. Program [BC087501]; National
   Institutes of Health [R01 CA085492, R01 CA102162]; Robert J. and Helen
   C. Kleberg Foundation; T.J. Martell Foundation; Vanderbilt Ingram Cancer
   Center Grant [CA068485]; VA grant [BX002929]; CDMRP [544824, BC087501]
   Funding Source: Federal RePORTER
FX This work was supported by the Department of Defense-Breast Cancer Res.
   Program postdoctoral fellowship awards BC087501 (to P.O.); and National
   Institutes of Health Grants R01 CA085492 and R01 CA102162, the Robert J.
   and Helen C. Kleberg Foundation and the T.J. Martell Foundation (to
   H.L.M.). Vanderbilt Ingram Cancer Center Grant number CA068485 provided
   core laboratory support. We would like to thank Brittany Brake of the
   Vanderbilt Antibody Protein Resource (VAPR) for technical assistance
   with cytokine arrays. Philip Owens is supported by VA grant BX002929.
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NR 46
TC 9
Z9 10
U1 0
U2 3
PU MDPI AG
PI BASEL
PA ST ALBAN-ANLAGE 66, CH-4052 BASEL, SWITZERLAND
SN 2072-6694
J9 CANCERS
JI Cancers
PD NOV
PY 2016
VL 8
IS 11
AR 100
DI 10.3390/cancers8110100
PG 18
WC Oncology
WE Science Citation Index Expanded (SCI-EXPANDED)
SC Oncology
GA EO7TA
UT WOS:000396891800001
OA Green Published, gold, Green Submitted
DA 2025-03-13
ER

PT J
AU Wu, JL
   Li, YY
   Sun, SJ
   Li, WJ
   Sun, JG
   Zhu, LP
   Wang, ZQ
   Yang, F
   Wang, Q
   Ding, HJ
   Ding, XY
   Guo, ZT
AF Wu, Jingliang
   Li, Yanying
   Sun, Shujie
   Li, Wenjun
   Sun, Jingui
   Zhu, Liping
   Wang, Zhiqiang
   Yang, Fan
   Wang, Qing
   Ding, Huajie
   Ding, Xueying
   Guo, Zhentao
TI The pH-sensitive chondroitin sulphate-based nanoparticles for
   co-delivery of doxorubicin and berberine enhance the treatment of breast
   cancer
SO INTERNATIONAL JOURNAL OF BIOLOGICAL MACROMOLECULES
LA English
DT Article
DE Breast cancer; cancer associated fibroblasts; Nanomicelle; Combination
   therapy
AB In the tumor microenvironment (TME), cancer associated fibroblasts (CAFs) facilitate drug resistance and tumor metastasis. Therefore, more and more attention has been focused on the regulation of TME by preventing the cross-talk between tumor cells and CAFs in the treatment of breast cancer. In this study, we have combined the benefits of deep drug penetration, pH sensitivity, and tumor-targeting delivery to prepare chondroitin sulphate (CS)-based nanomicelles (BBR/CS-DOX) for the co-delivery of doxorubicin (DOX) and berberine (BBR). A unique MCF-7 + MRC-5 co-cultured cell model and 4 T1 + NIH3T3 co-implanted mice model, were established to simulate the TME of breast cancer (BC). As expected, BBR/CS-DOX could accumulate in tumor egion, be taken up by both tumor cells and CAFs, and improve drug absorption and retention. Compared with free drugs, BBR/CSDOX demonstrated stonger pro-apoptotic and anti-metastatic effect in vitro and in vivo, respectively the histological studies showed that BBR/CS-DOX efficiently prevented the activation of fibroblasts, inhibited extracellular matrix (ECM) deposition, and decreased tumor angiogenesis, showing superior anti-tumor efficacy. In summary, BBR/CS-DOX has the potential to significantly enhance the therapeutic effect of breast cancer through inhibiting the "CAFs-tumor cells" crosstalk, and has promising clinical application prospects.
C1 [Wu, Jingliang; Li, Yanying; Sun, Shujie; Ding, Huajie; Ding, Xueying] Weifang Univ Sci & Technol, Sch Med, Weifang 262700, Peoples R China.
   [Li, Wenjun; Wang, Qing] Weifang Peoples Hosp, Dept Stomatol, Weifang 261000, Peoples R China.
   [Sun, Jingui] Shouguang Peoples Hosp, Dept Oncol, Weifang 262700, Peoples R China.
   [Zhu, Liping; Wang, Zhiqiang] Shouguang Hosp Tradit Chinese Med, Dept Med Oncol, Shouguang 262700, Peoples R China.
   [Yang, Fan] Shandong Kanghua Biotechnol Co Ltd, Weifang 261023, Peoples R China.
   [Guo, Zhentao] Shandong Second Med Univ, Dept Nephrol, Affiliated Hosp, Weifang 261041, Peoples R China.
C3 Weifang University of Science & Technology; Shandong Second Medical
   University
RP Sun, SJ (corresponding author), Weifang Univ Sci & Technol, Sch Med, Weifang 262700, Peoples R China.; Guo, ZT (corresponding author), Shandong Second Med Univ, Dept Nephrol, Affiliated Hosp, Weifang 261041, Peoples R China.
EM shujie202101@163.com; guozt@wfmc.edu.cn
RI Sun, Shujie/Y-2033-2018; Zhu, Li-Ping/AAF-7580-2020
FU National Natural Science Foundation of China [81803464]; Medical &
   Health Development Plan Project of Shandong Province [202213020516];
   Science and Technology Development Program in Weifang [2023GX059,
   2022ZJ1064]; Scientific Research Project of Weifang Health Committee in
   2023 [WFWSJK-2023-155]
FX This work was supported by the National Natural Science Foundation of
   China (No. 81803464) , the Medical & Health Development Plan Project of
   Shandong Province (No. 202213020516) , the Science and Technology
   Development Program in Weifang (Nos. 2023GX059, 2022ZJ1064) and the
   Scientific Research Project of Weifang Health Committee in 2023 (No.
   WFWSJK-2023-155) .
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NR 29
TC 0
Z9 0
U1 11
U2 11
PU ELSEVIER
PI AMSTERDAM
PA RADARWEG 29, 1043 NX AMSTERDAM, NETHERLANDS
SN 0141-8130
EI 1879-0003
J9 INT J BIOL MACROMOL
JI Int. J. Biol. Macromol.
PD NOV
PY 2024
VL 281
AR 136484
DI 10.1016/j.ijbiomac.2024.136484
EA OCT 2024
PN 4
PG 14
WC Biochemistry & Molecular Biology; Chemistry, Applied; Polymer Science
WE Science Citation Index Expanded (SCI-EXPANDED)
SC Biochemistry & Molecular Biology; Chemistry; Polymer Science
GA K0T6J
UT WOS:001341098900001
PM 39414206
DA 2025-03-13
ER

PT J
AU Rubinstein-Achiasaf, L
   Morein, D
   Ben-Yaakov, H
   Liubomirski, Y
   Meshel, T
   Elbaz, E
   Dorot, O
   Pichinuk, E
   Gershovits, M
   Weil, M
   Ben-Baruch, A
AF Rubinstein-Achiasaf, Linor
   Morein, Dina
   Ben-Yaakov, Hagar
   Liubomirski, Yulia
   Meshel, Tsipi
   Elbaz, Eti
   Dorot, Orly
   Pichinuk, Edward
   Gershovits, Michael
   Weil, Miguel
   Ben-Baruch, Adit
TI Persistent Inflammatory Stimulation Drives the Conversion of MSCs to
   Inflammatory CAFs That Promote Pro-Metastatic Characteristics in Breast
   Cancer Cells
SO CANCERS
LA English
DT Article
DE breast cancer; cancer-associated fibroblasts; inflammation; interleukin
   1&#946; mesenchymal stem cells; tumor necrosis factor &#945
ID MESENCHYMAL STEM-CELLS; NECROSIS-FACTOR-ALPHA; TNF-ALPHA; STROMAL CELLS;
   GENE-EXPRESSION; BONE-MARROW; CHEMOKINE RECEPTORS; TUMOR-DEVELOPMENT;
   FIBROBLASTS; INTERLEUKIN-1-BETA
AB Simple Summary
   Breast cancer progression is prominently regulated by the persistent presence of inflammatory mediators and by stromal cells that are located in the tumors. Here, we connected these two elements by demonstrating that potent pro-inflammatory cytokines (tumor necrosis factor alpha and interleukin 1 beta) lead to the conversion of mesenchymal stem cells (MSCs) to inflammatory cancer-associated fibroblasts (CAFs). These inflammation-driven CAFs secrete metastasis-promoting factors that elevate the dispersion, scattering, and migration of breast cancer cells via activation of tumor cell receptors that signal through Ras proteins and via G alpha i proteins; the latter receptors were identified as the chemokine receptors CCR2, CCR5, and CXCR1/2. Together, these findings demonstrate that, in breast tumors, chronic inflammation can induce the deleterious process of MSC-to-CAF conversion and thus sets pro-inflammatory mediators as key targets for inhibition, potentially leading to lower levels of pro-metastatic CAFs in breast tumors.
   The pro-inflammatory cytokines tumor necrosis factor alpha (TNF alpha) and interleukin 1 beta (IL-1 beta) are expressed simultaneously and have tumor-promoting roles in breast cancer. In parallel, mesenchymal stem cells (MSCs) undergo conversion at the tumor site to cancer-associated fibroblasts (CAFs), which are generally connected to enhanced tumor progression. Here, we determined the impact of consistent inflammatory stimulation on stromal cell plasticity. MSCs that were persistently stimulated by TNF alpha + IL-1 beta (generally 14-18 days) gained a CAF-like morphology, accompanied by prominent changes in gene expression, including in stroma/fibroblast-related genes. These CAF-like cells expressed elevated levels of vimentin and fibroblast activation protein (FAP) and demonstrated significantly increased abilities to contract collagen gels. Moreover, they gained the phenotype of inflammatory CAFs, as indicated by the reduced expression of alpha smooth muscle actin (alpha SMA), increased proliferation, and elevated expression of inflammatory genes and proteins, primarily inflammatory chemokines. These inflammatory CAFs released factors that enhanced tumor cell dispersion, scattering, and migration; the inflammatory CAF-derived factors elevated cancer cell migration by stimulating the chemokine receptors CCR2, CCR5, and CXCR1/2 and Ras-activating receptors, expressed by the cancer cells. Together, these novel findings demonstrate that chronic inflammation can induce MSC-to-CAF conversion, leading to the generation of tumor-promoting inflammatory CAFs.
C1 [Rubinstein-Achiasaf, Linor; Morein, Dina; Ben-Yaakov, Hagar; Liubomirski, Yulia; Meshel, Tsipi; Elbaz, Eti; Weil, Miguel; Ben-Baruch, Adit] Tel Aviv Univ, Shmunis Sch Biomed & Canc Res, George S Wise Fac Life Sci, IL-6997801 Tel Aviv, Israel.
   [Dorot, Orly; Pichinuk, Edward] Tel Aviv Univ, Blavatnik Ctr Drug Discovery, IL-6997801 Tel Aviv, Israel.
   [Gershovits, Michael] Weizmann Inst Sci, Nancy & Stephen Grand Israel Natl Ctr Personalize, IL-761001 Rehovot, Israel.
C3 Tel Aviv University; Tel Aviv University; Weizmann Institute of Science
RP Ben-Baruch, A (corresponding author), Tel Aviv Univ, Shmunis Sch Biomed & Canc Res, George S Wise Fac Life Sci, IL-6997801 Tel Aviv, Israel.
EM linoru@gmail.com; Dinamorein1@gmail.com; etzion.hagar1@gmail.com;
   yulialiub@gmail.com; tsipi.meshel@gmail.com; elbaztetro@gmail.com;
   orly.dorot@gmail.com; gershovm@weizmann.ac.il; weilmiguel@gmail.com;
   aditbb@tauex.tau.ac.il
OI Dorot, Orly/0000-0002-5467-2617; Pichinuk, Eddy/0000-0001-8488-8710
FU Israel Science Foundation; Federico Foundation
FX This study was supported by the Israel Science Foundation and by
   Federico Foundation.
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NR 106
TC 29
Z9 30
U1 1
U2 21
PU MDPI
PI BASEL
PA ST ALBAN-ANLAGE 66, CH-4052 BASEL, SWITZERLAND
EI 2072-6694
J9 CANCERS
JI Cancers
PD MAR
PY 2021
VL 13
IS 6
AR 1472
DI 10.3390/cancers13061472
PG 28
WC Oncology
WE Science Citation Index Expanded (SCI-EXPANDED)
SC Oncology
GA RE7SH
UT WOS:000634348400001
PM 33806906
OA gold, Green Published
DA 2025-03-13
ER

PT J
AU Lee, CM
   Hwang, Y
   Jeong, JW
   Kim, M
   Lee, JH
   Bae, SJ
   Ahn, SG
   Fang, SS
AF Lee, Chae Min
   Hwang, Yeseong
   Jeong, Jae Woong
   Kim, Minki
   Lee, Janghee
   Bae, Soong June
   Ahn, Sung Gwe
   Fang, Sungsoon
TI <i>BRCA1</i> mutation promotes sprouting angiogenesis in inflammatory
   cancer-associated fibroblast of triple-negative breast cancer
SO CELL DEATH DISCOVERY
LA English
DT Article
ID GERMLINE MUTATIONS; CELL; CARCINOMA; MEDIATOR; OUTCOMES; GROWTH; VEGF
AB Triple-negative breast cancer (TNBC) is an aggressive breast cancer subtype with inferior outcomes owing to its low treatment response and high invasiveness. Based on abundant cancer-associated fibroblasts (CAFs) and frequent mutation of breast cancer-associated 1 (BRCA1) in TNBC, the characteristics of CAFs in TNBC patients with BRCA1 mutation compared to wild-type were investigated using single-cell analysis. Intriguingly, we observed that characteristics of inflammatory CAFs (iCAFs) were enriched in patients with BRCA1 mutation compared to the wild-type. iCAFs in patients with BRCA1 mutation exhibited outgoing signals to endothelial cells (ECs) clusters, including chemokine (C-X-C motif) ligand (CXCL) and vascular endothelial growth factor (VEGF). During CXCL signaling, the atypical chemokine receptor 1 (ACKR1) mainly interacts with CXCL family members in tumor endothelial cells (TECs). ACKR1-high TECs also showed high expression levels of angiogenesis-related genes, such as ANGPT2, MMP1, and SELE, which might lead to EC migration. Furthermore, iCAFs showed VEGF signals for FLT1 and KDR in TECs, which showed high co-expression with tip cell marker genes, including ZEB1 and MAFF, involved in sprouting angiogenesis. Moreover, BRCA1 mutation patients with relatively abundant iCAFs and tip cell gene expression exhibited a limited response to neoadjuvant chemotherapy, including cisplatin and bevacizumab. Importantly, our study observed the intricate link between iCAFs-mediated angiogenesis and chemoresistance in TNBC with BRCA1 mutation.
C1 [Lee, Chae Min; Hwang, Yeseong; Kim, Minki; Fang, Sungsoon] Yonsei Univ Coll Med, Grad Sch Med Sci, Brain Korea Project 21, Seoul 03722, South Korea.
   [Lee, Chae Min; Hwang, Yeseong; Kim, Minki; Fang, Sungsoon] Yonsei Univ Coll Med, Gangnam Severance Hosp, Dept Biomed Sci, Seoul 03722, South Korea.
   [Jeong, Jae Woong] Yonsei Univ Coll Med, Dept Med, Seoul 03722, South Korea.
   [Lee, Janghee] Hallym Univ, Sacred Heart Hosp, Dept Surg, Dongtan 18450, South Korea.
   [Lee, Janghee] Yonsei Univ Grad Sch, Dept Med, Seoul 03722, South Korea.
   [Bae, Soong June; Ahn, Sung Gwe] Yonsei Univ Coll Med, Gangnam Severance Hosp, Dept Surg, Seoul 06273, South Korea.
   [Bae, Soong June; Ahn, Sung Gwe] Yonsei Univ Coll Med, Inst Breast Canc Precis Med, Seoul 06273, South Korea.
   [Fang, Sungsoon] Yonsei Univ Coll Med, Chron Intractable Dis Syst Med Res Ctr, Seoul 03722, South Korea.
   [Fang, Sungsoon] Yonsei Univ Coll Med, Severance Inst Vasc & Metab Res, Seoul 03722, South Korea.
C3 Yonsei University; Yonsei University Health System; Yonsei University;
   Yonsei University Health System; Yonsei University; Yonsei University
   Health System; Hallym University; Yonsei University; Yonsei University
   Health System; Yonsei University; Yonsei University Health System;
   Yonsei University; Yonsei University Health System; Yonsei University;
   Yonsei University Health System
RP Fang, SS (corresponding author), Yonsei Univ Coll Med, Grad Sch Med Sci, Brain Korea Project 21, Seoul 03722, South Korea.; Fang, SS (corresponding author), Yonsei Univ Coll Med, Gangnam Severance Hosp, Dept Biomed Sci, Seoul 03722, South Korea.; Ahn, SG (corresponding author), Yonsei Univ Coll Med, Gangnam Severance Hosp, Dept Surg, Seoul 06273, South Korea.; Ahn, SG (corresponding author), Yonsei Univ Coll Med, Inst Breast Canc Precis Med, Seoul 06273, South Korea.; Fang, SS (corresponding author), Yonsei Univ Coll Med, Chron Intractable Dis Syst Med Res Ctr, Seoul 03722, South Korea.; Fang, SS (corresponding author), Yonsei Univ Coll Med, Severance Inst Vasc & Metab Res, Seoul 03722, South Korea.
EM ASG2004@yuhs.ac; sfang@yuhs.ac
RI Ahn, Sung Gwe/AFD-8122-2022; FANG, Sungsoon/HKW-2279-2023
OI Hwang, Yeseong/0000-0002-1739-4443; Bae, Soong June/0000-0002-0012-9694;
   Lee, Chae Min/0009-0008-7290-4304; Fang, Sungsoon/0000-0003-0201-5567;
   Jeong, Jae Woong/0000-0003-4740-3467; Ahn, Sung Gwe/0000-0002-8778-9686
FU National Research Foundation of Korea (NRF)
FX No Statement Available
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NR 63
TC 3
Z9 3
U1 0
U2 5
PU SPRINGERNATURE
PI LONDON
PA CAMPUS, 4 CRINAN ST, LONDON, N1 9XW, ENGLAND
EI 2058-7716
J9 CELL DEATH DISCOV
JI Cell Death Discov.
PD JAN 5
PY 2024
VL 10
IS 1
AR 5
DI 10.1038/s41420-023-01768-5
PG 13
WC Cell Biology
WE Science Citation Index Expanded (SCI-EXPANDED)
SC Cell Biology
GA EE0H4
UT WOS:001137118900003
PM 38182557
OA gold, Green Submitted, Green Published
DA 2025-03-13
ER

PT J
AU Li, A
   Chen, P
   Leng, Y
   Kang, JH
AF Li, Ang
   Chen, Ping
   Leng, Ye
   Kang, Jiuhong
TI Histone deacetylase 6 regulates the immunosuppressive properties of
   cancer-associated fibroblasts in breast cancer through the
   STAT3-COX2-dependent pathway
SO ONCOGENE
LA English
DT Article
ID TUMOR-STROMA; HDAC6; MICROENVIRONMENT; CELLS; INFLAMMATION; INHIBITORS;
   CHEMOTHERAPY; METASTASES; PROMOTION; FIBROSIS
AB Cancer-associated fibroblasts (CAFs) are important components in breast tumors and essential for tumor progression and metastasis. However, the role of epigenetic modification in driving the function of CAFs within breast tumors is only marginally known. Herein, we reported that histone deacetylase 6 (HDAC6), one of class II histone deacetylases, was frequently upregulated in the CAFs of breast tumor and promotes an immunosuppressive microenvironment. The genetic or pharmacologic disruption of HDAC6 in CAFs delays tumor growth, inhibits the tumor recruitment of myeloid-derived suppressor cells and regulatory T cells, alters the macrophage phenotype switch, and increases the CD8+ and CD4+ T-cell activation in vivo. Mechanistically, we identified prostaglandin E2/cyclooxygenase-2 (COX2) as a major target of HDAC6 in CAFs by regulating STAT3 activation. Overexpressing COX2 in HDAC6-knockdown CAFs can completely restore the immunosuppressive properties of the fibroblasts. Clinically, a positive correlation among the stromal expression levels of HDAC6, p-STAT3, and COX2 in human breast cancer was observed. High-stromal expression of HDAC6 was markedly associated with poor survival outcome. Overall, our findings indicated that fibroblastic HDAC6 was a vital epigenetic mediator involved in programming an immunosuppressive tumor microenvironment that dampens antitumor immunity. Thus, HDAC6 may be a good potential target to improve breast cancer immunotherapy.
C1 [Li, Ang; Chen, Ping; Leng, Ye; Kang, Jiuhong] Tongji Univ, Clin & Translat Res Ctr, Shanghai Matern & Infant Hlth Hosp 1, Shanghai Key Lab Signaling & Dis Res,Sch Life Sci, 1239 Siping Rd, Shanghai 200092, Peoples R China.
C3 Tongji University
RP Kang, JH (corresponding author), Tongji Univ, Clin & Translat Res Ctr, Shanghai Matern & Infant Hlth Hosp 1, Shanghai Key Lab Signaling & Dis Res,Sch Life Sci, 1239 Siping Rd, Shanghai 200092, Peoples R China.
EM jhkang@tongji.edu.cn
FU Ministry of Science and Technology of China [2016YFA0101300]; Science
   and Technology Commission of Shanghai Municipality [16PJ1410200];
   Fundamental Research Funds for the Central Universities [1501219171,
   22120170068]
FX This work was supported by grants obtained from the Ministry of Science
   and Technology of China (grant #2016YFA0101300), Science and Technology
   Commission of Shanghai Municipality (grant #16PJ1410200), and the
   Fundamental Research Funds for the Central Universities (grant
   #1501219171, 22120170068).
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NR 50
TC 63
Z9 70
U1 1
U2 22
PU NATURE PUBLISHING GROUP
PI LONDON
PA MACMILLAN BUILDING, 4 CRINAN ST, LONDON N1 9XW, ENGLAND
SN 0950-9232
EI 1476-5594
J9 ONCOGENE
JI Oncogene
PD NOV 8
PY 2018
VL 37
IS 45
BP 5952
EP 5966
DI 10.1038/s41388-018-0379-9
PG 15
WC Biochemistry & Molecular Biology; Oncology; Cell Biology; Genetics &
   Heredity
WE Science Citation Index Expanded (SCI-EXPANDED)
SC Biochemistry & Molecular Biology; Oncology; Cell Biology; Genetics &
   Heredity
GA GZ6PQ
UT WOS:000449562500004
PM 29980788
DA 2025-03-13
ER

PT J
AU Zhao, LY
   Sun, Y
   Hou, YX
   Peng, QL
   Wang, LY
   Luo, HJ
   Tang, X
   Zeng, ZY
   Liu, MR
AF Zhao, Liuyang
   Sun, Yan
   Hou, Yixuan
   Peng, Qiongle
   Wang, Liyang
   Luo, Haojun
   Tang, Xi
   Zeng, Zongyue
   Liu, Manran
TI MiRNA expression analysis of cancer-associated fibroblasts and normal
   fibroblasts in breast cancer
SO INTERNATIONAL JOURNAL OF BIOCHEMISTRY & CELL BIOLOGY
LA English
DT Article
DE CAFs; miRNA; Breast cancer; Tumor microenvironment
ID GENE-EXPRESSION; MESENCHYMAL TRANSITION; STROMAL FIBROBLASTS; MICRORNA
   TARGETS; MESSENGER-RNAS; TUMOR STROMA; GROWTH; BETA; MICROENVIRONMENT;
   DIFFERENTIATION
AB Cancer-associated fibroblasts (CAFs) promote tumorigenesis, growth, invasion and metastasis of cancer, whereas normal fibroblasts (NFs) are thought to suppress tumor progression. Little is known about miRNAs expression differences between CAFs and NFs or the patient-to-patient variability in miRNAs expression in breast cancer. We established primary cultures of CAFs and paired NFs from six resected breast tumor tissues that had not previously received radiotherapy or chemotherapy treatment and analyzed with miRNAs microarrays. The array data were analyzed using paired SAM t-test and filtered according to alpha and q values. Pathway analysis was conducted using DAVID v6.7. We identified 11 dysregulated miRNAs in CAFs: three were up-regulated (miR-221-5p, miR-31-3p, miR-221-3p), while eight were down-regulated (miR-205, miR-200b, miR-200c, miR-141, miR-101, miR-342-3p, let-7g, miR-26b). Their target genes are known to affect cell differentiation, adhesion, migration, proliferation, secretion and cell-cell interaction. By our knowledge it is firstly identify the expression profiles of miRNAs between CAFs and NFs and revealed their regulation on the associated signaling pathways. (C) 2012 Elsevier Ltd. All rights reserved.
C1 [Zhao, Liuyang; Sun, Yan; Peng, Qiongle; Wang, Liyang; Luo, Haojun; Tang, Xi; Zeng, Zongyue; Liu, Manran] Chongqing Med Univ, Chinese Minist Educ, Key Lab Lab Med Diagnost, Chongqing 400016, Peoples R China.
   [Hou, Yixuan] Chongqing Med Univ, Expt Teaching Ctr Basic Med Sci, Chongqing 400016, Peoples R China.
   [Luo, Haojun] Chongqing Med Univ, Affiliated Hosp 1, Dept Gen Surg, Chongqing 400016, Peoples R China.
C3 Chongqing Medical University; Chongqing Medical University; Chongqing
   Medical University
RP Liu, MR (corresponding author), Chongqing Med Univ, Chinese Minist Educ, Key Lab Lab Med Diagnost, 1 Yi Xue Yuan Rd, Chongqing 400016, Peoples R China.
EM mliu-hncq@hotmail.com
RI Wang, Chien Ming/F-6598-2017
OI Peng, Qiongle/0000-0001-9035-3093; Sun, Yan/0000-0003-2595-0961; li,
   lu/0009-0009-8381-3093
FU National Natural Science Foundation of China [NSFC 81072147, NSFC
   30940096]; Natural Science Foundation of Chongqing Science & Technology
   Commission, China [CSTC2010BB5099]; Major Program of Chongqing Medical
   University [XBZD201006]; Doctoral Fund of Ministry of Education, China
   [20105503110001]; Scientific Research Foundation for the Returned
   Overseas Scholars of Chongqing Medical University
FX This work was supported in part by National Natural Science Foundation
   of China (NSFC 81072147, NSFC 30940096), the Natural Science Foundation
   of Chongqing Science & Technology Commission, China (CSTC2010BB5099),
   the Major Program of Chongqing Medical University XBZD201006, the
   Doctoral Fund of Ministry of Education, China (20105503110001) and the
   Scientific Research Foundation for the Returned Overseas Scholars of
   Chongqing Medical University. We deeply appreciate Dr. Sarah Hein and
   Prof. Yi Li from Baylor College of Medicine, USA, and Dr. Harvey Ho
   working at the University of Auckland, New Zealand revising this
   manuscript. We also deeply appreciate the anonymous reviewers for their
   helpful comments and suggestions.
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NR 50
TC 109
Z9 114
U1 0
U2 42
PU PERGAMON-ELSEVIER SCIENCE LTD
PI OXFORD
PA THE BOULEVARD, LANGFORD LANE, KIDLINGTON, OXFORD OX5 1GB, ENGLAND
SN 1357-2725
EI 1878-5875
J9 INT J BIOCHEM CELL B
JI Int. J. Biochem. Cell Biol.
PD NOV
PY 2012
VL 44
IS 11
BP 2051
EP 2059
DI 10.1016/j.biocel.2012.08.005
PG 9
WC Biochemistry & Molecular Biology; Cell Biology
WE Science Citation Index Expanded (SCI-EXPANDED)
SC Biochemistry & Molecular Biology; Cell Biology
GA 020DF
UT WOS:000309788200039
PM 22964023
DA 2025-03-13
ER

PT J
AU Wu, YF
   Chen, RJ
   Ni, ST
   Hu, KL
AF Wu, Yufan
   Chen, Rujing
   Ni, Shuting
   Hu, Kaili
TI Biomimetic " nano-spears " for CAFs-targeting: splintered three "
   shields " with enhanced cisplatin anti-TNBC efficiency
SO JOURNAL OF CONTROLLED RELEASE
LA English
DT Article
DE Triple -negative breast cancer; Silybin; Cisplatin; Cancer -associated
   fibroblasts; Biomimetic nanoparticles
ID CANCER-ASSOCIATED FIBROBLASTS; EPITHELIAL-MESENCHYMAL TRANSITION;
   NEGATIVE BREAST-CANCER; STROMAL FIBROBLASTS; CELLS; SILIBININ;
   MICROENVIRONMENT; NANOPARTICLES; DELIVERY; GROWTH
AB The treatment dilemma of triple-negative breast cancer (TNBC) revolves around drug resistance and metastasis. Cancer-associated fibroblasts (CAFs) contribute to cisplatin (Cis) resistance and further metastasis in TNBC, making TNBC a difficult-to-treat disease. The dense stromal barrier which restricts drug delivery, invasive phenotype of tumor cells, and immunosuppressive tumor microenvironment (TME) induced by CAFs serve as three "shields" for TNBC against Cis therapy. Here, we designed a silybin-loaded biomimetic nanoparticle coated with anisamide-modified red blood cell membrane (ARm@SNP) as a "nanospear" for CAFs-targeting, which could shatter the "shields" and significantly exhibit inhibitory effect on 4T1 cells in combination with Cis both in vitro and in vivo. The ARm@SNP/Cis elicited 4T1 tumor growth arrest and destroyed three "shields" as follows: disintegrating the stromal barrier by inhibiting blood vessels growth and the expression of fibronectin; decreasing 4T1 cell invasion and metastasis by affecting the TGF-beta/Twist/EMT pathway which impeded EMT activation; reversing the immunosuppressive microenvironment by increasing the activity and infiltration of immunocompetent cells. Based on CAFs-targeting, ARm@SNP reversed the resistance of Cis, remodeled the TME and inhibited invasion and metastasis while significantly improving the therapeutic effect of Cis on 4T1 tumorbearing mice, providing a promising approach for treating intractable TNBC.
C1 [Hu, Kaili] Shanghai Univ Tradit Chinese Med, Sch Pharm, Shanghai 201203, Peoples R China.
   [Wu, Yufan; Chen, Rujing; Ni, Shuting; Hu, Kaili] Shanghai Univ Tradit Chinese Med, Inst Interdisciplinary Integrat Med Res, Shanghai Frontiers Sci Ctr TCM Chem Biol, 1200 Cailun Rd, Shanghai 201203, Peoples R China.
   [Chen, Rujing] Shanghai Jiao Tong Univ, Ruijin Hosp, Dept Pharm, Sch Med, Shanghai 200025, Peoples R China.
C3 Shanghai University of Traditional Chinese Medicine; Shanghai University
   of Traditional Chinese Medicine; Shanghai Jiao Tong University
RP Hu, KL (corresponding author), Shanghai Univ Tradit Chinese Med, Sch Pharm, Shanghai 201203, Peoples R China.; Ni, ST; Hu, KL (corresponding author), Shanghai Univ Tradit Chinese Med, Inst Interdisciplinary Integrat Med Res, Shanghai Frontiers Sci Ctr TCM Chem Biol, 1200 Cailun Rd, Shanghai 201203, Peoples R China.
EM stella_ni2021@163.com; kaili-hu@163.com
RI Hu, Kaili/KQU-3514-2024
OI Hu, Kaili/0000-0003-0269-909X
FU The "Shuguang Program" by Shanghai Education Development Foundation;
   Shanghai Municipal Education Commission [22SG41]; National Natural
   Science Foundation of China [81773909]; Innovation Team and Talents
   Cultivation Program of National Administration of Traditional Chinese
   Medicine [ZYYCXTDD-202004]; Three-year Action Plan for Shanghai TCM
   Development and Inheritance Program [ZY[2021-2023]-0401]; Shanghai
   Municipal Commission of Health and Family Planning [2017YQ060];
   Combination of the medical care and health project of the Shanghai
   University of Traditional Chinese Medicine [YYKC-2021-01-008]
FX This work was supported by "Shuguang Program" supported by Shanghai
   Education Development Foundation and Shanghai Municipal Education
   Commission (22SG41), the National Natural Science Foundation of China
   (Grant No. 81773909), Innovation Team and Talents Cultivation Program of
   National Administration of Traditional Chinese Medicine
   (ZYYCXTDD-202004), Three-year Action Plan for Shanghai TCM Development
   and Inheritance Program (ZY[2021-2023]-0401), Shanghai Municipal
   Commission of Health and Family Planning (Grant No. 2017YQ060, China),
   and the combination of the medical care and health project of the
   Shanghai University of Traditional Chinese Medicine (YYKC-2021-01-008).
   We thank the staff members of the Integrated Laser Microscopy System at
   the National Facility for Protein Science in Shanghai (NFPS), Shanghai
   Advanced Research Institute, Chinese Academy of Sciences, China for
   instrument guidance. The graphical abstract and Fig. 2A were created
   with BioRender.com.
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NR 67
TC 3
Z9 3
U1 11
U2 25
PU ELSEVIER
PI AMSTERDAM
PA RADARWEG 29, 1043 NX AMSTERDAM, NETHERLANDS
SN 0168-3659
EI 1873-4995
J9 J CONTROL RELEASE
JI J. Control. Release
PD JUN
PY 2024
VL 370
BP 556
EP 569
DI 10.1016/j.jconrel.2024.04.053
EA MAY 2024
PG 14
WC Chemistry, Multidisciplinary; Pharmacology & Pharmacy
WE Science Citation Index Expanded (SCI-EXPANDED)
SC Chemistry; Pharmacology & Pharmacy
GA TJ2Y9
UT WOS:001240843600001
PM 38697316
DA 2025-03-13
ER

PT J
AU Cohen, N
   Shani, O
   Raz, Y
   Sharon, Y
   Hoffman, D
   Abramovitz, L
   Erez, N
AF Cohen, N.
   Shani, O.
   Raz, Y.
   Sharon, Y.
   Hoffman, D.
   Abramovitz, L.
   Erez, N.
TI Fibroblasts drive an immunosuppressive and growth-promoting
   microenvironment in breast cancer via secretion of Chitinase 3-like 1
SO ONCOGENE
LA English
DT Article
ID TUMOR-ASSOCIATED MACROPHAGES; INFLAMMATION; CELLS; EXPRESSION; YKL-40;
   PROGRESSION; METASTASIS; CHI3L1; CHEMOTHERAPY; RESPONSES
AB Cancer-Associated Fibroblasts (CAFs) are the most prominent stromal cell type in breast tumors. CAFs promote tumor growth and metastasis by multiple mechanisms, including by mediating tumor-promoting inflammation. Immune modulation in the tumor microenvironment plays a central role in determining disease outcome. However, the functional interactions of CAFs with immune cells are largely unknown. Here we report a novel signaling axis between fibroblasts, cancer cells and immune cells in breast tumors that drives an immunosuppressive microenvironment, mediated by CAF-derived Chi3L1. We demonstrate that Chi3L1 is highly upregulated in CAFs isolated from mammary tumors and pulmonary metastases of transgenic mice, and in the stroma of human breast carcinomas. Genetic ablation of Chi3L1 in fibroblasts in vivo attenuated tumor growth, macrophage recruitment and reprogramming to an M2-like phenotype, enhanced tumor infiltration by CD8(+) and CD4(+) T cells and promoted a Th1 phenotype. These results indicate that CAF-derived Chi3L1 promotes tumor growth and shifts the balance of the immune milieu towards type 2 immunity. Taken together, our findings implicate fibroblast-derived Chi3L1 as a novel key player in the complex reciprocal interactions of stromal cells that facilitate tumor progression and metastasis, and suggest that targeting Chi3L1 may be clinically beneficial in breast cancer.
C1 [Cohen, N.; Shani, O.; Raz, Y.; Sharon, Y.; Hoffman, D.; Abramovitz, L.; Erez, N.] Tel Aviv Univ, Sackler Sch Med, Dept Pathol, IL-69978 Tel Aviv, Israel.
   [Raz, Y.] Tel Aviv Sourasky Med Ctr, Dept Obstet & Gynecol, Tel Aviv, Israel.
C3 Tel Aviv University; Sackler Faculty of Medicine; Tel Aviv University;
   Sackler Faculty of Medicine; Tel Aviv Sourasky Medical Center
RP Erez, N (corresponding author), Tel Aviv Univ, Sackler Sch Med, Dept Pathol, IL-69978 Tel Aviv, Israel.
EM netaerez@post.tau.ac.il
RI Yana, Yael/S-7100-2019; Erez, Neta/G-8584-2012
OI Erez, Neta/0000-0001-6506-9074; Cohen, Noam/0009-0003-7047-8843;
   Abramovitz, Lilach/0000-0001-9961-9986
FU European Research Council under the European Union's Horizon research
   and innovation programme [637069 MetCAF]; Israel Science Foundation
   [813/12]; Israel Cancer Association; Israel Cancer Research Fund
   (Research Career Development Award)
FX This research was supported by grants to NE from the European Research
   Council under the European Union's Horizon 2020 research and innovation
   programme (grant agreement no. 637069 MetCAF), from the Israel Science
   Foundation (#813/12), the Israel Cancer Association and The Israel
   Cancer Research Fund (Research Career Development Award). We would like
   to thank Dr Yaron Carmi for scientific discussions, Shahar Biechonski
   and Hila Schwartz for their help with data analysis and helpful
   discussions, and Elad Yana for graphical assistance. We thank Dr Ariel
   Munitz for critical reading of the manuscript. This work was performed
   in partial fulfillment of the requirements for a PhD of Noam Cohen,
   Sackler School of Medicine, Tel Aviv University.
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NR 53
TC 214
Z9 235
U1 2
U2 17
PU NATURE PUBLISHING GROUP
PI LONDON
PA MACMILLAN BUILDING, 4 CRINAN ST, LONDON N1 9XW, ENGLAND
SN 0950-9232
EI 1476-5594
J9 ONCOGENE
JI Oncogene
PD AUG 3
PY 2017
VL 36
IS 31
BP 4457
EP 4468
DI 10.1038/onc.2017.65
PG 12
WC Biochemistry & Molecular Biology; Oncology; Cell Biology; Genetics &
   Heredity
WE Science Citation Index Expanded (SCI-EXPANDED)
SC Biochemistry & Molecular Biology; Oncology; Cell Biology; Genetics &
   Heredity
GA FC4JL
UT WOS:000406806000008
PM 28368410
OA hybrid, Green Accepted, Green Published
DA 2025-03-13
ER

PT J
AU Yamaguchi, K
   Hara, Y
   Kitano, I
   Hamamoto, T
   Kiyomatsu, K
   Yamasaki, F
   Yamaguchi, R
   Nakazono, T
   Egashira, R
   Imaizumi, T
   Irie, H
AF Yamaguchi, Ken
   Hara, Yukiko
   Kitano, Isao
   Hamamoto, Takahiro
   Kiyomatsu, Kazumitsu
   Yamasaki, Fumio
   Yamaguchi, Rin
   Nakazono, Takahiko
   Egashira, Ryoko
   Imaizumi, Takeshi
   Irie, Hiroyuki
TI Relationship between MRI findings and invasive breast cancer with
   podoplanin-positive cancer-associated fibroblasts
SO BREAST CANCER
LA English
DT Article
DE Breast cancer; Cancer-associated fibroblasts; Magnetic resonance
   imaging; Podoplanin
ID STROMAL FIBROBLASTS; POOR-PROGNOSIS; TUMOR STROMA; EXPRESSION;
   MICROENVIRONMENT; ENHANCEMENT; CARCINOMAS; VALUES; WOMEN
AB Objective Purpose of our study is to assess the relationship between MRI findings and invasive breast cancer (IBC) with cancer-associated fibroblasts (CAFs) that are positive for podoplanin. Methods We retrospectively analyzed the consecutive 109 IBCs. The IBCs were dichotomized as with (+) or without (-) podoplanin-positive CAFs. In MRI analyses, the dichotomized IBCs were compared the lesion to muscle ratio (L/M ratio) in STIR images, the ADC value, the distribution of kinetic parameters, and morphological findings. Results Of the 109 IBCs, 28 (26%) IBCs had podoplanin(+) CAFs. Compared to the podoplanin(-) group, the podoplanin(+) group tended to have a more malignant pathological status. In the STIR images, the podoplanin(+) group had significantly higher L/M ratio (7.59 vs. 6.55, p = 0.040). In a dynamic study, the podoplanin(+) group had a significantly higher percentage of the washout pattern (42.21% vs. 29.43%, p = 0.045). There were 23 mass lesions and 5 non-mass enhancement (NME) lesions in the podoplanin(+) group, and 69 mass lesions and 12 NME lesions in the podoplanin(-) group. The mass lesions of the podoplanin(-) group had a significantly higher likelihood of showing an irregular shape (n = 47 vs. 8, p = 0.035). The podoplanin(+) group's lesions had a significantly higher likelihood of showing a circumscribed margin (n = 14 vs. 6, p < 0.001) and a rim enhancement (n = 10 vs. 13, p = 0.047). In multivariate analyses, only high nuclear grade was significant predictive value of podoplanin(+) CAFs. Conclusion Although not significant in multivariate analyses, MRI findings may be used to determine the podoplanin-positive CAF status of invasive breast cancer.
C1 [Yamaguchi, Ken; Nakazono, Takahiko; Egashira, Ryoko; Imaizumi, Takeshi; Irie, Hiroyuki] Saga Univ, Fac Med, Dept Radiol, 5-1-1 Nabeshima, Saga 8498501, Japan.
   [Hara, Yukiko; Kitano, Isao] Saga Cent Hosp, Dept Radiol, 3-8-1 Hyogominami, Saga 8498522, Japan.
   [Hamamoto, Takahiro] Ajisai Clin, 1-9-38 Ekimaechuo, Saga 8400801, Japan.
   [Kiyomatsu, Kazumitsu] Saga Cent Hosp, Dept Surg, 3-8-1 Hyogominami, Saga 8498522, Japan.
   [Yamasaki, Fumio] Saga Cent Hosp, Dept Pathol, 3-8-1 Hyogominami, Saga 8498522, Japan.
   [Yamaguchi, Rin] Kurume Univ Med Ctr, Dept Pathol & Lab Med, 155-1 Kokubu, Kurume, Fukuoka 8590863, Japan.
C3 Saga University
RP Yamaguchi, K (corresponding author), Saga Univ, Fac Med, Dept Radiol, 5-1-1 Nabeshima, Saga 8498501, Japan.
EM yamaguk@cc.saga-u.ac.jp; hayukira@yahoo.co.jp;
   kitanoisao130@yahoo.co.jp; hamamoto@ajisaiclinic.com;
   kiyomatsu-kazumitsu@saga.jcho.go.jp; saga_yamasakif@yahoo.co.jp;
   rin@med.kurume-u.ac.jp; nakazot@cc.saga-u.ac.jp;
   egashira@cc.saga-u.ac.jp; imaizumt@cc.saga-u.ac.jp; irie@cc.saga-u.ac.jp
RI Egashira, Ryoko/AAO-8510-2021
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NR 37
TC 5
Z9 6
U1 0
U2 4
PU SPRINGER JAPAN KK
PI TOKYO
PA SHIROYAMA TRUST TOWER 5F, 4-3-1 TORANOMON, MINATO-KU, TOKYO, 105-6005,
   JAPAN
SN 1340-6868
EI 1880-4233
J9 BREAST CANCER-TOKYO
JI Breast Cancer
PD MAY
PY 2021
VL 28
IS 3
BP 572
EP 580
DI 10.1007/s12282-020-01198-6
EA JAN 2021
PG 9
WC Oncology; Obstetrics & Gynecology
WE Science Citation Index Expanded (SCI-EXPANDED)
SC Oncology; Obstetrics & Gynecology
GA RR2EP
UT WOS:000604454000002
PM 33389554
DA 2025-03-13
ER

PT J
AU -Tetsuo, FS
   Arioka, M
   Miura, K
   Inoue, T
   Igawa, K
   Tomooka, K
   Sasaguri, T
AF -Tetsuo, Fumi Seto
   Arioka, Masaki
   Miura, Koichi
   Inoue, Takeru
   Igawa, Kazunobu
   Tomooka, Katsuhiko
   Sasaguri, Toshiyuki
TI DIF-1 exhibits anticancer activity in breast cancer via inhibition of
   CXCLs/CXCR2 axis-mediated communication between cancer-associated
   fibroblasts and cancer cells
SO INTERNATIONAL IMMUNOPHARMACOLOGY
LA English
DT Article
DE Cancer-associated fibroblast; C-X-C type chemokine ligand; C-X-C type
   chemokine receptor 2; Differentiation-inducing factor-1;
   Tumor-associated macrophage; Tumor microenvironment
ID DIFFERENTIATION-INDUCING FACTOR; TUMOR-ASSOCIATED MACROPHAGES; FACTOR-I;
   CYCLIN D1; CHEMOTHERAPY; METASTASIS; EXPRESSION; MICROENVIRONMENT;
   PHOSPHORYLATION; IMMUNOTHERAPY
AB The tumor microenvironment (TME), largely composed of tumor-associated macrophages (TAMs) and cancerassociated fibroblasts (CAFs), plays a key role in cancer progression. A small molecule, differentiationinducing factor-1 (DIF-1) secreted by Dictyostelium discoideum, is known to exhibit anticancer activity; however, its effect on the TME remains unknown. In this study, we investigated the effect of DIF-1 on the TME using mouse triple-negative breast cancer 4T1-GFP cells, mouse macrophage RAW 264.7 cells, and mouse primary dermal fibroblasts (DFBs). Polarization of 4T1 cell-conditioned medium-induced macrophage into TAMs was not affected by DIF-1. In contrast, DIF-1 decreased 4T1 cell co-culturing-induced C-X-C motif chemokine ligand 1 (CXCL1), CXCL5, and CXCL7 expression in DFBs and suppressed DFB differentiation into CAF-like cells. Additionally, DIF-1 inhibited C-X-C motif chemokine receptor 2 (CXCR2) expression in 4T1 cells. Immunohistochemical analyses of tumor tissue samples excised from breast cancer-bearing mice showed that DIF-1 did not affect the number of CD206-positive TAMs; however, it decreased the number of alpha-smooth muscle actin-positive CAFs and CXCR2 expression. These results indicated that the anticancer effect of DIF-1 was partially attributed to the inhibition of CXCLs/CXCR2 axis-mediated communication between breast cancer cells and CAFs.
C1 [-Tetsuo, Fumi Seto; Arioka, Masaki; Miura, Koichi; Inoue, Takeru; Sasaguri, Toshiyuki] Kyushu Univ, Fac Med Sci, Dept Clin Pharmacol, Fukuoka, Japan.
   [-Tetsuo, Fumi Seto] Nagasaki Univ, Grad Sch Biochem Sci, Dept Microbiol & Oral Infect, Nagasaki, Japan.
   [Arioka, Masaki] Univ Occupat & Environm Hlth, Sch Med, Dept Pharmacol, Kitakyushu, Japan.
   [Igawa, Kazunobu] Kumamoto Univ, Grad Sch Sci & Technol, Dept Chem, Kumamoto, Japan.
   [Tomooka, Katsuhiko] Kyushu Univ, Inst Mat Chem & Engn, Kasuga, Japan.
   [Arioka, Masaki] Univ Occupat & Environm Hlth, Sch Med, Dept Pharmacol, 1-1 Iseigaoka,Yahatanishi ku, Kitakyushu, Fukuoka 8078555, Japan.
   [Sasaguri, Toshiyuki] Kyushu Univ, Fac Med Sci, Dept Clin Pharmacol, 3-1-1 Maidashi,Higashi ku, Fukuoka 8128582, Japan.
C3 Kyushu University; Nagasaki University; University of Occupational &
   Environmental Health - Japan; Kumamoto University; Kyushu University;
   University of Occupational & Environmental Health - Japan; Kyushu
   University
RP Arioka, M (corresponding author), Univ Occupat & Environm Hlth, Sch Med, Dept Pharmacol, 1-1 Iseigaoka,Yahatanishi ku, Kitakyushu, Fukuoka 8078555, Japan.; Sasaguri, T (corresponding author), Kyushu Univ, Fac Med Sci, Dept Clin Pharmacol, 3-1-1 Maidashi,Higashi ku, Fukuoka 8128582, Japan.
EM tetsuo.fumi@nagasaki-u.ac.jp; arioka@med.uoeh-u.ac.jp;
   miura.koichi.468@m.kyushu-u.ac.jp; moeyo9dragons11@gmail.com;
   igawa@kumamoto-u.ac.jp; ktomooka@cm.kyushu-u.ac.jp;
   sasaguri.toshiyuki.922@m.kyushu-u.ac.jp
RI Igawa, Kazunobu/AAI-3003-2020; Arioka, Masaki/HHR-9578-2022
OI Arioka, Masaki/0000-0001-7722-0843
FU JSPS KAKENHI [JP17K15581, JP20K07292, JP20K22709]; Fukuoka Foundation
   for Sound Health Cancer Research Fund; Medical Science Promotion
   Foundation; Fukuoka Public Health Promotion Organization
FX This study was supported by grants from JSPS KAKENHI (grant numbers:
   JP17K15581, JP20K07292, and JP20K22709), the Fukuoka Foundation for
   Sound Health Cancer Research Fund to M.A, Kaibara Morikazu Medical
   Science Promotion Foundation to M.A, and Fukuoka Public Health Promotion
   Organization to F.S-T.
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   Zhang HF, 2017, CELL DEATH DIS, V8, DOI 10.1038/cddis.2017.180
   Zhou ZJ, 2019, CLIN CANCER RES, V25, P3317, DOI 10.1158/1078-0432.CCR-18-3567
NR 61
TC 3
Z9 3
U1 0
U2 6
PU ELSEVIER
PI AMSTERDAM
PA RADARWEG 29, 1043 NX AMSTERDAM, NETHERLANDS
SN 1567-5769
EI 1878-1705
J9 INT IMMUNOPHARMACOL
JI Int. Immunopharmacol.
PD APR
PY 2023
VL 117
AR 109913
DI 10.1016/j.intimp.2023.109913
EA FEB 2023
PG 10
WC Immunology; Pharmacology & Pharmacy
WE Science Citation Index Expanded (SCI-EXPANDED)
SC Immunology; Pharmacology & Pharmacy
GA G8JV7
UT WOS:000991564600001
PM 36812674
OA Bronze
DA 2025-03-13
ER

PT J
AU Martinez-Outschoorn, UE
   Pavlides, S
   Whitaker-Menezes, D
   Daumer, KM
   Milliman, JN
   Chiavarina, B
   Migneco, G
   Witkiewicz, AK
   Martinez-Cantarin, MP
   Flomenberg, N
   Howell, A
   Pestell, RG
   Lisanti, MP
   Sotgia, F
AF Martinez-Outschoorn, Ubaldo E.
   Pavlides, Stephanos
   Whitaker-Menezes, Diana
   Daumer, Kristin M.
   Milliman, Janet N.
   Chiavarina, Barbara
   Migneco, Gemma
   Witkiewicz, Agnieszka K.
   Martinez-Cantarin, Maria P.
   Flomenberg, Neal
   Howell, Anthony
   Pestell, Richard G.
   Lisanti, Michael P.
   Sotgia, Federica
TI Tumor cells induce the cancer associated fibroblast phenotype via
   caveolin-1 degradation Implications for breast cancer and DCIS therapy
   with autophagy inhibitors
SO CELL CYCLE
LA English
DT Article
DE autophagy; cancer associated fibroblasts; caveolin-1; chloroquine;
   lysosomal degradation; myofibroblast; TGFbeta signaling; tumor stroma
ID TGF-BETA; STROMAL FIBROBLASTS; VIMENTIN EXPRESSION; SYSTEMIC-SCLEROSIS;
   GENE-EXPRESSION; GROWTH; TENASCIN; PROGRESSION; ACTIVATION; MMP-9
AB Loss of stromal caveolin 1 (Cav-1) is a novel biomarker for cancer-associated fibroblasts that predicts poor clinical outcome in breast cancer and DCIS patients. We hypothesized that epithelial cancer cells may have the ability to drive Cav-1 downregulation in adjacent normal fibroblasts, thereby promoting the cancer associated fibroblast phenotype. to test this hypothesis directly, here we developed a novel co-culture model employing (i) human breast cancer cells (MCF7), and (ii) immortalized fibroblasts (hTERT-BJ1), which are grown under defined experimental conditions. Importantly, we show that co-culture of immortalized human fibroblasts with MCF7 breast cancer cells leads to Cav-1 downregulation in fibroblasts. these results were also validated using primary cultures of normal human mammary fibroblasts co-cultured with MCF7 cells. In this system, we show that Cav-1 downregulation is mediated by autophagic/lysosomal degradation, as pre-treatment with lysosome-specific inhibitors rescues Cav-1 expression. Functionally, we demonstrate that fibroblasts co-cultured with MCF7 breast cancer cells acquire a cancer associated fibroblast phenotype, characterized by Cav-1 downregulation, increased expression of myofibroblast markers and extracellular matrix proteins, and constitutive activation of TGF beta/Smad2 signaling. siRNA-mediated Cav-1 downregulation mimics several key changes that occur in co-cultured fibroblasts, clearly indicating that a loss of Cav-1 is a critical initiating factor, driving stromal fibroblast activation during tumorigenesis. As such, this co-culture system can now be used as an experimental model for generating "synthetic" cancer associated fibroblasts (CAFs). More specifically, these "synthetic" CAFs could be used for drug screening to identify novel therapeutics that selectively target the Cav-1-negative tumor micro-environment. our findings also suggest that chloroquine, or other autophagy/lysosome inhibitors, may be useful as anti-cancer agents, to therapeutically restore the expression of stromal Cav-1 in cancer associated fibroblasts. We discuss this possibility, in light of the launch of a new clinical trial that uses chloroquine to treat DCIS patients: PINC (preventing Invasive Breast Neoplasia with Cholorquine) [See http://clinicaltrials.gov/show/NCT01023477].//clinicaltrials.gov/show/NCT01023477
C1 [Martinez-Outschoorn, Ubaldo E.; Flomenberg, Neal; Lisanti, Michael P.] Thomas Jefferson Univ, Dept Med Oncol, Philadelphia, PA 19107 USA.
   [Pavlides, Stephanos; Whitaker-Menezes, Diana; Daumer, Kristin M.; Milliman, Janet N.; Chiavarina, Barbara; Migneco, Gemma; Witkiewicz, Agnieszka K.; Martinez-Cantarin, Maria P.; Flomenberg, Neal; Pestell, Richard G.; Lisanti, Michael P.; Sotgia, Federica] Thomas Jefferson Univ, Jefferson Stem Cell Biol & Regenerat Med Ctr, Philadelphia, PA 19107 USA.
   [Martinez-Outschoorn, Ubaldo E.; Pavlides, Stephanos; Whitaker-Menezes, Diana; Daumer, Kristin M.; Milliman, Janet N.; Chiavarina, Barbara; Migneco, Gemma; Pestell, Richard G.; Lisanti, Michael P.; Sotgia, Federica] Thomas Jefferson Univ, Dept Stem Cell Biol & Regenerat Med, Philadelphia, PA 19107 USA.
   [Martinez-Outschoorn, Ubaldo E.; Pavlides, Stephanos; Whitaker-Menezes, Diana; Daumer, Kristin M.; Milliman, Janet N.; Chiavarina, Barbara; Migneco, Gemma; Pestell, Richard G.; Lisanti, Michael P.; Sotgia, Federica] Thomas Jefferson Univ, Dept Canc Biol, Kimmel Canc Ctr, Philadelphia, PA 19107 USA.
   [Witkiewicz, Agnieszka K.] Thomas Jefferson Univ, Dept Pathol, Jefferson Ctr Pancreat Biliary & Related Canc, Philadelphia, PA 19107 USA.
   [Martinez-Cantarin, Maria P.] Thomas Jefferson Univ, Dept Med, Div Nephrol, Philadelphia, PA 19107 USA.
   [Howell, Anthony; Lisanti, Michael P.; Sotgia, Federica] Univ Manchester, Manchester Breast Ctr, Manchester M13 9PL, Lancs, England.
   [Howell, Anthony; Lisanti, Michael P.; Sotgia, Federica] Univ Manchester, Breakthrough Breast Canc Res Unit, Paterson Inst Canc Res, Sch Canc Enabling Sci & Technol,Manchester Acad H, Manchester M13 9PL, Lancs, England.
C3 Thomas Jefferson University; Thomas Jefferson University; Thomas
   Jefferson University; Thomas Jefferson University; Thomas Jefferson
   University; Thomas Jefferson University; University of Manchester;
   University of Manchester; Paterson Institute for Cancer Research
RP Lisanti, MP (corresponding author), Thomas Jefferson Univ, Dept Med Oncol, Philadelphia, PA 19107 USA.
EM michael.lisanti@kimmelcancercenter.org; federica.sotgia@jefferson.edu
RI Pavlides, Stephanos/F-9673-2011; Lisanti, Michael/C-6866-2013; Martinet,
   Wim/I-7375-2015; Pestell, Richard/JQW-3484-2023
OI Sotgia, Federica/0000-0003-2826-4529; Howell,
   Anthony/0000-0002-6233-719X; Martinez Cantarin, Maria
   P/0000-0002-4631-6292; Martinez-Outschoorn, Ubaldo/0000-0003-1483-4551
FU W.W. Smith Charitable Trust; Breast Cancer Alliance (BCA); American
   Cancer Society (ACS); NIH/NCI [R01-CA-080250, R01-CA-098779,
   R01-CA-120876, R01-AR-055660, R01-CA-70896, R01-CA-75503, R01-CA-86072,
   R01-CA-107382]; Susan G. Komen Breast Cancer Foundation; Breast Cancer
   Alliance, Inc.; Susan G. Komen Career Catalyst; Dr. Ralph and Marian C.
   Falk Medical Research Trust; NIH/NCI Cancer Center Core [P30-CA-56036];
   Margaret Q. Landenberger Research Foundation; Pennsylvania Department of
   Health; Breakthrough Breast Cancer in the U.K.; European Research
   Council
FX F. S. and her laboratory were supported by grants from the W.W. Smith
   Charitable Trust, the Breast Cancer Alliance (BCA), and a Research
   Scholar Grant from the American Cancer Society (ACS). M. P. L. was
   supported by grants from the NIH/NCI (R01-CA-080250; R01-CA-098779;
   R01-CA-120876; R01-AR-055660), and the Susan G. Komen Breast Cancer
   Foundation. Agnieszka K. Witkiewicz was supported by a Young
   Investigator Award from Breast Cancer Alliance, Inc., and a Susan G.
   Komen Career Catalyst Grant. R. G. P. was supported by grants from the
   NIH/NCI (R01-CA-70896, R01-CA-75503, R01-CA-86072, and R01-CA-107382)
   and the Dr. Ralph and Marian C. Falk Medical Research Trust. The Kimmel
   Cancer Center was supported by the NIH/NCI Cancer Center Core grant
   P30-CA-56036 (to R. G. P.). Funds were also contributed by the Margaret
   Q. Landenberger Research Foundation (to M. P. L.). This project is
   funded, in part, under a grant with the Pennsylvania Department of
   Health (to M. P. L. and F. S.). The Department specifically disclaims
   responsibility for any analyses, interpretations or conclusions. This
   work was also supported, in part, by a Centre grant in Manchester from
   Breakthrough Breast Cancer in the U.K. (to A. H.) and an Advanced ERC
   Grant from the European Research Council. Finally, we also thank Dr.
   Jose Martinez (Madrid, Spain) for his continued advice and intellectual
   support.
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NR 47
TC 203
Z9 230
U1 0
U2 34
PU TAYLOR & FRANCIS INC
PI PHILADELPHIA
PA 530 WALNUT STREET, STE 850, PHILADELPHIA, PA 19106 USA
SN 1538-4101
EI 1551-4005
J9 CELL CYCLE
JI Cell Cycle
PD JUN 15
PY 2010
VL 9
IS 12
BP 2423
EP 2433
DI 10.4161/cc.9.12.12048
PG 11
WC Cell Biology
WE Science Citation Index Expanded (SCI-EXPANDED)
SC Cell Biology
GA 615QC
UT WOS:000279149000031
PM 20562526
OA Bronze
DA 2025-03-13
ER

PT J
AU Fang, JX
   Xiao, L
   Joo, KI
   Liu, YR
   Zhang, CP
   Liu, SL
   Conti, PS
   Li, ZB
   Wang, P
AF Fang, Jinxu
   Xiao, Liang
   Joo, Kye-Il
   Liu, Yarong
   Zhang, Chupei
   Liu, Shuanglong
   Conti, Peter S.
   Li, Zibo
   Wang, Pin
TI A potent immunotoxin targeting fibroblast activation protein for
   treatment of breast cancer in mice
SO INTERNATIONAL JOURNAL OF CANCER
LA English
DT Article
DE immunotoxin; fibroblast activation protein; tumor-associated fibroblast;
   breast cancer; tumor microenvironment; positron emission tomography
ID CARCINOMA-ASSOCIATED FIBROBLASTS; SINGLE-CHAIN ANTIBODY; TUMOR STROMA;
   RECOMBINANT IMMUNOTOXIN; EXTRACELLULAR-MATRIX; THERAPEUTIC TARGET;
   ANTITUMOR-ACTIVITY; MMP-9 EXPRESSION; TGF-BETA; GROWTH
AB Fibroblast activation protein (FAP) is highly expressed in the tumor-associated fibroblasts (TAFs) of most human epithelial cancers. FAP plays a critical role in tumorigenesis and cancer progression, which makes it a promising target for novel anticancer therapy. However, mere abrogation of FAP enzymatic activity by small molecules is not very effective in inhibiting tumor growth. In this study, we have evaluated a novel immune-based approach to specifically deplete FAP-expressing TAFs in a mouse 4T1 metastatic breast cancer model. Depletion of FAP-positive stromal cells by FAP-targeting immunotoxin alpha FAP-PE38 altered levels of various growth factors, cytokines, chemokines and matrix metalloproteinases, decreased the recruitment of tumor-infiltrating immune cells in the tumor microenvironment and suppressed tumor growth. In addition, combined treatment with alpha FAP-PE38 and paclitaxel potently inhibited tumor growth in vivo. Our findings highlight the potential use of immunotoxin alpha FAP-PE38 to deplete FAP-expressing TAFs and thus provide a rationale for the use of this immunotoxin in cancer therapy.
C1 [Fang, Jinxu; Xiao, Liang; Joo, Kye-Il; Liu, Yarong; Zhang, Chupei; Wang, Pin] Univ So Calif, Mork Family Dept Chem Engn & Mat Sci, 3710 McClintock Ave,RTH509, Los Angeles, CA 90089 USA.
   [Liu, Shuanglong; Conti, Peter S.; Li, Zibo] Univ So Calif, Dept Radiol, Mol Imaging Ctr, Los Angeles, CA USA.
   [Wang, Pin] Univ So Calif, Dept Biomed Engn, Los Angeles, CA 90089 USA.
   [Wang, Pin] Univ So Calif, Dept Pharmacol & Pharmaceut Sci, Los Angeles, CA USA.
C3 University of Southern California; University of Southern California;
   University of Southern California; University of Southern California
RP Wang, P (corresponding author), Univ So Calif, Mork Family Dept Chem Engn & Mat Sci, 3710 McClintock Ave,RTH509, Los Angeles, CA 90089 USA.
EM pinwang@usc.edu
RI Liu, Shuanglong/AAC-7273-2019; Li, Zi-Jian/IWM-1489-2023
OI Joo, Kye Il/0000-0001-8834-5561; li, zibo/0000-0002-1063-0298
FU National Institutes of Health [R01AI068978, R01CA170820, R01EB017206,
   P01CA132681]; Joint Center for Translational Medicine, National Cancer
   Institute [P30CA014089]; Ming Hsieh Institute for Research on
   Engineering Medicine for Cancer
FX Grant sponsor: National Institutes of Health; Grant numbers:
   R01AI068978, R01CA170820, R01EB017206, P01CA132681; Grant sponsor: Joint
   Center for Translational Medicine, the National Cancer Institute; Grant
   number: P30CA014089; Grant sponsor: Ming Hsieh Institute for Research on
   Engineering Medicine for Cancer
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NR 53
TC 91
Z9 108
U1 2
U2 63
PU WILEY-BLACKWELL
PI HOBOKEN
PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA
SN 0020-7136
EI 1097-0215
J9 INT J CANCER
JI Int. J. Cancer
PD FEB 15
PY 2016
VL 138
IS 4
BP 1013
EP 1023
DI 10.1002/ijc.29831
PG 11
WC Oncology
WE Science Citation Index Expanded (SCI-EXPANDED)
SC Oncology
GA DC4BH
UT WOS:000369164200023
PM 26334777
OA Green Accepted, Bronze
DA 2025-03-13
ER

PT J
AU Magesh, P
   Thankachan, S
   Venkatesh, T
   Suresh, PS
AF Magesh, Priyanila
   Thankachan, Sanu
   Venkatesh, Thejaswini
   Suresh, Padmanaban S.
TI Breast cancer fibroblasts and cross-talk
SO CLINICA CHIMICA ACTA
LA English
DT Review
DE Cancer-associated fibroblasts; Metabolism; Warburg effect; Extracellular
   matrix; G-protein estrogen receptor; Exosomes
ID TYROSINE KINASE INHIBITOR; TUMOR-GROWTH; OXIDATIVE STRESS; STROMAL
   FIBROBLASTS; METABOLIC SYMBIOSIS; PHASE-II; EXTRACELLULAR-MATRIX;
   GLUCOSE-METABOLISM; HYDROGEN-PEROXIDE; N-ACETYLCYSTEINE
AB The breast tumor microenvironment is one of the crucial elements supporting breast cancer tumor progression and metastasis. The fibroblasts are the chief cellular component of the stromal microenvironment and are pathologically activated and differentiated into breast cancer-associated fibroblasts (CAFs). The catabolic phenotype of breast CAFs arises due to metabolic reprogramming of these fibroblasts under pseudo-hypoxic conditions. The metabolic intermediates and ATP produced by the breast CAFs are exploited by the neigh-boring cancer cells for energy generation. The growth factors, cytokines, and chemokines secreted by the CAFs help fuel tumor growth, invasion, and dissemination. Moreover, the interplay between breast CAFs and cancer cells, mediated by the growth factors, ROS, metabolic intermediates, exosomes, and catabolite transporters, aids in building a favorable microenvironment that promotes cancer cell proliferation, tumor progression, and metastasis. Therefore, identifying effective means to target the reprogrammed metabolism of the breast CAFs and the cross-communication between CAFs and cancer cells serve as promising strategies to develop anti-cancer therapeutics. Henceforth, the scope of the present review ranges from discussing the underlying characteris-tics of breast CAFs, mechanisms of metabolic reprogramming in breast CAFs, and the nature of interactions between breast CAFs and cancer cells to studying the intricacies of reprogrammed metabolism targeted cancer therapy.
C1 [Magesh, Priyanila; Thankachan, Sanu; Suresh, Padmanaban S.] Natl Inst Technol, Sch Biotechnol, Calicut 673601, Kerala, India.
   [Venkatesh, Thejaswini] Cent Univ Kerala, Dept Biochem & Mol Biol, Kasaragod 671316, India.
C3 National Institute of Technology (NIT System); National Institute of
   Technology Calicut; Central University of Kerala
RP Suresh, PS (corresponding author), Natl Inst Technol, Sch Biotechnol, Calicut 673601, Kerala, India.
EM sureshps@nitc.ac.in
RI Venkatesh, Thejaswini/ABC-4002-2021; P.S, Suresh/AAX-9666-2020
OI M, Priyanila/0000-0001-6919-6564; Thankachan, Sanu/0000-0002-7160-8799
FU Faculty seed research grant of National Institute of Technology, Calicut
   and Department of Biotechnology [BT/PR16307/MED/30/1729/2016]; Min-istry
   of Education, Govt of India; NIT Calicut for the fellowship
FX PSS thank Faculty seed research grant of National Institute of
   Technology, Calicut and Department of Biotechnology
   (BT/PR16307/MED/30/1729/2016) Govt of India for the support. ST thank
   the Min-istry of Education, Govt of India and NIT Calicut for the
   fellowship. We apologize to many scientists whose research studies were
   not included in this review due to page/word limit.
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NR 175
TC 8
Z9 8
U1 2
U2 11
PU ELSEVIER
PI AMSTERDAM
PA RADARWEG 29, 1043 NX AMSTERDAM, NETHERLANDS
SN 0009-8981
EI 1873-3492
J9 CLIN CHIM ACTA
JI Clin. Chim. Acta
PD OCT
PY 2021
VL 521
BP 158
EP 169
DI 10.1016/j.cca.2021.07.011
EA JUL 2021
PG 12
WC Medical Laboratory Technology
WE Science Citation Index Expanded (SCI-EXPANDED)
SC Medical Laboratory Technology
GA UA6RX
UT WOS:000685288700008
PM 34270953
DA 2025-03-13
ER

PT J
AU Nocquet, L
   Roul, J
   Lefebvre, CC
   Duarte, L
   Campone, M
   Juin, PP
   Souazé, F
AF Nocquet, Lisa
   Roul, Julie
   Lefebvre, Chloe C.
   Duarte, Laurine
   Campone, Mario
   Juin, Philippe P.
   Souaze, Frederique
TI Low BCL-xL expression in triple-negative breast cancer cells favors
   chemotherapy efficacy, and this effect is limited by cancer-associated
   fibroblasts
SO SCIENTIFIC REPORTS
LA English
DT Article
DE Apoptosis; Breast cancer; Cancer-associated fibroblasts; BCL-2 family;
   Chemotherapy
ID CHEMORESISTANCE; INHIBITOR; SURVIVAL; PROTEIN; FAMILY
AB Triple negative breast cancers (TNBC) present a poor prognosis primarily due to their resistance to chemotherapy. This resistance is known to be associated with elevated expression of certain anti-apoptotic members within the proteins of the BCL-2 family (namely BCL-xL, MCL-1 and BCL-2). These regulate cell death by inhibiting pro-apoptotic protein activation through binding and sequestration and they can be selectively antagonized by BH3 mimetics. Yet the individual influences of BCL-xL, MCL-1, and BCL-2 on the sensitivity of TNBC cells to chemotherapy, and their regulation by cancer-associated fibroblasts (CAFs), major components of the tumor stroma and key contributors to therapy resistance remain to be delineated. Using gene editing or BH3 mimetics to inhibit anti-apoptotic BCL-2 family proteins in TNBC line MDA-MB-231, we show that BCL-xL and MCL-1 promote cancer cell survival through compensatory mechanisms. This cell line shows limited sensitivity to chemotherapy, in line with the clinical resistance observed in TNBC patients. We elucidate that BCL-xL plays a pivotal role in therapy response, as its depletion or pharmacological inhibition heightened chemotherapy effectiveness. Moreover, BCL-xL expression is associated with chemotherapy resistance in patient-derived tumoroids where its pharmacological inhibition enhances ex vivo response to chemotherapy. In a co-culture model of cancer cells and CAFs, we observe that even in a context where BCL-xL reduced expression renders cancer cells more susceptible to chemotherapy, those in contact with CAFs display reduced sensitivity to chemotherapy. Thus CAFs exert a profound pro-survival effect in breast cancer cells, even in a setting highly favoring cell death through combined chemotherapy and absence of the main actor of chemoresistance, BCL-xL.
C1 [Nocquet, Lisa; Roul, Julie; Lefebvre, Chloe C.; Duarte, Laurine; Campone, Mario; Juin, Philippe P.; Souaze, Frederique] Univ Nantes, CNRS, INSERM, CRCI2NA, F-44000 Nantes, France.
   [Nocquet, Lisa; Roul, Julie; Lefebvre, Chloe C.; Duarte, Laurine; Juin, Philippe P.; Souaze, Frederique] Equipe Labellisee LIGUE Canc, Paris, France.
   [Nocquet, Lisa; Roul, Julie; Lefebvre, Chloe C.; Duarte, Laurine; Campone, Mario; Juin, Philippe P.; Souaze, Frederique] SIRIC ILIAD, Angers, France.
   [Roul, Julie; Campone, Mario; Juin, Philippe P.] ICO Rene Gauducheau, St Herblain, France.
C3 Nantes Universite; Centre National de la Recherche Scientifique (CNRS);
   Institut National de la Sante et de la Recherche Medicale (Inserm);
   UNICANCER; Institut de Cancerologie de l'Ouest (ICO)
RP Juin, PP; Souazé, F (corresponding author), Univ Nantes, CNRS, INSERM, CRCI2NA, F-44000 Nantes, France.; Juin, PP; Souazé, F (corresponding author), Equipe Labellisee LIGUE Canc, Paris, France.; Juin, PP; Souazé, F (corresponding author), SIRIC ILIAD, Angers, France.; Juin, PP (corresponding author), ICO Rene Gauducheau, St Herblain, France.
EM philippe.juin@univ-nantes.fr
RI Souazé, Frédérique/K-7937-2015
OI Frederique, Souaze/0000-0003-0476-2603; Lefebvre,
   Chloe/0000-0002-1866-7853
FU French ministry of Higher Education, Research and Innovation; Ligue
   contre le cancer [CD44]; INCa [SIRIC ILIAD INCa-DGOS INSERM-ITMO
   Cancer-18011, PLBIO021-129NN]; departmental committee of LIGUE Contre le
   Cancer [CD44, CD53, CD22]; Ligue Nationale Contre le Cancer (LNCC);
   Association Ruban Rose
FX We thank members of the "Stress adaptation and tumor escape" laboratory
   for their support. We benefited from technical support from the
   Cytometry Core facility (CytoCell) of Nantes University. L. Nocquet was
   a recipient of French ministry of Higher Education, Research and
   Innovation and was supported by a fellowship from Ligue contre le cancer
   (CD44). This work was supported by INCa (SIRIC ILIAD INCa-DGOS
   INSERM-ITMO Cancer-18011 and PLBIO021-129NN), and departmental committee
   of LIGUE Contre le Cancer CD44, CD53 and CD22. P.P.J.'s laboratory is
   labelized by the Ligue Nationale Contre le Cancer (LNCC). P.P.J.
   acknowledges the Association Ruban Rose for providing support.
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NR 38
TC 2
Z9 2
U1 2
U2 3
PU NATURE PORTFOLIO
PI BERLIN
PA HEIDELBERGER PLATZ 3, BERLIN, 14197, GERMANY
SN 2045-2322
J9 SCI REP-UK
JI Sci Rep
PD JUN
PY 2024
VL 14
IS 1
AR 14177
DI 10.1038/s41598-024-64696-z
PG 10
WC Multidisciplinary Sciences
WE Science Citation Index Expanded (SCI-EXPANDED)
SC Science & Technology - Other Topics
GA ZN4F9
UT WOS:001275958700033
PM 38898061
OA gold
DA 2025-03-13
ER

PT J
AU Honda, CK
   Kurozumi, S
   Fujii, T
   Pourquier, D
   Khellaf, L
   Boissiere, F
   Horiguchi, J
   Oyama, T
   Shirabe, K
   Colinge, J
   Yokobori, T
   Turtoi, A
AF Honda, Chikako Kanno
   Kurozumi, Sasagu
   Fujii, Takaaki
   Pourquier, Didier
   Khellaf, Lakhdar
   Boissiere, Florence
   Horiguchi, Jun
   Oyama, Tetsunari
   Shirabe, Ken
   Colinge, Jacques
   Yokobori, Takehiko
   Turtoi, Andrei
TI Cancer-associated fibroblast spatial heterogeneity and EMILIN1
   expression in the tumor microenvironment modulate TGF-8 activity and
   CD8<SUP>+</SUP> T-cell infiltration in breast cancer
SO THERANOSTICS
LA English
DT Article
DE spatial transcriptomics; cancer invasion; tumor immunity; CAF
   subpopulations; patient outcome
ID SINGLE-CELL; BETA; BEVACIZUMAB; PEMBROLIZUMAB; CHEMOTHERAPY;
   LYMPHOCYTES; TRIAL
AB Rationale: The tumor microenvironment (TME) and its multifaceted interactions with cancer cells are major targets for cancer treatment. Single -cell technologies have brought major insights into the TME, but the resulting complexity often precludes conclusions on function. Methods: We combined single -cell RNA sequencing and spatial transcriptomic data to explore the relationship between different cancer -associated fibroblast (CAF) populations and immune cell exclusion in breast tumors. The significance of the findings was then evaluated in a cohort of tumors (N=75) from breast cancer patients using immunohistochemistry analysis. Results: Our data show for the first time the degree of spatial organization of different CAF populations in breast cancer. We found that IL-iCAFs, Detox-iCAFs, and IFN gamma-iCAFs tended to cluster together, while Wound-myCAFs, TGF8-myCAFs, and ECM-myCAFs formed another group that overlapped with elevated TGF-8 signaling. Differential gene expression analysis of areas with CD8+ T -cell infiltration/exclusion within the TGF-8 signaling -rich zones identified elastin microfibrillar interface protein 1 (EMILIN1) as a top modulated gene. EMILIN1, a TGF-8 inhibitor, was upregulated in IFN gamma-iCAFs directly modulating TGF8 immunosuppressive function. Histological analysis of 75 breast cancer samples confirmed that high EMILIN1 expression in the tumor margins was related to high CD8+ T -cell infiltration, consistent with our spatial gene expression analysis. High EMILIN1 expression was also associated with better prognosis of patients with breast cancer, underscoring its functional significance for the recruitment of cytotoxic T cells into the tumor area. Conclusion: Our data show that correlating TGF-8 signaling to a CAF subpopulation is not enough because proteins with TGF-8-modulating activity originating from other CAF subpopulations can alter its activity. Therefore, therapeutic targeting should remain focused on biological processes rather than on specific CAF subtypes.
C1 [Honda, Chikako Kanno; Kurozumi, Sasagu; Fujii, Takaaki; Shirabe, Ken] Gunma Univ, Grad Sch Med, Dept Gen Surg Sci, Maebashi, Gunma, Japan.
   [Kurozumi, Sasagu; Horiguchi, Jun] Int Univ Hlth & Welf, Dept Breast Surg, Chiba, Japan.
   [Pourquier, Didier; Khellaf, Lakhdar; Boissiere, Florence; Colinge, Jacques; Turtoi, Andrei] Inst Reg Canc Montpellier ICM Val dAurelle, Montpellier, France.
   [Pourquier, Didier; Khellaf, Lakhdar; Turtoi, Andrei] INSERM U1194, Tumor Microenvironm & Resistance Treatment Lab, Montpellier, France.
   [Khellaf, Lakhdar; Turtoi, Andrei] Univ Montpellier, Montpellier, France.
   [Oyama, Tetsunari] Gunma Univ, Grad Sch Med, Dept Pathol & Diagnost, Maebashi, Gunma, Japan.
   [Colinge, Jacques] INSERM U1194, Canc Bioinformat & Syst Biol Team, Montpellier, France.
   [Yokobori, Takehiko; Turtoi, Andrei] Gunma Univ, Initiat Adv Res GIAR, Div Integrated Oncol Res, Maebashi, Gunma, Japan.
C3 Gunma University; International University of Health & Welfare;
   UNICANCER; Universite de Montpellier; Institut Regional du Cancer
   Montpellier / Val d'Aurelle (ICM); Institut National de la Sante et de
   la Recherche Medicale (Inserm); Universite de Montpellier; Universite de
   Montpellier; Gunma University; Institut National de la Sante et de la
   Recherche Medicale (Inserm); Universite de Montpellier; Gunma University
RP Colinge, J; Turtoi, A (corresponding author), Inst Reg Canc Montpellier ICM Val dAurelle, Montpellier, France.; Turtoi, A (corresponding author), INSERM U1194, Tumor Microenvironm & Resistance Treatment Lab, Montpellier, France.; Turtoi, A (corresponding author), Univ Montpellier, Montpellier, France.; Colinge, J (corresponding author), INSERM U1194, Canc Bioinformat & Syst Biol Team, Montpellier, France.; Yokobori, T; Turtoi, A (corresponding author), Gunma Univ, Initiat Adv Res GIAR, Div Integrated Oncol Res, Maebashi, Gunma, Japan.
EM jacques.colinge@umontpellier.fr; bori45@gunma-u.ac.jp;
   andrei.turtoi@inserm.fr
RI Shirabe, Ken/AFS-4583-2022
FU Gunma University; LabEx MabImprove Grant; Fondation ARC [PJA
   20141201975]
FX The authors want to thank Ms. Mariko Nakamura, Kao Abe, Kei Masuda,
   Kumiko Sudo, Yukiko Suto, Kyoko Miyoshi, Miyoko Suzuki, Chiho Noguchi,
   Saori Suto, Sayaka Okada, and Harumi Kanai for experimental assistance.
   This work was supported by grants from Gunma University. A.T. is
   supported by a LabEx MabImprove Grant. J.C. was supported by a Fondation
   ARC grant PJA 20141201975. No funding body had any role in the study
   design, data collection and analysis, decision to publish, or
   preparation of the manuscript.
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NR 47
TC 8
Z9 8
U1 4
U2 11
PU IVYSPRING INT PUBL
PI LAKE HAVEN
PA PO BOX 4546, LAKE HAVEN, NSW 2263, AUSTRALIA
SN 1838-7640
J9 THERANOSTICS
JI Theranostics
PY 2024
VL 14
IS 5
BP 1873
EP 1885
DI 10.7150/thno.90627
PG 13
WC Medicine, Research & Experimental
WE Science Citation Index Expanded (SCI-EXPANDED)
SC Research & Experimental Medicine
GA LE6C0
UT WOS:001185133100017
PM 38505604
OA gold, Green Published
DA 2025-03-13
ER

PT J
AU Zhou, J
   Wang, XH
   Zhao, YX
   Chen, C
   Xu, XY
   Sun, Q
   Wu, HY
   Chen, M
   Sang, JF
   Su, L
   Tang, XQ
   Shi, XB
   Zhang, Y
   Yu, Q
   Yao, YZ
   Zhang, WJ
AF Zhou, Jing
   Wang, Xiao-Hua
   Zhao, Yi-Xin
   Chen, Cheng
   Xu, Xin-Yun
   Sun, Qi
   Wu, Hong-Yan
   Chen, Ming
   Sang, Jian-Feng
   Su, Lei
   Tang, Xiao-Qiao
   Shi, Xian-Biao
   Zhang, Yin
   Yu, Qiao
   Yao, Yong-Zhong
   Zhang, Wei-Jie
TI Cancer-Associated Fibroblasts Correlate with Tumor-Associated
   Macrophages Infiltration and Lymphatic Metastasis in Triple Negative
   Breast Cancer Patients
SO JOURNAL OF CANCER
LA English
DT Article
DE triple-negative breast cancer; cancer-associated fibroblasts;
   tumor-associated macrophages; lymphatic metastasis; prognosis
ID SMOOTH MUSCLE ACTIN; CLINICOPATHOLOGICAL FEATURES; MESENCHYMAL
   TRANSITION; ACTIVATION PROTEIN; POOR-PROGNOSIS; GROWTH; PROGRESSION;
   EXPRESSION; CARCINOMA; CELLS
AB Background: Cancer-associated fibroblasts (CAFs) have been shown to be among the most prominent cells in tumor microenvironment and play a significant role in accelerating tumor metastasis by interacting with other type of cells. Tumor-associated macrophages (TAMs), the predominant tumor-infiltrating immune cells, also play important roles in cancer progression. Here, we aimed to evaluate the effects of CAFs on infiltration of TAMs and lymphatic metastasis in triple-negative breast cancer (TNBC).
   Material and methods: The study included 278 patients with histologically confirmed TNBC. Immunohistochemical staining of alpha-smooth muscle actin and fibroblast activation protein were used to identify CAFs. Polarized functional status of infiltrated TAMs was detected by expression of CD163. The clinicopathological features were assessed from all the patients' medical records.
   Results: The CAFs-related markers were found to be expressed more frequently in TNBC patents with aggressive behaviors, including recurrence and poor histological differentiation. High activation of CAFs was positively correlated with elevated infiltration of polarized CD163-positive TAMs and lymph node metastasis in TNBC patients. Multivariate Cox analysis revealed that the activation of CAFs, TAMs infiltration, and lymph node metastasis were independent prognostic factors for disease-free survival in TNBC patients.
   Conclusion: Cancer-associated fibroblasts were associated with infiltration of CD163-positive macrophages and lymphatic metastasis, and may be potential prognostic predictors of TNBC.
C1 [Zhou, Jing; Sang, Jian-Feng; Su, Lei; Tang, Xiao-Qiao; Shi, Xian-Biao; Zhang, Yin; Yao, Yong-Zhong; Zhang, Wei-Jie] Nanjing Univ, Med Sch, Affiliated Drum Tower Hosp, Dept Gen Surg, Nanjing, Jiangsu, Peoples R China.
   [Wang, Xiao-Hua] Nanjing Med Univ, Jiangsu Canc Hosp, Dept Med Oncol, Nanjing, Jiangsu, Peoples R China.
   [Zhao, Yi-Xin; Yao, Yong-Zhong] Southeast Univ, Sch Med, Nanjing, Jiangsu, Peoples R China.
   [Chen, Cheng] Nanjing Med Univ, Jiangsu Canc Hosp, Dept Radiotherapy, Nanjing, Jiangsu, Peoples R China.
   [Xu, Xin-Yun; Sun, Qi; Wu, Hong-Yan; Chen, Ming] Nanjing Univ, Med Sch, Affiliated Drum Tower Hosp, Dept Pathol, Nanjing, Jiangsu, Peoples R China.
   [Yu, Qiao] Nanjing Med Univ, Jiangsu Canc Hosp, Dept Breast Surg, Nanjing, Jiangsu, Peoples R China.
   [Zhou, Jing] Kunshan Fourth Peoples Hosp, Dept Gen Surg, Suzhou, Peoples R China.
C3 Nanjing University; Nanjing Medical University; Southeast University -
   China; Nanjing Medical University; Nanjing University; Nanjing Medical
   University
RP Yao, YZ; Zhang, WJ (corresponding author), Nanjing Univ, Med Sch, Affiliated Drum Tower Hosp, Dept Gen Surg, Nanjing, Jiangsu, Peoples R China.; Yao, YZ (corresponding author), Southeast Univ, Sch Med, Nanjing, Jiangsu, Peoples R China.
EM loyal1006@hotmail.com; zhangweijie1616@163.com
RI zhang, weijie/JQX-1450-2023; Chen, Dongyang/AFQ-0269-2022; Su,
   Lei/AAA-8317-2021; Wang, Xiaohua/AAH-5067-2020; yu, qiao/KFT-2125-2024
OI Sang, Jianfeng/0000-0003-1724-7897
FU National Natural Science Foundation of China [81201909, 81572338,
   81672380]; Nanjing Medical Science and Technology Development program
   [YKK12072, YKK15061];  [WSN-078]
FX This work was supported by grants from the National Natural Science
   Foundation of China (Grant Nos. 81201909, 81572338 and 81672380),
   Nanjing Medical Science and Technology Development program (Nos.
   YKK12072 and YKK15061). This work was also a C class sponsored project
   of Jiangsu provincial Six Talent Peaks (WSN-078).
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NR 31
TC 57
Z9 60
U1 0
U2 14
PU IVYSPRING INT PUBL
PI LAKE HAVEN
PA PO BOX 4546, LAKE HAVEN, NSW 2263, AUSTRALIA
SN 1837-9664
J9 J CANCER
JI J. Cancer
PY 2018
VL 9
IS 24
BP 4635
EP 4641
DI 10.7150/jca.28583
PG 7
WC Oncology
WE Science Citation Index Expanded (SCI-EXPANDED)
SC Oncology
GA HC0FS
UT WOS:000451473100008
PM 30588247
OA gold, Green Published, Green Submitted
DA 2025-03-13
ER

PT J
AU Friedman, G
   Levi-Galibov, O
   David, E
   Bornstein, C
   Giladi, A
   Dadiani, M
   Mayo, A
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   Mayer, S
   Nevo, R
   Stein, Y
   Balint-Lahat, N
   Barshack, I
   Ali, HR
   Caldas, C
   Nili-Gal-Yam, E
   Alon, U
   Amit, I
   Scherz-Shouval, R
AF Friedman, Gil
   Levi-Galibov, Oshrat
   David, Eyal
   Bornstein, Chamutal
   Giladi, Amir
   Dadiani, Maya
   Mayo, Avi
   Halperin, Coral
   Pevsner-Fischer, Meirav
   Lavon, Hagar
   Mayer, Shimrit
   Nevo, Reinat
   Stein, Yaniv
   Balint-Lahat, Nora
   Barshack, Iris
   Ali, H. Raza
   Caldas, Carlos
   Nili-Gal-Yam, Einav
   Alon, Uri
   Amit, Ido
   Scherz-Shouval, Ruth
TI Cancer-associated fibroblast compositions change with breast cancer
   progression linking the ratio of S100A4<SUP>+</SUP> and PDPN<SUP>+</SUP>
   CAFs to clinical outcome
SO NATURE CANCER
LA English
DT Article
ID CLASS-II EXPRESSION; RNA-SEQ; CELLS; MYOFIBROBLASTS; HETEROGENEITY;
   SUPPRESSOR; CONTRIBUTE; EVOLUTION; NICHE
AB Tumors are supported by cancer-associated fibroblasts (CAFs). CAFs are heterogeneous and carry out distinct cancer-associated functions. Understanding the full repertoire of CAFs and their dynamic changes as tumors evolve could improve the precision of cancer treatment. Here we comprehensively analyze CAFs using index and transcriptional single-cell sorting at several time points along breast tumor progression in mice, uncovering distinct subpopulations. Notably, the transcriptional programs of these subpopulations change over time and in metastases, transitioning from an immunoregulatory program to wound-healing and antigen-presentation programs, indicating that CAFs and their functions are dynamic. Two main CAF subpopulations are also found in human breast tumors, where their ratio is associated with disease outcome across subtypes and is particularly correlated with BRCA mutations in triple-negative breast cancer. These findings indicate that the repertoire of CAF changes over time in breast cancer progression, with direct clinical implications. Scherz-Shouval and colleagues characterize the dynamic changes in cancer-associated fibroblast subpopulations during breast cancer progression. They find that the ratio of S100A4(+) and PDPN+ CAF subsets is associated with clinical outcome.
C1 [Friedman, Gil; Levi-Galibov, Oshrat; Halperin, Coral; Pevsner-Fischer, Meirav; Lavon, Hagar; Mayer, Shimrit; Nevo, Reinat; Stein, Yaniv; Scherz-Shouval, Ruth] Weizmann Inst Sci, Dept Biomol Sci, Rehovot, Israel.
   [David, Eyal; Bornstein, Chamutal; Giladi, Amir; Amit, Ido] Weizmann Inst Sci, Dept Immunol, Rehovot, Israel.
   [Dadiani, Maya] Canc Res Ctr, Chaim Sheba Med Ctr, Tel Hashomer, Israel.
   [Mayo, Avi; Alon, Uri] Weizmann Inst Sci, Dept Mol Cell Biol, Rehovot, Israel.
   [Balint-Lahat, Nora; Barshack, Iris] Pathol Inst, Tel Hashomer, Israel.
   [Barshack, Iris] Tel Aviv Univ, Sackler Fac Med, Tel Aviv, Israel.
   [Ali, H. Raza; Caldas, Carlos] Univ Cambridge, Canc Res UK Cambridge Inst, Cambridge, England.
   [Caldas, Carlos] Univ Cambridge, Dept Oncol, Cambridge, England.
   [Caldas, Carlos] Canc Res UK Canc Ctr, Breast Canc Programme, Cambridge, England.
   [Nili-Gal-Yam, Einav] Chaim Sheba Med Ctr, Inst Oncol, Tel Hashomer, Israel.
C3 Weizmann Institute of Science; Weizmann Institute of Science; Chaim
   Sheba Medical Center; Weizmann Institute of Science; Tel Aviv
   University; Sackler Faculty of Medicine; Cancer Research UK; University
   of Cambridge; CRUK Cambridge Institute; University of Cambridge; Cancer
   Research UK; Chaim Sheba Medical Center
RP Scherz-Shouval, R (corresponding author), Weizmann Inst Sci, Dept Biomol Sci, Rehovot, Israel.; Amit, I (corresponding author), Weizmann Inst Sci, Dept Immunol, Rehovot, Israel.
EM ido.amit@weizmann.ac.il; ruth.shouval@weizmann.ac.il
RI mayo, avi/N-3756-2019; Amit, Iddo/G-1443-2013; Caldas,
   Carlos/U-7250-2019
OI Gal-Yam, Einav/0000-0003-1059-7923; Stein, Yaniv/0000-0002-0331-772X;
   Amit, Ido/0000-0003-2968-877X; Barshack, Iris/0000-0001-8216-8963;
   Caldas, Carlos/0000-0003-3547-1489; Lavon, Hagar/0009-0008-5733-9642;
   Mayer, Shimrit/0000-0003-4634-3562; Dadiani, Maya/0000-0002-1561-0755
FU Cancer Research UK [C19767/A27145]; Merck KGaA, Darmstadt, Germany; Chan
   Zuckerberg Initiative; HHMI International Scholar award; European
   Research Council Consolidator Grant (ERC-COG) [724471-HemTree2.0];
   Wolfson Foundation and Family Charitable Trust; Thompson Family
   Foundation [509044]; Israel Science Foundation [703/15, 401/17, 1384/1];
   Ernest and Bonnie Beutler Research Program for Excellence in Genomic
   Medicine; Helen and Martin Kimmel award for innovative investigation;
   NeuroMac DFG/Transregional Collaborative Research Center Grant, an
   International Progressive MS Alliance/NMSS [PA-1604 08459]; Adelis
   Foundation; European Research Council (ERC) [754320]; Israel Cancer
   Research Fund; Laura Gurwin Flug Family Fund; Peter and Patricia Gruber
   Awards; Comisaroff Family Trust; Estate of Annice Anzelewitz; Estate of
   Mordecai M. Roshwal
FX We thank O. Golani and Y. Addadi (MICC Cell Observatory, WIS) for their
   assistance with imaging and image analysis. We thank V. Kiss (Department
   of Biomolecular Sciences, WIS) for his assistance with imaging. We thank
   Z. Granot (HUJI) and R. Alon for providing cell lines. We thank members
   of the Scherz-Shouval laboratory for valuable input on the manuscript.
   U.A. is supported by Cancer Research UK (grant C19767/A27145). I.A. is
   an Eden and Steven Romick Professorial Chair, supported by Merck KGaA,
   Darmstadt, Germany, the Chan Zuckerberg Initiative, the HHMI
   International Scholar award, the European Research Council Consolidator
   Grant (ERC-COG) 724471-HemTree2.0, an SCA award of the Wolfson
   Foundation and Family Charitable Trust, the Thompson Family Foundation,
   an MRA Established Investigator Award (509044), the Israel Science
   Foundation (703/15), the Ernest and Bonnie Beutler Research Program for
   Excellence in Genomic Medicine, the Helen and Martin Kimmel award for
   innovative investigation, the NeuroMac DFG/Transregional Collaborative
   Research Center Grant, an International Progressive MS Alliance/NMSS
   PA-1604 08459 and an Adelis Foundation grant. R.S.S. is supported by the
   Israel Science Foundation (grant nos. 401/17 and 1384/1), the European
   Research Council (ERC grant agreement 754320), the Israel Cancer
   Research Fund, the Laura Gurwin Flug Family Fund, the Peter and Patricia
   Gruber Awards, the Comisaroff Family Trust, the Estate of Annice
   Anzelewitz and the Estate of Mordecai M. Roshwal. R.S.S. is the
   incumbent of the Ernst and Kaethe Ascher Career Development Chair in
   Life Sciences.
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NR 50
TC 181
Z9 193
U1 5
U2 25
PU NATURE PORTFOLIO
PI BERLIN
PA HEIDELBERGER PLATZ 3, BERLIN, 14197, GERMANY
EI 2662-1347
J9 NAT CANCER
JI Nat. Cancer
PD JUL
PY 2020
VL 1
IS 7
BP 692
EP +
DI 10.1038/s43018-020-0082-y
PG 29
WC Oncology
WE Science Citation Index Expanded (SCI-EXPANDED)
SC Oncology
GA QC5LY
UT WOS:000614876100006
PM 35122040
OA Green Accepted
HC Y
HP N
DA 2025-03-13
ER

PT J
AU Luo, HJ
   Liu, MR
   Luo, SJ
   Yu, TH
   Wu, CY
   Yang, GL
   Tu, G
AF Luo, Haojun
   Liu, Manran
   Luo, Shujuan
   Yu, Tenghua
   Wu, Chengyi
   Yang, Guanglun
   Tu, Gang
TI Dynamic monitoring of GPER-mediated estrogenic effects in breast cancer
   associated fibroblasts: An alternative role of estrogen in mammary
   carcinoma development
SO STEROIDS
LA English
DT Article
DE Breast cancer; GPER; CAFs; Estrogenic effects; Tumor microenvironment
ID PROTEIN-COUPLED RECEPTOR; GROWTH-FACTOR RECEPTOR; TUMOR-STROMA RATIO;
   GENE-EXPRESSION; GPR30; CELLS; ADHESION; TRANSACTIVATION; PROLIFERATION;
   STIMULATION
AB Cancer associated fibroblasts (CAFs) are crucial contributors to breast cancer development. Estrogen affects mammary stroma in both physiological and pathophysiological conditions. We show here that estrogen (G-protein coupled) receptor (GPER) could be detected by immunohistochemistry in stromal fibroblasts of primary breast cancers. The presence of GPER expression was further confirmed by immunofluorescence and quantitative PCR in CAFs isolated from primary breast cancers. Based on dynamic monitoring by real time cell analyzer (RTCA) system, 17-beta-estradiol (E2) as well as GPER specific agonist G1 were observed to trigger transient cell index increasing within an hour in a dosage-dependent manner in breast CAFs. In addition, E2 and Cl stimulated intracellular calcium modulation and phosphorylation of extracellular signal-regulated kinase (ERK) 1/2 within seconds and minutes in CAFs, respectively. Moreover, E2 and G1 promoted cell proliferation of breast CAFs measured by RTCA monitoring, cell viability assay and cell cycle analysis, and this promotion could be blocked by a GPER-selective antagonist G15. Interestingly, dynamic RTCA monitoring indicated that E2 increased adhesion of resuspended cells, and microscopy confirmed that E2 stimulated cell spreading. Both the adhesion and spreading were proposed to be mediated by GPER, since G1 also stimulated these effects similar to E2, and G15 reduced them. Moreover, GPER was found to mediate migration that was increased by E2 and G1 but reduced by G15 in RTCA cell migration assay and transwell assay. Accordingly, GPER mediates not only rapid actions but also slow effects including adhesion/spreading, proliferation and migration in breast CAFs. Estrogen is likely to affect tumor associated stroma and contributes to mammary carcinoma development through CAFs. (C) 2016 Published by Elsevier Inc.
C1 [Luo, Haojun] Chongqing Med Univ, Affiliated Hosp 2, Dept Thyroid & Breast Surg, Chongqing 400010, Peoples R China.
   [Liu, Manran] Chongqing Med Univ, Chinese Minist Educ, Key Lab Lab Med Diagnost, Chongqing 400016, Peoples R China.
   [Luo, Shujuan] Chongqing Hlth Ctr Women & Children, Dept Gynecol & Obstet, Chongqing 400010, Peoples R China.
   [Yu, Tenghua; Wu, Chengyi; Yang, Guanglun; Tu, Gang] Chongqing Med Univ, Affiliated Hosp 1, Dept Endocrine & Breast Surg, Chongqing 400016, Peoples R China.
C3 Chongqing Medical University; Chongqing Medical University; Chongqing
   Medical University
RP Tu, G (corresponding author), 1 You Yi Rd, Chongqing 400016, Peoples R China.
EM tugang68@126.com
OI li, lu/0009-0009-8381-3093
FU National Natural Science Foundation of China [81372389, 81402184]
FX This work was supported by the National Natural Science Foundation of
   China (81372389 and 81402184). We appreciate Prof. Hua Tang from the Key
   Laboratory of Molecular Biology for Infectious Diseases, Ministry of
   Education Medicine, Chongqing Medical University, for his kind help. We
   appreciate Dongyu Jia at Cedars Sinai Medical Center (Los Angeles,
   United States) for proofreading our manuscript.
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NR 52
TC 15
Z9 18
U1 1
U2 26
PU ELSEVIER SCIENCE INC
PI NEW YORK
PA STE 800, 230 PARK AVE, NEW YORK, NY 10169 USA
SN 0039-128X
EI 1878-5867
J9 STEROIDS
JI Steroids
PD AUG
PY 2016
VL 112
BP 1
EP 11
DI 10.1016/j.steroids.2016.03.013
PG 11
WC Biochemistry & Molecular Biology; Endocrinology & Metabolism
WE Science Citation Index Expanded (SCI-EXPANDED)
SC Biochemistry & Molecular Biology; Endocrinology & Metabolism
GA DS2LX
UT WOS:000380602100001
PM 27016131
DA 2025-03-13
ER

PT J
AU Yang, SS
   Ma, S
   Dou, H
   Liu, F
   Zhang, SY
   Jiang, C
   Xiao, M
   Huang, YX
AF Yang, Shan-Shan
   Ma, Shuang
   Dou, He
   Liu, Feng
   Zhang, Shi-Yuan
   Jiang, Cong
   Xiao, Min
   Huang, Yuan-Xi
TI Breast cancer-derived exosomes regulate cell invasion and metastasis in
   breast cancer via miR-146a to activate cancer associated fibroblasts in
   tumor microenvironment
SO EXPERIMENTAL CELL RESEARCH
LA English
DT Article
DE Breast cancer-derived exosome; miR-146a; CAFs; TXNIP; Invasion and
   metastasis; Wnt pathway
ID SIGNALING PATHWAY; PROGRESSION
AB Objective: To explore the effects of breast cancer (BC)-derived exosomes on invasion and migration of BC cells. Methods: Exosomes (Exo-MA, Exo-M7, Exo-M1) were extracted from normal breast epithelial cells (MCF-10A), BC cells (MCF-7/MDA-MB-231) and BC cells with miR-146a overexpression or knockdown using multi-step differential centrifugation. Morphologies and sizes of exosomes were observed by transmission electron microscope (TEM) and particle size analysis respectively. BC mouse models were injected with DIR labeled ExoMA, Exo-M7 or Exo-M1. The epithelial-mesenchymal transition (EMT) in BC cells was determined by PCR and Western blot. PKH67 labeled Exo-MA, Exo-M7 and Exo-M1 were incubated with NFs or MCF-7 to measure the activation of CAFs. Cell invasion and migration abilities were determined by scratch test and Transwell assay. Results: Exo-MA, Exo-M7, Exo-M1 were successfully extracted with positive expressions of Alix, CD63 and TSG101. Contents of Ki67, N-cadherin, Vimentin and Snail-1 were increased but E-cadherin was decreased, compared to Exo-MA group. Exo-M7 or Exo-M1 could increase BC cell proliferation and enhance EMT in nude mouse. Exo-M7 and Exo-M1 could accelerate the transformation of NFs into CAFs and promote the recruitment of CAFs in MCF-7. Transfection of miR-146a could promote the transformation of NFs into CAFs and promote cell invasion and migration of MCF-7 cells. As a target gene of miR-146a, TXNIP could inhibit the activation of CAFs. miR-146a overexpression or TXNIP silence enhance the activation of Wnt signal pathway. Conclusion: BC-derived exosomes promote the activation of CAFs through miR-146a/TXNIP axis to activate Wnt pathway, which in turn enhances invasion and metastasis of BC cells.
C1 [Yang, Shan-Shan] Harbin Med Univ Canc Hosp, Dept Gynecol Radiotherapy, Harbin 150081, Heilongjiang, Peoples R China.
   [Ma, Shuang; Dou, He; Liu, Feng; Zhang, Shi-Yuan; Jiang, Cong; Xiao, Min; Huang, Yuan-Xi] Harbin Med Univ Canc Hosp, Dept Breast Surg, 150 Haping Rd, Harbin 150081, Heilongjiang, Peoples R China.
C3 Harbin Medical University; Harbin Medical University
RP Xiao, M; Huang, YX (corresponding author), Harbin Med Univ Canc Hosp, Dept Breast Surg, 150 Haping Rd, Harbin 150081, Heilongjiang, Peoples R China.
EM xiaomin@hrbmu.edu.cn; doctor_hyx@126.com
RI 杨, 姗姗/HKW-8946-2023; Xiao, Min/F-6184-2013; Zhang, Shi-Yuan/Q-1355-2016
FU National Natural Science Foundation of China [81872145, 81872460];
   Harbin Medical University Cancer Hospital [JY2016-01, JCQN2018-06,
   JY2016-05]; Pandeng project of National Cancer Center [NCC201808B020]
FX This work was supported by grants from the National Natural Science
   Foundation of China (No. 81872145 and No. 81872460), Research project
   grant of Harbin Medical University Cancer Hospital (No. JY2016-01, No.
   JCQN2018-06 and No. JY2016-05), and Pandeng project of National Cancer
   Center (NCC201808B020).
CR [Anonymous], SEMIN CANC BIOL
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NR 44
TC 122
Z9 128
U1 0
U2 36
PU ELSEVIER INC
PI SAN DIEGO
PA 525 B STREET, STE 1900, SAN DIEGO, CA 92101-4495 USA
SN 0014-4827
EI 1090-2422
J9 EXP CELL RES
JI Exp. Cell Res.
PD JUN 15
PY 2020
VL 391
IS 2
AR 111983
DI 10.1016/j.yexcr.2020.111983
PG 14
WC Oncology; Cell Biology
WE Science Citation Index Expanded (SCI-EXPANDED)
SC Oncology; Cell Biology
GA LR2AH
UT WOS:000535497700005
PM 32268136
DA 2025-03-13
ER

PT J
AU Wang, BX
   Xi, CF
   Liu, MW
   Sun, HC
   Liu, S
   Song, L
   Kang, H
AF Wang, Bixiao
   Xi, Chunfang
   Liu, Mingwei
   Sun, Haichen
   Liu, Shuang
   Song, Lei
   Kang, Hua
TI Breast fibroblasts in both cancer and normal tissues induce phenotypic
   transformation of breast cancer stem cells: a preliminary study
SO PEERJ
LA English
DT Article
DE Cancer stem cell; Fibroblast; Breast; Phenotypic transformation; Breast
   cancer; ALDH1; CD44CD24
ID EPITHELIAL-MESENCHYMAL TRANSITION; EXPRESSION; ROLES; HETEROGENEITY;
   PROGRESSION; PATHWAYS; INVASION; NICHE; ALDH1
AB Background: Breast cancer stem cells (BCSCs) are associated with the invasion of breast cancer. In recent years, studies have demonstrated different phenotypes among BCSCs. Furthermore, BCSCs of diverse phenotypes are present at different tumour sites and different histological stages. Fibroblasts are involved in the phenotypic transformation of BCSCs. Cancer-associated fibroblasts (CAFs) participate in the induction of epithelial-mesenchymal transition, thereby promoting the acquisition of stem cell characteristics, but little is known about the role of normal fibroblasts (NFs) in the phenotypic transformation of BCSCs or about the effect of CAFs and NFs on BCSC phenotypes.
   Methods: A total of six pairs of primary CAFs and NFs were isolated from surgical samples of breast cancer patients and subjected to morphological, immunohistochemical, cell invasion and proteomics analyses. After establishing a cell culture system with conditioned medium from CAFs and NFs, we used the mammosphere formation assay to explore the effect of CAFs and NFs on the self-renewal ability of BCSCs. The effect of CAFs and NFs on the phenotypic differentiation of BCSCs was further analysed by flow cytometry and immunofluorescence.
   Results: The isolated CAFs and NFs did not show significant differences in cell morphology or alpha-smooth muscle actin (alpha-SMA) expression, but cell invasion and proteomics analyses demonstrated heterogeneity among these fibroblasts. Both CAFs and NFs could promote the generation of BCSCs, but CAFs displayed a greater ability than NFs in promoting mammosphere formation. Conditioned medium from CAFs increased the proportion of aldehyde dehydrogenase-1 positive (ALDH1(+)) BCSCs, but conditioned medium from NFs was more likely to promote the generation of CD44(+)CD24(-) BCSCs from MCF-7 cells.
   Discussion: This study validated the heterogeneity among CAFs and NFs and expanded on the conclusion that fibroblasts promote the generation of cancer stem cells. Our results particularly emphasized the effect of NFs on the phenotypic transformation of BCSCs. In addition, this study further highlighted the roles of CAFs and NFs in the induction of different phenotypes in BCSCs.
C1 [Wang, Bixiao; Xi, Chunfang; Kang, Hua] Capital Med Univ, Xuanwu Hosp, Dept Gen Surg, Beijing, Peoples R China.
   [Xi, Chunfang] Shanxi Prov Peoples Hosp, Dept Breast Surg, Taiyuan, Shanxi, Peoples R China.
   [Liu, Mingwei; Song, Lei] Beijing Proteome Res Ctr, Natl Ctr Prot Sci, State Key Lab Prote, Beijing, Peoples R China.
   [Sun, Haichen; Liu, Shuang] Capital Med Univ, Xuanwu Hosp, Surg Lab, Beijing, Peoples R China.
C3 Capital Medical University; Shanxi People's Hospital; Capital Medical
   University
RP Kang, H (corresponding author), Capital Med Univ, Xuanwu Hosp, Dept Gen Surg, Beijing, Peoples R China.
EM kanghuamd@163.com
FU National Natural Science Foundation of China [81172517]; Beijing Breast
   Prevention Institute of Breast Cancer Prevention and Treatment Research
   Fund
FX This work was supported by the National Natural Science Foundation of
   China (No. 81172517) and Beijing Breast Prevention Institute of Breast
   Cancer Prevention and Treatment Research Fund. The funders had no role
   in study design, data collection and analysis, decision to publish, or
   preparation of the manuscript.
CR Al-Hajj M, 2003, P NATL ACAD SCI USA, V100, P3983, DOI 10.1073/pnas.0530291100
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NR 35
TC 19
Z9 22
U1 0
U2 9
PU PEERJ INC
PI LONDON
PA 341-345 OLD ST, THIRD FLR, LONDON, EC1V 9LL, ENGLAND
SN 2167-8359
J9 PEERJ
JI PeerJ
PD MAY 15
PY 2018
VL 6
AR e4805
DI 10.7717/peerj.4805
PG 19
WC Multidisciplinary Sciences
WE Science Citation Index Expanded (SCI-EXPANDED)
SC Science & Technology - Other Topics
GA GG3YC
UT WOS:000432628600007
PM 29780673
OA Green Submitted, Green Published, gold
DA 2025-03-13
ER

PT J
AU Santolla, MF
   Lappano, R
   Cirillo, F
   Rigiracciolo, DC
   Sebastiani, A
   Abonante, S
   Tassone, P
   Tagliaferri, P
   Di Martino, MT
   Maggiolini, M
   Vivacqua, A
AF Santolla, Maria Francesca
   Lappano, Rosamaria
   Cirillo, Francesca
   Rigiracciolo, Damiano Cosimo
   Sebastiani, Anna
   Abonante, Sergio
   Tassone, Pierfrancesco
   Tagliaferri, Pierosandro
   Di Martino, Maria Teresa
   Maggiolini, Marcello
   Vivacqua, Adele
TI miR-221 stimulates breast cancer cells and cancer-associated fibroblasts
   (CAFs) through selective interference with the A20/c-Rel/CTGF signaling
SO JOURNAL OF EXPERIMENTAL & CLINICAL CANCER RESEARCH
LA English
DT Article
DE Breast cancer; CAFs; miR-221; A20; C-Rel; CTGF
ID NF-KAPPA-B; TISSUE GROWTH-FACTOR; INDUCED PROTEIN-3 TNFAIP3;
   ANTITUMOR-ACTIVITY; IMMUNE-RESPONSE; EXPRESSION; A20; INHIBITOR;
   MICRORNAS; RECEPTOR
AB Background: MicroRNA (miRNAs) are non-coding small RNA molecules that regulate gene expression by inhibiting the translation of target mRNAs. Among several dysregulated miRNAs in human cancer, the up-regulation of miR-221 has been associated with development of a variety of hematologic and solid malignancies. In this study, we investigated the involvement of miR-221 in breast cancer.
   Methods: TaqMan microRNA assay was used to detect the miR-221 levels in normal cells and in MDA-MB 231 and SkBr3 breast cancer cells as well as in main players of the tumor microenvironment, namely cancer-associated fibroblasts (CAFs). miR-221 mimic sequence and locked nucleic acid (LNA)-i-miR-221 construct were used to induce or inhibit, respectively, the miR-221 expression in cells used. Quantitative PCR and western blotting analysis were performed to evaluate the levels of the miR-221 target gene A20 (TNFAIP3), as well as the member of the NF-kappa B complex namely c-Rel and the connective tissue growth factor (CTGF). Chromatin immunoprecipitation (ChIP) assay was performed to ascertain the recruitment of c-Rel to the CTFG promoter. Finally, the cell growth and migration in the presence of LNA-i-miR-221 or silencing c-Rel and CTGF by specific short hairpin were assessed by cell count, colony formation and boyden chambers assays. Statistical analysis was performed by ANOVA.
   Results: We first demonstrated that LNA-i-miR-221 inhibits both endogenous and ectopic expression of miR-221 in our experimental models. Next, we found that the A20 down-regulation, as well as the up-regulation of c-Rel induced by miR-221 were no longer evident using LNA-i-miR-221. Moreover, we established that the miR-221 dependent recruitment of c-Rel to the NF-kappa B binding site located within the CTGF promoter region is prevented by using LNA-i-miR-221. Furthermore, we determined that the up-regulation of CTGF mRNA and protein levels by miR-221 is no longer evident using LNA-i-miR221 and silencing c-Rel. Finally, we assessed that cell growth and migration induced by miR-221 in MDA-MB 231 and SkBr3 breast cancer cells as well as in CAFs are abolished by LNAi-miR-221 and silencing c-Rel or CTGF.
   Conclusions: Overall, these data provide novel insights into the stimulatory action of miR-221 in breast cancer cells and CAFs, suggesting that its inhibition may be considered toward targeted therapeutic approaches in breast cancer patients.
C1 [Santolla, Maria Francesca; Lappano, Rosamaria; Cirillo, Francesca; Rigiracciolo, Damiano Cosimo; Sebastiani, Anna; Maggiolini, Marcello; Vivacqua, Adele] Univ Calabria, Dept Pharm Hlth & Nutr Sci, Arcavacata Di Rende, Italy.
   [Abonante, Sergio] Reg Hosp Cosenza, Cosenza, Italy.
   [Tassone, Pierfrancesco; Tagliaferri, Pierosandro; Di Martino, Maria Teresa] Magna Graecia Univ Catanzaro, Dept Expt & Clin Med, Catanzaro, Italy.
C3 University of Calabria; Magna Graecia University of Catanzaro
RP Maggiolini, M (corresponding author), Univ Calabria, Dept Pharm Hlth & Nutr Sci, Arcavacata Di Rende, Italy.; Di Martino, MT (corresponding author), Magna Graecia Univ Catanzaro, Dept Expt & Clin Med, Catanzaro, Italy.
EM teresadm@unicz.it; marcellomaggiolini@yahoo.it
RI Rigiracciolo, Damiano Cosimo/GRS-9234-2022; Tassone,
   Pierfrancesco/AIA-5373-2022; Maggiolini, Marcello/Z-4729-2019; Santolla,
   Maria/AAH-5481-2020; Tagliaferri, Pierosandro/K-9546-2016; CIRILLO,
   FRANCESCA/K-2612-2018; vivacqua, adele/I-2771-2015
OI Rigiracciolo, Damiano Cosimo/0000-0003-1161-6380; vivacqua,
   adele/0000-0001-5333-8396; Tassone, Pierfrancesco/0000-0002-8298-6787;
   Santolla, Maria Francesca/0000-0002-4838-5953; Lappano,
   Rosamaria/0000-0002-9374-9701; DI MARTINO, Maria
   Teresa/0000-0002-8205-2706
FU Italian Association for Cancer Research (AIRC) [9980]; Innovative
   immunotherapeutic treatments of human cancer, MultiUnit - Multi Unit
   Regional (AIRC foundation) [16695]; Innovative immunotherapeutic
   treatments of human cancer, MultiUnit - Multi Unit Regional (CARICAL
   foundation) [16695]; AIRC [IG 16719]; Fondazione Umberto Veronesi
FX This work has been supported by the Italian Association for Cancer
   Research (AIRC), Special Program Molecular Clinical Oncology - 5 per
   mille n. 9980, 2010/15 PI: PT and 5 x 1000 Molecular Clinical Oncology
   Extension Program, n. 9980, 2016/18 PI: PT and partially by Innovative
   immunotherapeutic treatments of human cancer, MultiUnit - Multi Unit
   Regional n. 16695 (co-financed by AIRC and CARICAL foundation), 2015/18
   PI: PT. MM was supported by (AIRC, IG 16719). MFS was supported by
   Fondazione Umberto Veronesi (Post-Doctoral Fellowship 2018).
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NR 60
TC 45
Z9 48
U1 1
U2 10
PU BMC
PI LONDON
PA CAMPUS, 4 CRINAN ST, LONDON N1 9XW, ENGLAND
SN 1756-9966
J9 J EXP CLIN CANC RES
JI J. Exp. Clin. Cancer Res.
PD MAY 2
PY 2018
VL 37
AR 94
DI 10.1186/s13046-018-0767-6
PG 12
WC Oncology
WE Science Citation Index Expanded (SCI-EXPANDED)
SC Oncology
GA GE8OK
UT WOS:000431490800001
PM 29716623
OA Green Published, gold
DA 2025-03-13
ER

PT J
AU Valenti, G
   Quinn, HM
   Heynen, GJJE
   Lan, LX
   Holland, JD
   Vogel, R
   Wulf-Goldenberg, A
   Birchmeier, W
AF Valenti, Giovanni
   Quinn, Hazel M.
   Heynen, Guus J. J. E.
   Lan, Linxiang
   Holland, Jane D.
   Vogel, Regina
   Wulf-Goldenberg, Annika
   Birchmeier, Walter
TI Cancer Stem Cells Regulate Cancer-Associated Fibroblasts via Activation
   of Hedgehog Signaling in Mammary Gland Tumors
SO CANCER RESEARCH
LA English
DT Article
ID IN-VITRO PROPAGATION; BREAST-CANCER; STROMAL FIBROBLASTS; INITIATING
   CELLS; NICHE; IDENTIFICATION; POPULATIONS; PREDICTS; DATABASE; GROWTH
AB Many tumors display intracellular heterogeneity with subsets of cancer stem cells (CSC) that sustain tumor growth, recurrence, and therapy resistance. Cancer- associated fibroblasts (CAF) have been shown to support and regulate CSC function. Here, we investigate the interactions between CSCs and CAFs in mammary gland tumors driven by combined activation of Wnt/beta-catenin and Hgf/Met signaling in mouse mammary epithelial cells. In this setting, CSCs secrete the Hedgehog ligand SHH, which regulate CAFs via paracrine activation of Hedgehog signaling. CAFs subsequently secrete factors that promote expansion and self- renewal of CSCs. In vivo treatment of tumors with the Hedgehog inhibitor vismodegib reduce CAF and CSC expansion, resulting in an overall delay of tumor formation. Our results identify a novel intracellular signaling module that synergistically regulates CAFs and CSCs. Targeting CAFs with Hedgehog inhibitors may offer a novel therapeutic strategy against breast cancer. (C) 2017 AACR.
C1 [Valenti, Giovanni; Quinn, Hazel M.; Heynen, Guus J. J. E.; Lan, Linxiang; Holland, Jane D.; Vogel, Regina; Birchmeier, Walter] Helmholtz Soc, Max Delbrueck Ctr Mol Med MDC, Canc Res Program, Berlin, Germany.
   [Wulf-Goldenberg, Annika] EPO, Berlin, Germany.
C3 Helmholtz Association; Max Delbruck Center for Molecular Medicine
RP Birchmeier, W (corresponding author), Max Delbrueck Ctr Mol Med, Robert Roessle Str 10, D-13125 Berlin, Germany.
EM wbirch@mdc-berlin.de
OI Lan, Linxiang/0000-0002-8409-4336
FU MDC; Humboldt University of Berlin
FX G. Valenti was a recipient and H.M. Quinn is presently a recipient of
   the International PhD fellowship of the MDC and the Humboldt University
   of Berlin.
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NR 50
TC 127
Z9 136
U1 2
U2 34
PU AMER ASSOC CANCER RESEARCH
PI PHILADELPHIA
PA 615 CHESTNUT ST, 17TH FLOOR, PHILADELPHIA, PA 19106-4404 USA
SN 0008-5472
EI 1538-7445
J9 CANCER RES
JI Cancer Res.
PD APR 15
PY 2017
VL 77
IS 8
BP 2134
EP 2147
DI 10.1158/0008-5472.CAN-15-3490
PG 14
WC Oncology
WE Science Citation Index Expanded (SCI-EXPANDED)
SC Oncology
GA ER9ZQ
UT WOS:000399186100029
PM 28202523
OA Green Submitted, Green Accepted
DA 2025-03-13
ER

PT J
AU Alcaraz, LB
   Mallavialle, A
   Mollevi, C
   Boissière-Michot, F
   Mansouri, H
   Simony-Lafontaine, J
   Laurent-Matha, V
   Chardès, T
   Jacot, W
   Turtoi, A
   Roger, P
   Guiu, S
   Liaudet-Coopman, E
AF Alcaraz, Lindsay B.
   Mallavialle, Aude
   Mollevi, Caroline
   Boissiere-Michot, Florence
   Mansouri, Hanane
   Simony-Lafontaine, Joelle
   Laurent-Matha, Valerie
   Chardes, Thierry
   Jacot, William
   Turtoi, Andrei
   Roger, Pascal
   Guiu, Severine
   Liaudet-Coopman, Emmanuelle
TI SPARC in cancer-associated fibroblasts is an independent poor prognostic
   factor in non-metastatic triple-negative breast cancer and exhibits
   pro-tumor activity
SO INTERNATIONAL JOURNAL OF CANCER
LA English
DT Article
DE CAF; osteonectin; single-cell mRNA sequencing; SPARC; TNBC
ID MATRICELLULAR PROTEIN SPARC; INFILTRATING LYMPHOCYTES; MESENCHYMAL
   TRANSITION; EXPRESSION; OSTEONECTIN; HETEROGENEITY; PROLIFERATION;
   METASTASIS; CARCINOMAS; MIGRATION
AB Triple-negative breast cancer (TNBC) is the most aggressive breast cancer subtype and lacks specific targeted therapeutic agents. The current mechanistic evidence from cell-based studies suggests that the matricellular protein SPARC has a tumor-promoting role in TNBC; however, data on the clinical relevance of SPARC expression/secretion by tumor and stromal cells in TNBC are limited. Here, we analyzed by immunohistochemistry the prognostic value of tumor and stromal cell SPARC expression in 148 patients with non-metastatic TNBC and long follow-up (median: 5.4 years). We also quantified PD-L1 and PD-1 expression. We detected SPARC expression in tumor cells (42.4%), cancer-associated fibroblasts (CAFs; 88.1%), tumor-associated macrophages (77.1%), endothelial cells (75.2%) and tumor-infiltrating lymphocytes (9.8%). Recurrence-free survival was significantly lower in patients with SPARC-expressing CAFs. Multivariate analysis showed that SPARC expression in CAFs was an independent prognostic factor. We also detected tumor and stromal cell SPARC expression in TNBC cytosols, and in patient-derived xenografts and cell lines. Furthermore, we analyzed publicly available single-cell mRNA sequencing data and found that in TNBC, SPARC is expressed by different CAF subpopulations, including myofibroblasts and inflammatory fibroblasts that are involved in tumor-related processes. We then showed that fibroblast-secreted SPARC had a tumor-promoting role by inhibiting TNBC cell adhesion and stimulating their motility and invasiveness. Overall, our study demonstrates that SPARC expression in CAFs is an independent prognostic marker of poor outcome in TNBC. Patients with SPARC-expressing CAFs could be eligible for anti-SPARC targeted therapy.
C1 [Alcaraz, Lindsay B.; Mallavialle, Aude; Mansouri, Hanane; Laurent-Matha, Valerie; Chardes, Thierry; Jacot, William; Turtoi, Andrei; Roger, Pascal; Guiu, Severine; Liaudet-Coopman, Emmanuelle] Univ Montpellier, IRCM, INSERM, ICM,U1194, 208 Rue Apothicaires, F-34298 Montpellier 5, France.
   [Mollevi, Caroline] Univ Montpellier, Biometry Unit, ICM, Montpellier, France.
   [Mollevi, Caroline] Univ Montpellier, Desbrest Inst Epidemiol & Publ Hlth, INSERM, Montpellier, France.
   [Boissiere-Michot, Florence; Simony-Lafontaine, Joelle; Jacot, William] ICM, Translat Res Unit, Montpellier, France.
   [Mansouri, Hanane] IRCM, RHEM, Montpellier, France.
   [Jacot, William; Guiu, Severine] ICM, Dept Med Oncol, Montpellier, France.
   [Roger, Pascal] CHU, Dept Pathol, Nimes, France.
C3 Universite de Montpellier; Institut National de la Sante et de la
   Recherche Medicale (Inserm); UNICANCER; Universite de Montpellier;
   Institut Regional du Cancer Montpellier / Val d'Aurelle (ICM); Institut
   National de la Sante et de la Recherche Medicale (Inserm); Institut
   National de la Sante et de la Recherche Medicale (Inserm); Universite de
   Montpellier; Institut National de la Sante et de la Recherche Medicale
   (Inserm); UNICANCER; Universite de Montpellier; Institut Regional du
   Cancer Montpellier / Val d'Aurelle (ICM); Institut National de la Sante
   et de la Recherche Medicale (Inserm); Universite de Montpellier;
   UNICANCER; Institut Regional du Cancer Montpellier / Val d'Aurelle
   (ICM); Institut National de la Sante et de la Recherche Medicale
   (Inserm); UNICANCER; Universite de Montpellier; Institut Regional du
   Cancer Montpellier / Val d'Aurelle (ICM); Universite de Montpellier; CHU
   de Nimes
RP Alcaraz, LB; Liaudet-Coopman, E (corresponding author), Univ Montpellier, IRCM, INSERM, ICM,U1194, 208 Rue Apothicaires, F-34298 Montpellier 5, France.
EM lindsay.alcaraz@inserm.fr; emmanuelle.liaudet-coopman@inserm.fr
RI Liaudet-Coopman, Emmanuelle/N-4744-2017; Turtoi, Andrei/ABD-1271-2021;
   Mollevi, Caroline/AAA-6839-2019; Boissiere-Michot,
   Florence/AAL-6506-2021; Chardes, Thierry/B-5420-2019
OI Jacot, William/0000-0001-7834-061X; Boissiere-Michot,
   Florence/0000-0003-2431-5157; Chardes, Thierry/0000-0002-1836-7439;
   mallavialle, aude/0000-0002-9380-6788; Turtoi,
   Andrei/0000-0003-3813-6635; liaudet-coopman,
   emmanuelle/0000-0001-9313-9690; Valerie,
   LAURENT-MATHA/0000-0002-3277-7397; Alcaraz, Lindsay/0000-0003-1912-7186
FU French National Research Agency [ANR-10-LABX-53-01]; ICM Biobank
   [BB-0033-00059]
FX French National Research Agency, Grant/Award Number: ANR-10-LABX-53-01;
   ICM Biobank, Grant/Award Number: BB-0033-00059
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NR 67
TC 13
Z9 15
U1 2
U2 13
PU WILEY
PI HOBOKEN
PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA
SN 0020-7136
EI 1097-0215
J9 INT J CANCER
JI Int. J. Cancer
PD MAR 15
PY 2023
VL 152
IS 6
BP 1243
EP 1258
DI 10.1002/ijc.34345
EA NOV 2022
PG 16
WC Oncology
WE Science Citation Index Expanded (SCI-EXPANDED)
SC Oncology
GA 8C1XU
UT WOS:000892599200001
PM 36346290
OA Green Submitted, Green Published, hybrid
DA 2025-03-13
ER

PT J
AU Jena, BC
   Das, CK
   Banerjee, I
   Das, S
   Bharadwaj, D
   Majumder, R
   Mandal, M
AF Jena, Bikash Chandra
   Das, Chandan Kanta
   Banerjee, Indranil
   Das, Subhayan
   Bharadwaj, Deblina
   Majumder, Ranabir
   Mandal, Mahitosh
TI Paracrine TGF-131 from breast cancer contributes to chemoresistance in
   cancer associated fibroblasts via upregulation of the p44/42 MAPK
   signaling pathway
SO BIOCHEMICAL PHARMACOLOGY
LA English
DT Article
DE Chemoresistance; Cancer-associated fibroblasts; Breast cancer; TGF-131;
   p44; 42 MAPK pathway
ID GROWTH-FACTOR-BETA; RESISTANCE; CELLS; ADENOCARCINOMA; METASTASIS;
   MIGRATION; ALTERS
AB Conventionally, Cancer-associated fibroblasts (CAFs) are considered as an inducer of chemoresistance in cancer cells. However, the underlying mechanism by which carcinomas induce chemoresistance in CAFs through tumorstroma cross-talk is largely unknown. Henceforth, we uncovered a network of paracrine signals between carcinoma and CAFs that drives chemoresistance in CAFs. Acquired tamoxifen and 5-Fu resistant cell lines MCF-7 and MDA-MB-468 respectively showed higher apoptotic resistance compared to the parental cell. Besides, chemoresistant breast cancer cells showed overexpression of TGF-131 and have the higher potential to induce CAF phenotype in the normal dermal fibroblasts in a paracrine manner through the TGF-131 cytokine, compared to their parental cell. Moreover, the chemoresistant cancer cells augmented the EMT markers with a reduction of Ecadherin in the CAFs. Importantly we found out that the TGF- 131 enriched conditioned media from both of the resistant cells triggered chemoresistance in the CAFs by p44/42 MAPK signaling axis. Mechanistically, pharmacological and genetic blockade of TGF-131 inhibits p44/42 MAPK activation with the subsequent restoration of chemosensitivity in the CAFs. Altogether we ascertained that chemoresistant cancer cells have tremendous potential to modulate the CAFs compared to the parental counterpart. Targeting TGF-131 and p44/42 MAPK signaling in the future may help to abrogate the chemoresistance in the CAFs.
C1 [Jena, Bikash Chandra; Das, Chandan Kanta; Banerjee, Indranil; Das, Subhayan; Bharadwaj, Deblina; Majumder, Ranabir; Mandal, Mahitosh] Indian Inst Technol Kharagpur, Sch Med Sci & Technol, Kharagpur 721302, W Bengal, India.
C3 Indian Institute of Technology System (IIT System); Indian Institute of
   Technology (IIT) - Kharagpur
RP Mandal, M (corresponding author), Indian Inst Technol Kharagpur, Sch Med Sci & Technol, Kharagpur 721302, W Bengal, India.
EM mahitosh@smst.iitkgp.ernet.in
RI Das, Subhayan/G-3453-2018; Mandal, Mahitosh/GMW-6195-2022; Majumder,
   Ranabir/AAV-8169-2021; Bharadwaj, Deblina/HRY-9848-2023
OI Majumder, Ranabir/0000-0003-3585-3276; Jena, Bikash
   Chandra/0000-0002-6672-9254
FU CSIR India; SERB India; ICMR; DST-INSPIRE; Ministry of Education, Govt.
   of India; Indian Institute of Technology Kharagpur, India
FX Authors are thankful to CSIR India, SERB India for JC Bose Fellowship,
   ICMR, DST-INSPIRE, Ministry of Education, Govt. of India, and Indian
   Institute of Technology Kharagpur, India for providing financial
   support.
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NR 51
TC 36
Z9 36
U1 1
U2 2
PU PERGAMON-ELSEVIER SCIENCE LTD
PI OXFORD
PA THE BOULEVARD, LANGFORD LANE, KIDLINGTON, OXFORD OX5 1GB, ENGLAND
SN 0006-2952
EI 1873-2968
J9 BIOCHEM PHARMACOL
JI Biochem. Pharmacol.
PD APR
PY 2021
VL 186
AR 114474
DI 10.1016/j.bcp.2021.114474
EA FEB 2021
PG 15
WC Pharmacology & Pharmacy
WE Science Citation Index Expanded (SCI-EXPANDED)
SC Pharmacology & Pharmacy
GA RN5TR
UT WOS:000640415300001
DA 2025-03-13
ER

PT J
AU Yang, Y
   Wu, HY
   Fan, SX
   Bi, YQ
   Hao, M
   Shang, J
AF Yang, Yang
   Wu, Haiying
   Fan, Shaoxia
   Bi, Yanqing
   Hao, Min
   Shang, Jian
TI Cancer-associated fibroblast-derived LRRC15 promotes the migration and
   invasion of triple-negative breast cancer cells via Wnt/β-catenin
   signalling pathway regulation
SO MOLECULAR MEDICINE REPORTS
LA English
DT Article
DE triple-negative basal-like breast cancer; leucine-rich repeat-containing
   protein 15; Wnt/beta-catenin signalling pathway; cancer-associated
   fibroblasts
ID EPITHELIAL-MESENCHYMAL TRANSITION; METASTASIS; EXPRESSION; COMPLEX
AB Triple-negative breast cancer (TNBC) is a highly aggressive tumour subtype associated with poor prognosis. The function of leucine-rich repeat-containing protein 15 (LRRC15), a member of the leucine-rich repeat superfamily, in TNBC has not yet been elucidated. The aim of this study was to identify the combined role of LRRC15 and Wnt/beta-catenin signalling pathway in the development of TNBC. The expression of LRRC15 in TNBC tissues was analysed using data from The Cancer Genome Atlas. Cell migration and invasion assays were conducted to study the function of LRRC15 in TNBC. The expression of Wnt/beta-catenin signalling proteins was analysed via western blotting. The effect of LRRC15 on beta-catenin nuclear localisation was measured by performing western blotting and luciferase assays. It was found that high LRRC15 expression was associated with poor prognosis in patients with TNBC. High expression of LRRC15 in cancer-associated fibroblasts (CAFs) promoted cell migration and invasion in TNBC cells. In addition, TNBC cells with LRRC15 overexpression in CAFs showed an aberrant increase in beta-catenin activity concomitant with nuclear localisation of beta-catenin, which inhibited its degradation. These results showed that LRRC15 promoted tumour migration and invasion in TNBC cells by regulating the Wnt/beta-catenin signalling pathway.
C1 [Yang, Yang; Wu, Haiying; Fan, Shaoxia; Bi, Yanqing; Hao, Min; Shang, Jian] Dongying Peoples Hosp, Dept Breast & Thyroid Surg, 317 Dongcheng South 1st Rd, Dongying 257091, Shandong, Peoples R China.
RP Fan, SX (corresponding author), Dongying Peoples Hosp, Dept Breast & Thyroid Surg, 317 Dongcheng South 1st Rd, Dongying 257091, Shandong, Peoples R China.
EM shaoxiafsx@tom.com
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NR 34
TC 14
Z9 15
U1 2
U2 16
PU SPANDIDOS PUBL LTD
PI ATHENS
PA POB 18179, ATHENS, 116 10, GREECE
SN 1791-2997
EI 1791-3004
J9 MOL MED REP
JI Mol. Med. Rep.
PD JAN
PY 2022
VL 25
IS 1
AR 2
DI 10.3892/mmr.2021.12518
PG 8
WC Oncology; Medicine, Research & Experimental
WE Science Citation Index Expanded (SCI-EXPANDED)
SC Oncology; Research & Experimental Medicine
GA XA0NK
UT WOS:000720354900001
PM 34726255
OA hybrid, Green Published
DA 2025-03-13
ER

PT J
AU Avalle, L
   Raggi, L
   Monteleone, E
   Savino, A
   Viavattene, D
   Statello, L
   Camperi, A
   Stabile, SA
   Salemme, V
   De Marzo, N
   Marino, F
   Guglielmi, C
   Lobascio, A
   Zanini, C
   Forni, M
   Incarnato, D
   Defilippi, P
   Oliviero, S
   Poli, V
AF Avalle, Lidia
   Raggi, Laura
   Monteleone, Emanuele
   Savino, Aurora
   Viavattene, Daniele
   Statello, Luisa
   Camperi, Andrea
   Stabile, Simona Aversano
   Salemme, Vincenzo
   De Marzo, Niccolo
   Marino, Francesca
   Guglielmi, Chiara
   Lobascio, Andrea
   Zanini, Cristina
   Forni, Marco
   Incarnato, Danny
   Defilippi, Paola
   Oliviero, Salvatore
   Poli, Valeria
TI STAT3 induces breast cancer growth via ANGPTL4, MMP13 and STC1 secretion
   by cancer associated fibroblasts
SO ONCOGENE
LA English
DT Article
ID MESENCHYMAL TRANSITION; STROMAL FIBROBLASTS; MONOCLONAL-ANTIBODY; TUMORS
   REVEALS; UP-REGULATION; METASTASIS; EXPRESSION; TRANSFORMATION; PROMOTES
AB In the tumor microenvironment, Cancer Associated Fibroblasts (CAFs) become activated by cancer cells and increase their secretory activity to produce soluble factors that contribute to tumor cells proliferation, invasion and dissemination to distant organs. The pro-tumorigenic transcription factor STAT3 and its canonical inducer, the pro-inflammatory cytokine IL-6, act conjunctly in a positive feedback loop that maintains high levels of IL-6 secretion and STAT3 activation in both tumor and stromal cells. Here, we demonstrate that STAT3 is essential for the pro-tumorigenic functions of murine breast cancer CAFs both in vitro and in vivo, and identify a STAT3 signature significantly enriched for genes encoding for secreted proteins. Among these, ANGPTL4, MMP13 and STC-1 were functionally validated as STAT3-dependent mediators of CAF pro-tumorigenic functions by different approaches. Both in vitro and in vivo CAFs activities were moreover impaired by MMP13 inhibition, supporting the feasibility of a therapeutic approach based on inhibiting STAT3-induced CAF-secreted proteins. The clinical potential of such an approach is supported by the observation that an equivalent CAF-STAT3 signature in humans is expressed at high levels in breast cancer stromal cells and characterizes patients with a shorter disease specific survival, including those with basal-like disease.
C1 [Avalle, Lidia; Raggi, Laura; Monteleone, Emanuele; Savino, Aurora; Viavattene, Daniele; Statello, Luisa; Camperi, Andrea; Stabile, Simona Aversano; Salemme, Vincenzo; De Marzo, Niccolo; Marino, Francesca; Guglielmi, Chiara; Lobascio, Andrea; Defilippi, Paola; Poli, Valeria] Univ Torino, Dept Mol Biotechnol & Hlth Sci, Via Nizza 52, I-10126 Turin, Italy.
   [Zanini, Cristina; Forni, Marco] BioAir SPA Sci Dept, Via Nizza 52, I-10126 Turin, Italy.
   [Incarnato, Danny; Oliviero, Salvatore] Univ Torino, Dept Life Sci & Syst Biol, Via Nizza 52, I-10126 Turin, Italy.
   [Raggi, Laura] San Raffaele Telethon Inst Gene Therapy SR TIGET, Milan, Italy.
   [Monteleone, Emanuele] Univ Vita Salute San Raffaele, Milan, Italy.
   [Statello, Luisa] Univ Navarra, Ctr Appl Med Res, Pio XII 55 Ave, Pamplona 31008, Spain.
   [Guglielmi, Chiara] Univ Hosp Pisa, Dept Lab Med, Sect Mol Genet, Pisa, Italy.
   [Incarnato, Danny] Univ Groningen, Dept Mol Genet, Groningen Biomol Sci & Biotechnol Inst GBB, NL-9747 AG Groningen, Netherlands.
C3 University of Turin; University of Turin; Fondazione Telethon; San
   Raffaele Telethon Institute For Gene Therapy (Sr-Tiget); Vita-Salute San
   Raffaele University; University of Navarra; University of Pisa; Azienda
   Ospedaliero Universitaria Pisana; University of Groningen
RP Avalle, L; Poli, V (corresponding author), Univ Torino, Dept Mol Biotechnol & Hlth Sci, Via Nizza 52, I-10126 Turin, Italy.
EM lidia.avalle@unito.it; valeria.poli@unito.it
RI AVALLE, Lidia/AAX-8735-2020; Statello, Luisa/AAU-5115-2021; Savino,
   Aurora/ABG-4185-2021; Monteleone, Emanuele/AAC-4847-2022; oliviero,
   salvatore/R-6657-2019; Guglielmi, Chiara/K-5220-2016
OI Incarnato, Danny/0000-0003-3944-2327; Aversano Stabile,
   Simona/0000-0003-0775-1774; Viavattene, Daniele/0000-0002-6216-3986;
   Salemme, Vincenzo/0000-0001-9431-9693; Monteleone,
   Emanuele/0000-0001-7440-900X; Zanini, Cristina/0000-0002-6554-2113;
   AVALLE, Lidia/0000-0002-5060-633X
FU Italian Cancer Research Association (AIRC) [IG16930, IG 20240]; Italian
   Ministry of University and Research (MIUR PRIN); Truus and Gerrit van
   Riemsdijk Foundation, Liechtenstein, donation; Piedmont Region
   (Deflect); Fondazione Umberto Veronesi
FX The authors wish to thank D. Taverna, C. Ambrogio, E. Calautti, M.
   Mazzone for critically reading the manuscript. This work was supported
   by the Italian Cancer Research Association (AIRC, IG16930 to V.P.; IG
   20240 to S.O.); the Italian Ministry of University and Research (MIUR
   PRIN 2017 to V.P.); the Truus and Gerrit van Riemsdijk Foundation,
   Liechtenstein, donation to V.P.; Piedmont Region (Deflect). L. Avalle
   was supported by Fondazione Umberto Veronesi.
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NR 55
TC 51
Z9 55
U1 4
U2 18
PU SPRINGERNATURE
PI LONDON
PA CAMPUS, 4 CRINAN ST, LONDON, N1 9XW, ENGLAND
SN 0950-9232
EI 1476-5594
J9 ONCOGENE
JI Oncogene
PD MAR 4
PY 2022
VL 41
IS 10
BP 1456
EP 1467
DI 10.1038/s41388-021-02172-y
EA JAN 2022
PG 12
WC Biochemistry & Molecular Biology; Oncology; Cell Biology; Genetics &
   Heredity
WE Science Citation Index Expanded (SCI-EXPANDED)
SC Biochemistry & Molecular Biology; Oncology; Cell Biology; Genetics &
   Heredity
GA ZN2JO
UT WOS:000744825500001
PM 35042959
DA 2025-03-13
ER

PT J
AU Li, HX
   Liu, W
   Zhang, XY
   Wang, YF
AF Li, Huixin
   Liu, Wei
   Zhang, Xiaoyu
   Wang, Yongfeng
TI Cancer-associated fibroblast-secreted collagen triple helix repeat
   containing-1 promotes breast cancer cell migration, invasiveness and
   epithelial-mesenchymal transition by activating the Wnt/β-catenin
   pathway
SO ONCOLOGY LETTERS
LA English
DT Article
DE cancer-associated fibroblasts; collagen triple helix repeat
   containing-1; epithelial-mesenchymal transition; breast cancer;
   Wnt/beta-catenin signaling pathway
ID POOR-PROGNOSIS; TUMOR MICROENVIRONMENT; CTHRC1 EXPRESSION; CARCINOMA;
   EMT; PROTEIN; PROLIFERATION; METASTASIS; ADHESION; ARTERIES
AB Cancer-associated fibroblasts (CAFs) are continuously activated and are one of the most important cellular components of the tumor matrix. The role of CAFs in the tumor microenvironment has been widely recognized. However, the underlying molecular mechanism by which CAFs promote tumor characteristics in breast cancer (BC) remains poorly understood. The aim of the present study was to investigate the potential mechanisms and the possible pathways of collagen triple helix repeat containing-1 (CTHRC1) in the epithelial-mesenchymal transition (EMT) of BC cells. The level of CTHRC1 in BC tissues was found to be higher than that in adjacent-normal tissues. CAFs isolated from BC tissues secreted significantly greater amounts of CTHRC1 than normal fibroblasts. Furthermore, CAFs promoted the migration, invasiveness and EMT of BC cells by secreting CTHRC1, which activates the Wnt/beta-catenin signaling pathway. However, the use of neutralizing antibodies towards CTHRC1, or the specific inhibitor Dickkopf-1, to inhibit the Wnt/beta catenin pathway significantly alleviated the CAF-induced malignant phenotypes of BC cells. Collectively, the data indicate that CAFs in the tumor microenvironment promote BC cell malignant behaviors via the CTHRC1/Wnt/beta-catenin signaling pathway. Furthermore, weakening CAF-BC cell communication by suppressing CTHRC1 expression may be a novel strategy for treating BC.
C1 [Li, Huixin; Liu, Wei; Zhang, Xiaoyu] Cangzhouentral Hosp, Dept Thyroid & Breast 3, Cangzhou 061000, Hebei, Peoples R China.
   [Wang, Yongfeng] Hebei Engn Univ, Affiliated Hosp, Dept Neurosurg, 81 Congtai Rd, Handan 056002, Hebei, Peoples R China.
RP Wang, YF (corresponding author), Hebei Engn Univ, Affiliated Hosp, Dept Neurosurg, 81 Congtai Rd, Handan 056002, Hebei, Peoples R China.
EM wangyongfeng0221@163.com
RI Zhang, xiaoyu/GXA-3206-2022
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NR 46
TC 17
Z9 17
U1 2
U2 14
PU SPANDIDOS PUBL LTD
PI ATHENS
PA POB 18179, ATHENS, 116 10, GREECE
SN 1792-1074
EI 1792-1082
J9 ONCOL LETT
JI Oncol. Lett.
PD DEC
PY 2021
VL 22
IS 6
AR 814
DI 10.3892/ol.2021.13075
PG 10
WC Oncology
WE Science Citation Index Expanded (SCI-EXPANDED)
SC Oncology
GA WF3WE
UT WOS:000706238000001
PM 34671428
DA 2025-03-13
ER

PT J
AU Huang, T
   Lu, C
   Zhang, Y
   Lin, BY
   Zhang, ZJ
   Zhu, D
   Wang, L
   Lu, YZ
AF Huang, Ting
   Lu, Cheng
   Zhang, Ying
   Lin, Bi-yun
   Zhang, Zhe-jun
   Zhu, Di
   Wang, Liang
   Lu, Yuanzhi
TI Effect of activating cancer-associated fibroblasts biomarker TNC on
   immune cell infiltration and prognosis in breast cancer
SO ANNALS OF MEDICINE
LA English
DT Article
DE Cancer-associated fibroblasts; tumor microenvironment; breast cancer;
   prognosis
ID STROMAL FIBROBLASTS; TENASCIN-C; GROWTH; MYOFIBROBLASTS; HETEROGENEITY;
   TAMOXIFEN
AB Background: Cancer-associated fibroblasts (CAFs) are the most important components of the tumor microenvironment (TME). CAFs are heterogeneous and involved in tumor tumorigenesis and drug resistance, contributing to TME remodeling and predicting clinical outcomes as prognostic factors. However, the effect of CAFs the TME and the prognosis of patients with breast cancer (BC) is not fully understood. This study investigated the correlation between CAFs-activating biomarkers immune cell infiltration and survival in patients with breast cancer.Methods: RNA sequencing data and survival information for patients with breast cancer were downloaded from The Cancer Genome Atlas (TCGA) using R software. We then analyzed the correlation between CAFs-expressing biomarkers and immune cells using the clusterProfiler package, and evaluated the prognostic role of appealing genes using the Survminer package. Immunohistochemical (IHC) staining was used to determine the expression levels of TNC in 160 breast cancer samples pathologically diagnosed as invasive ductal carcinoma that were not otherwise specified (IDC-NOS).Results: Data analysis showed that CAFs-expressing genes was higher than in normal tissues (p < 0.05). Pathway enrichment revealed that the overexpression of CAFs-related genes was mainly enriched in the focal adhesion and phosphoinositol-3 kinase-serine/threonine kinase (PI3K-AKT) signaling pathways. Immune infiltration analysis suggested that high expression of CAFs-related genes was significantly positively correlated with the infiltration of naive B cells and resting dendritic cells and inversely correlated with macrophages cell infiltration. In addition, high TNC expression in tumor cells was associated with the most adverse clinicopathological features and reduced metastasis-free survival (MFS) (hazard ratio (HR) 0.574, 95% confidence interval (CI) 0.404-0.815, p = 0.035).Conclusions: This study found that CAFs may participate in immunosuppression and regulate tumor cell proliferation and invasion. High TNC expression is associated with several adverse clinicopathological features, and high TNC expression in tumor cells has been identified as an independent prognostic factor for IDC-NOS.
C1 [Huang, Ting; Zhang, Zhe-jun; Zhu, Di; Lu, Yuanzhi] Jinan Univ, Affiliated Hosp 1, Dept Clin Pathol, Guangzhou, Peoples R China.
   [Lu, Cheng] Hainan Med Univ, Affiliated Hosp 2, Haikou, Peoples R China.
   [Zhang, Ying; Wang, Liang] Jinan Univ, Affiliated Hosp 1, Dept Oncol, Guangzhou, Peoples R China.
   [Lin, Bi-yun] Guangdong Med Univ, Affiliated Hosp, Biotissue Repository, Zhanjiang, Peoples R China.
   [Lu, Yuanzhi] Jinan Univ, Affiliated Hosp 1, Dept Clin Pathol, 613 Huangpu West Ave, Guangzhou, Guangdong, Peoples R China.
   [Wang, Liang] Jinan Univ, Affiliated Hosp 1, Dept Oncol, 613 Huangpu West Ave, Guangzhou, Guangdong, Peoples R China.
C3 Jinan University; Hainan Medical University; Jinan University; Guangdong
   Medical University; Jinan University; Jinan University
RP Lu, YZ (corresponding author), Jinan Univ, Affiliated Hosp 1, Dept Clin Pathol, 613 Huangpu West Ave, Guangzhou, Guangdong, Peoples R China.; Wang, L (corresponding author), Jinan Univ, Affiliated Hosp 1, Dept Oncol, 613 Huangpu West Ave, Guangzhou, Guangdong, Peoples R China.
EM wangliang@jnu.edu.cn; u@jnu.edu.cn
RI HUANG, TING/M-9464-2018; Huang, Siyuan/AAQ-6784-2020
FU National Natural Science Foundation of China [81572606]
FX This study was supported by a grant from the National Natural Science
   Foundation of China [grant number 81572606]. The funders had no role in
   the study design, data collection and analysis, decision to publish, or
   preparation of the manuscript.
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NR 39
TC 3
Z9 3
U1 4
U2 11
PU TAYLOR & FRANCIS LTD
PI ABINGDON
PA 2-4 PARK SQUARE, MILTON PARK, ABINGDON OR14 4RN, OXON, ENGLAND
SN 0785-3890
EI 1365-2060
J9 ANN MED
JI Ann. Med.
PD DEC 12
PY 2023
VL 55
IS 2
AR 2250987
DI 10.1080/07853890.2023.2250987
PG 14
WC Medicine, General & Internal
WE Science Citation Index Expanded (SCI-EXPANDED)
SC General & Internal Medicine
GA X7PV2
UT WOS:001100334000001
PM 38375814
OA Green Published, gold
DA 2025-03-13
ER

PT J
AU Martínez-López, A
   García-Casas, A
   Bragado, P
   Orimo, A
   Castañeda-Saucedo, E
   Castillo-Lluva, S
AF Martinez-Lopez, Angelica
   Garcia-Casas, Ana
   Bragado, Paloma
   Orimo, Akira
   Castaneda-Saucedo, Eduardo
   Castillo-Lluva, Sonia
TI Inhibition of RAC1 activity in cancer associated fibroblasts favours
   breast tumour development through IL-1β upregulation
SO CANCER LETTERS
LA English
DT Article
DE Stromal RAC1; Cancer-associated fibroblasts; Breast cancer; IL-1 beta
ID CARCINOMA-ASSOCIATED FIBROBLASTS; GTPASE RAC1; METASTASIS; ACTIVATION;
   CELLS; PROMOTES; BETA; INTERLEUKIN-1-BETA; EXPRESSION; DRIVES
AB Cancer-associated fibroblasts (CAFs) are highly abundant stromal components in the tumour microenvironment. These cells contribute to tumorigenesis and indeed, they have been proposed as a target for anti-cancer therapies. Similarly, targeting the Rho-GTPase RAC1 has also been suggested as a potential therapeutic target in cancer. Here, we show that targeting RAC1 activity, either pharmacologically or by genetic silencing, increases the pro-tumorigenic activity of CAFs by upregulating IL-1 beta secretion. Moreover, inhibiting RAC1 activity shifts the CAF subtype to a more aggressive phenotype. Thus, as RAC1 suppresses the secretion of IL-1 beta by CAFs, reducing RAC1 activity in combination with the depletion of this cytokine should be considered as an interesting therapeutic option for breast cancer in which tumour cells retain intact IL-1 beta signalling.
C1 [Martinez-Lopez, Angelica; Garcia-Casas, Ana; Castillo-Lluva, Sonia] Univ Complutense, Fac Ciencias Quim & Biol, Dept Bioquim & Biol Mol, Madrid 28040, Spain.
   [Martinez-Lopez, Angelica; Castaneda-Saucedo, Eduardo] Univ Autonoma Guerrero, Fac Ciencias Quim Biol, Lab Biol Celular Canc, Chilpancingo, Mexico.
   [Garcia-Casas, Ana; Bragado, Paloma; Castillo-Lluva, Sonia] Inst Invest Sanitarias San Carlos IdISSC, Madrid 28040, Spain.
   [Bragado, Paloma] Univ Complutense, Fac Farm, Dept Bioquim & Biol Mol, Madrid 28040, Spain.
   [Orimo, Akira] Juntendo Univ, Dept Pathol & Oncol, Sch Med, Tokyo, Japan.
C3 Complutense University of Madrid; Complutense University of Madrid;
   Juntendo University
RP Castillo-Lluva, S (corresponding author), Univ Complutense, Fac Ciencias Quim & Biol, Dept Bioquim & Biol Mol, Madrid 28040, Spain.
EM sonica01@ucm.es
RI García-Casas, Ana/KPY-7855-2024; CASTILLO-LLUVA, SONIA/AAA-1776-2020;
   Lopez, Angelica/JTS-8187-2023; Bragado Domingo, Paloma/A-8679-2015;
   CASTANEDA-SAUCEDO, EDUARDO/I-8157-2019
OI Bragado Domingo, Paloma/0000-0002-7642-1245; Castillo-LLuva,
   Sonia/0000-0001-5357-7178; CASTANEDA-SAUCEDO,
   EDUARDO/0000-0002-0669-4408; Martinez-Lopez,
   Angelica/0000-0001-9407-1368
FU Consejo Nacional de Ciencia y Tecnolog'a (CONACYT) Pre-doctoral Training
   Grant; FPU grant from the Spanish Ministry of Science, Innovation and
   Uni-versity; MINECO/FEDER research [PID2019-104991RB-I00]; Ramon y Cajal
   research contract from the Spanish Ministry of Economy and
   Competi-tiveness; MINECO/FEDER research grant [SAF2015-64499-R,
   RTI2018-094130-B-100]
FX A.M-L is supported by a Consejo Nacional de Ciencia y Tecnolog'a
   (CONACYT) Pre-doctoral Training Grant. A.G.-C. is the recipient of a FPU
   grant from the Spanish Ministry of Science, Innovation and Uni-versity.
   P.B-D work was supported by a MINECO/FEDER research grant
   (PID2019-104991RB-I00) . S.C.-L. was the recipient of a Ramon y Cajal
   research contract from the Spanish Ministry of Economy and
   Competi-tiveness. The work carried out by the group of S.C-L was
   supported by a MINECO/FEDER research grant (SAF2015-64499-R;
   RTI2018-094130-B-100) .
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NR 62
TC 7
Z9 7
U1 0
U2 8
PU ELSEVIER IRELAND LTD
PI CLARE
PA ELSEVIER HOUSE, BROOKVALE PLAZA, EAST PARK SHANNON, CO, CLARE, 00000,
   IRELAND
SN 0304-3835
EI 1872-7980
J9 CANCER LETT
JI Cancer Lett.
PD NOV 28
PY 2021
VL 521
BP 14
EP 28
DI 10.1016/j.canlet.2021.08.014
EA AUG 2021
PG 15
WC Oncology
WE Science Citation Index Expanded (SCI-EXPANDED)
SC Oncology
GA WA3DQ
UT WOS:000702770200002
PM 34419498
OA Green Accepted, hybrid
DA 2025-03-13
ER

PT J
AU Gao, C
   Jian, C
   Wang, LL
   Liu, YJ
   Xiong, YQ
   Wu, TT
   Shi, C
AF Gao, Chen
   Jian, Chen
   Wang, Lulu
   Liu, Yajing
   Xiong, Yiquan
   Wu, Tingting
   Shi, Chen
TI FAP-targeting biomimetic nanosystem to restore the activated
   cancer-associated fibroblasts to quiescent state for breast cancer
   radiotherapy
SO INTERNATIONAL JOURNAL OF PHARMACEUTICS
LA English
DT Article
DE Cancer-associated fibroblasts; Breast cancer; Vitamin D receptor;
   Calcipotriol; Biomimetic nanoplatform
AB Cancer associated fibroblasts (CAFs) are one of the most important stromal cells in the tumor microenvironment, playing a pivotal role in the development, recurrence, metastasis, and immunosuppression of cancer and treatment resistance. Here, we developed a core-shell biomimetic nanosystem termed as FAP-C NPs. This system was comprised of 4T1 extracellular vesicles fused with a FAP single-chain antibody fragment to form the biomimetic shell, and PLGA nanoparticles loaded with calcipotriol as the core. The FAP-modified shell endowed this nanosystem with active targeting ability to CAFs. Calcipotriol, a vitamin D analog, can activate the vitamin D receptor expressed on CAFs, promoting their transition from an activated to quiescent state. This process would help to reduce the pro-tumorigenic signals generated by CAFs, inhibit the stemness of cancer cells, and attenuate the inhibitory effect of CAFs on immune cells. The hydrated particle size of FAP-C NPs was approximately 206 nm, with a narrow distribution (polydispersity index < 0.2). The zeta potential of FAP-C NPs was -12.63 +/- 0.61 mV. FAP-C NPs can restore CAFs to a quiescent state to shield the function of activated CAFs, inhibit tumor cell stemness, facilitate the maturation of dendritic cell, and relieve the inhibition of CAFs on lymphocytes. Besides, when combined with radiotherapy, this biomimetic nanosystem could inhibit the activation of CAFs, improve the sensitivity to radiation, and stimulate potent anti-tumor immune response with a 2-fold increase in the infiltration of cytotoxic T cells in tumor microenvironment, thereby effectively suppressing tumor growth with the tumor inhibitory rate as 78.3 %. Therefore, FAP-C NPs hold great potential for targeted breast cancer therapy.
C1 [Gao, Chen; Jian, Chen; Wang, Lulu; Liu, Yajing; Wu, Tingting; Shi, Chen] Huazhong Univ Sci & Technol, Union Hosp, Tongji Med Coll, Dept Pharm, Wuhan 430022, Peoples R China.
   [Gao, Chen; Jian, Chen; Wang, Lulu; Liu, Yajing; Wu, Tingting; Shi, Chen] Hubei Prov Clin Res Ctr Precis Med Crit Illness, Wuhan 430022, Peoples R China.
   [Xiong, Yiquan] Huazhong Univ Sci & Technol, Union Hosp, Tongji Med Coll, Dept Breast & Thyroid Surg, Wuhan 430022, Peoples R China.
C3 Huazhong University of Science & Technology; Huazhong University of
   Science & Technology
RP Wu, TT; Shi, C (corresponding author), Huazhong Univ Sci & Technol, Union Hosp, Tongji Med Coll, Dept Pharm, Wuhan 430022, Peoples R China.
EM tingtingwu1202@163.com; whxhchen@163.com
FU National Natural Science Foundation of China [82073402]; Cancer Center
   of Wuhan Union Hospital
FX This study received funding from the National Natural Science Foundation
   of China (No. 82073402) . The authors gratefully acknowledge the Medical
   Subcenter of Huazhong University of Science and Technology (HUST)
   Analytical and Testing Center for TEM imaging. Special thanks are
   extended to the Cancer Center of Wuhan Union Hospital for their support
   with radiation therapy. Scheme 1 and the graphical abstract were
   prepared using Biorender.com .
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NR 49
TC 0
Z9 0
U1 8
U2 8
PU ELSEVIER
PI AMSTERDAM
PA RADARWEG 29, 1043 NX AMSTERDAM, NETHERLANDS
SN 0378-5173
EI 1873-3476
J9 INT J PHARMACEUT
JI Int. J. Pharm.
PD FEB 10
PY 2025
VL 670
AR 125190
DI 10.1016/j.ijpharm.2025.125190
EA JAN 2025
PG 13
WC Pharmacology & Pharmacy
WE Science Citation Index Expanded (SCI-EXPANDED)
SC Pharmacology & Pharmacy
GA S5S4Y
UT WOS:001398815200001
PM 39788396
DA 2025-03-13
ER

PT J
AU Wang, HB
   Wei, H
   Wang, JS
   Li, L
   Chen, AY
   Li, ZG
AF Wang, Hongbin
   Wei, Hong
   Wang, Jingsong
   Li, Lin
   Chen, Anyue
   Li, Zhigao
TI MicroRNA-181d-5p-Containing Exosomes Derived from CAFs Promote EMT by
   Regulating CDX2/HOXA5 in Breast Cancer
SO MOLECULAR THERAPY-NUCLEIC ACIDS
LA English
DT Article
ID MESENCHYMAL TRANSITION; EXPRESSION; FIBROBLASTS; CDX2; HOXA5; GENE;
   MICRORNA; CELLS
AB Recently, novel mechanisms underlying the pro-tumorigenic effects of cancer-associated fibroblasts (CAFs) have been identified in several cancers, including breast cancer. CAFs can secrete exosomes that are loaded with proteins, lipids, and RNAs to affect tumor microenvironment. Herein, we identify CAF-derived exosomes that can transfer miR-181d-5p to enhance the aggressiveness of breast cancer. Cancerous tissues and matched paracancerous tissues were surgically resected from 122 patients with breast cancer. Chromatin immunoprecipitation (ChIP) and dual luciferase reporter assays were employed to identify interaction between homeobox A5 (HOXA5) and caudal-related homeobox 2 (CDX2), as well as between CDX2 and miR-181d-5p, respectively. Human breast cancer Michigan Cancer Foundation-7 (MCF-7) cells were cocultured with CAF-derived exosomes. 5-Ethynyl-2'-deoxyuridine (EdU) assay, TUNEL staining, Transwell invasion assays, and scratch tests were carried out to evaluate MCF-7 cell functions. Nude mice bearing xenografted MCF-7 cells were injected with CAF-derived exosomes, and the tumor formation was evaluated. HOXA5 expressed at a poor level in breast cancer tissues, and its overexpression retarded MCF-7 cell proliferation, invasion, migration, and epithelial-mesenchymal transition (EMT) and facilitated its apoptosis in vitro. miR-181d-5p targets CDX2, a transcription factor binding to HOXA5 promoter. Coculture of CAFs and MCF-7 cells showed that CAFs prolonged proliferation and antagonized apoptosis of MCF-7 cells via release of exosomes. Coculture of MCF-7 cells and exosomes derived from CAFs identified miR-181d-5p as a mediator of the exosomal effects on MCF-7 cells, in part, via downregulation of CDX2 and HOXA5. CAF-derived exosomes containing miR181d-5p promoted the tumor growth of nude mice bearing xenografted MCF-7 cells. In conclusion, exosomal miR-181d-5p plays a key role in CAF-mediated effects on tumor environment in breast cancer, likely via CDX2 and HOXA5.
C1 [Wang, Hongbin; Wang, Jingsong; Li, Lin; Chen, Anyue; Li, Zhigao] Harbin Med Univ, Canc Hosp, Ward 2, Dept Breast Surg, 150 Haping Rd, Harbin 150081, Heilongjiang, Peoples R China.
   [Wei, Hong] Harbin Med Univ, Affiliated Hosp 2, Inpatient Dept Ultrasound, Harbin 150001, Peoples R China.
C3 Harbin Medical University; Harbin Medical University
RP Li, ZG (corresponding author), Harbin Med Univ, Canc Hosp, Ward 2, Dept Breast Surg, 150 Haping Rd, Harbin 150081, Heilongjiang, Peoples R China.
EM lzg_1964@yeah.net
RI Wang, James/JAD-0675-2023; Wang, Shiyao/JLL-7826-2023
FU National Natural Science Foundation of China [81573001]; National
   Natural Science Foundation [81872157]; Harbin Applied Technology
   Research and Development Project Plan (Harbin Science and Technology
   Bureau) [2016RAQXJ174]
FX We give our sincere gratitude to the reviewers for their valuable
   suggestions. This study was supported by the National Natural Science
   Foundation of China (no. 81573001) and the National Natural Science
   Foundation (81872157) to H. Wang and the Harbin Applied Technology
   Research and Development Project Plan (Harbin Science and Technology
   Bureau) (no. 2016RAQXJ174).
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NR 39
TC 140
Z9 148
U1 3
U2 48
PU CELL PRESS
PI CAMBRIDGE
PA 50 HAMPSHIRE ST, FLOOR 5, CAMBRIDGE, MA 02139 USA
SN 2162-2531
J9 MOL THER-NUCL ACIDS
JI Mol. Ther.-Nucl. Acids
PD MAR 6
PY 2020
VL 19
BP 654
EP 667
DI 10.1016/j.omtn.2019.11.024
PG 14
WC Medicine, Research & Experimental
WE Science Citation Index Expanded (SCI-EXPANDED)
SC Research & Experimental Medicine
GA KU2SH
UT WOS:000519557700057
PM 31955007
OA gold, Green Published
DA 2025-03-13
ER

PT J
AU Gua, P
   Ding, WT
   Zhu, WT
   Shen, L
   Zhang, L
   Wang, W
   Wang, RT
   Wang, WH
   Wang, YH
   Yan, B
   Sun, X
AF Gua, Peng
   Ding, Wentao
   Zhu, Wenting
   Shen, Ling
   Zhang, Lei
   Wang, Wei
   Wang, Ruitao
   Wang, Wenhao
   Wang, Yanhao
   Yan, Bin
   Sun, Xing
TI MIR4435-2HG: A novel biomarker for triple-negative breast cancer
   diagnosis and prognosis, activating cancer-associated fibroblasts and
   driving tumor invasion through EMT associated with JNK/c-Jun and p38
   MAPK signaling pathway activation
SO INTERNATIONAL IMMUNOPHARMACOLOGY
LA English
DT Article
DE MIR4435-2HG; Triple Negative Breast Neoplasms; Biological Markers; MAP
   Kinase Signaling System; Cancer-Associated Fibroblasts; Tumor
   Microenvironment
ID PROLIFERATION; MIGRATION; SUPPRESSES; CELLS
AB Background: Breast cancer has the highest incidence rate and causes the most fatalities among all female cancers worldwide. Triple-negative breast cancer (TNBC) is known for its strong invasiveness and higher rates of recurrence. In this research, we aimed to identify MIR4435-2HG as a promising long non-coding RNA (lncRNA) biomarker and therapeutic target for TNBC. Methods: Utilizing clinicopathological information and transcriptome data from The Cancer Genome Atlas (TCGA) database, we assessed the clinical relevance of MIR4435-2HG in breast cancer through univariate and multivariate COX regression, receiver operating characteristic (ROC) analysis, as well as Kaplan-Meier survival analysis. To investigate the biological role of MIR4435-2HG in TNBC, we conducted gene set enrichment analysis (GSEA), as well as Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) analyses. Additionally, we constructed and validated a nomogram to predict disease-free survival (DFS). Both the R package "pRRophetic" and the Tumor Immune Dysfunction and Exclusion (TIDE) algorithm were employed to forecast the sensitivity to different therapeutics between the high- and low-MIR4435-2HG groups. We employed single-cell RNA sequencing analysis and tumor microenvironment infiltration analysis to investigate the potential involvement of MIR4435-2HG in the TNBC tumor microenvironment. Cellular biological behaviors were assessed utilizing CCK-8, transwell assays, and wound-healing assays. Furthermore, we performed RNA-seq, qRTPCR, and western blotting analyses to elucidate and confirm the specific mechanisms underlying the role of MIR4435-2HG in TNBC. Results: In our study, we have identified MIR4435-2HG as a significant diagnostic and prognostic factor for TNBC. We observed that MIR4435-2HG is widely expressed and might have a significant impact on the reshaping of the TNBC tumor microenvironment. Patients with TNBC in the high-MIR4435-2HG group may show reduced sensitivity to cisplatin, doxorubicin, and gemcitabine and have an increased propensity for immune escape. Knockdown of MIR4435-2HG inhibits cancer-associated fibroblasts (CAFs) activation. Notably, MIR4435-2HG predominantly enhances the migratory and invasive capabilities of TNBC cells through the epithelial- mesenchymal transition (EMT) process. Mechanistically, we validated that MIR4435-2HG activates the JNK/cJun and p38 non-classical MAPK signaling pathway in TNBC cells. Conclusions: Our findings highlight the significant potential of MIR4435-2HG as a highly promising biomarker for TNBC. Targeting MIR4435-2HG could represent an appealing therapeutic approach for TNBC.
C1 [Gua, Peng; Ding, Wentao; Zhu, Wenting; Shen, Ling; Zhang, Lei; Wang, Wei; Wang, Ruitao; Wang, Yanhao] Shanghai Jiao Tong Univ, Shanghai Gen Hosp, Sch Med, Dept Gen Surg, Shanghai 201620, Peoples R China.
   [Shen, Ling; Zhang, Lei] Nanjing Med Univ, Shanghai Gen Hosp, Clin Med Sch, Shanghai 211166, Peoples R China.
   [Wang, Wenhao] Shanghai Jiao Tong Univ, Shanghai Gen Hosp, Sch Med, Dept Urol, Shanghai 201620, Peoples R China.
   [Wang, Yanhao] Fudan Univ, Shanghai Canc Ctr, Dept Breast Surg, 270 Dongan Rd, Shanghai 200032, Peoples R China.
C3 Shanghai Jiao Tong University; Nanjing Medical University; Shanghai Jiao
   Tong University; Fudan University
RP Yan, B; Sun, X (corresponding author), Shanghai Gen Hosp, Xin Songjiang Rd 650, Shanghai 201620, Peoples R China.
EM yanbin8988@sjtu.edu.cn; xingsun_sjtu@aliyun.com
RI Wang, Yanhao/HOH-6051-2023; Wang, Wenhao/ABO-5766-2022
FU National Natural Science Foundation of China [82172907]
FX This work was supported by National Natural Science Foundation of China
   [grant number 82172907] .
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NR 32
TC 0
Z9 0
U1 2
U2 2
PU ELSEVIER
PI AMSTERDAM
PA RADARWEG 29, 1043 NX AMSTERDAM, NETHERLANDS
SN 1567-5769
EI 1878-1705
J9 INT IMMUNOPHARMACOL
JI Int. Immunopharmacol.
PD DEC 5
PY 2024
VL 142
AR 113191
DI 10.1016/j.intimp.2024.113191
EA SEP 2024
PN B
PG 14
WC Immunology; Pharmacology & Pharmacy
WE Science Citation Index Expanded (SCI-EXPANDED)
SC Immunology; Pharmacology & Pharmacy
GA H3A3D
UT WOS:001322191600001
PM 39317050
DA 2025-03-13
ER

PT J
AU Zhang, B
   Liu, Y
   Yu, JS
   Lin, X
AF Zhang, Bo
   Liu, Yang
   Yu, Jinsong
   Lin, Xi
TI Upregulation of FGF9 and NOVA1 in cancer-associated fibroblasts promotes
   cell proliferation, invasion and migration of triple negative breast
   cancer
SO DRUG DEVELOPMENT RESEARCH
LA English
DT Article
DE cancer-associated fibroblasts; FGF9; NOVA1; triple negative breast
   cancer
ID GROWTH-FACTOR 9; GASTRIC-CANCER; METASTASIS; EXPRESSION;
   MICROENVIRONMENT; ANTIGEN; PROTEIN
AB Cancer-associated fibroblasts (CAFs) play a pivotal role in cancer progression. This study aimed to explore the roles of CAFs-derived Fibroblast growth factor 9 (FGF9) and Neuro-oncological ventral antigen 1 (NOVA1) in triple negative breast cancer (TNBC) progression. MDA-MB-231 and BT-549 cells were cocultured with CAF conditioned-medium (CAF-CM) or normal fibroblasts conditioned-medium (NF-CM). MTT, EdU, colony formation, wound healing, transwell migration, and invasion assays were employed to determine cell proliferation, migration and invasion, respectively. Western blot and RT-qPCR were carried out to examine the protein and mRNA expression of FGF9 and NOVA1. Xenograft tumor experiments were conducted to evaluate the effects of CAFs, FGF9, and NOVA1 on tumor growth in vivo. Our results showed that CAFs significantly promoted the proliferation, invasion, and migration of TNBC cells. FGF9 and NOVA1 were significantly upregulated in TNBC CAFs, tissues and cells. CAF-CM also could increase the expression of FGF9 and NOVA1 in TNBC cells. Knockdown of FGF9 or NOVA1 could hamper cell proliferation, invasion, migration, and EMT of TNBC cells. Moreover, CAFs with FGF9/NOVA1 knockdown also could inhibit TNBC progression. Besides, CAFs significantly accelerated tumor growth in vivo, which was blocked by FGF9/NOVA1 knockdown in nude mice. In conclusion, our results indicated the tumor-promoting role of CAFs in TNBC progression. FGF9 and NOVA1 upregulation in CAFs induced cell proliferation, migration and invasion in vitro, and facilitated tumor growth in vivo in TNBC development.
C1 [Zhang, Bo] Nanyang First Peoples Hosp, Dept Thyroid & Breast Surg, Nanyang, Peoples R China.
   [Liu, Yang] Nanyang Cent Hosp, Endocrinol Dept Integrated Chinese & Western Med, Nanyang, Peoples R China.
   [Yu, Jinsong] Henan Univ, Dept Thyroid & Breast Surg, Nanyang Peoples Hosp 1, Nanyang, Peoples R China.
   [Yu, Jinsong] Henan Univ, Nanyang Peoples Hosp 1, Key Lab Thyroid Tumor Prevent & Treatment, Nanyang, Peoples R China.
   [Lin, Xi] Tiantai Cty Peoples Hosp, Dept Herniat Surg, 1 Kangning Middle Rd,Shifeng St, Taizhou 317200, Peoples R China.
C3 Henan University; Henan University
RP Lin, X (corresponding author), Tiantai Cty Peoples Hosp, Dept Herniat Surg, 1 Kangning Middle Rd,Shifeng St, Taizhou 317200, Peoples R China.
EM lxttxrmyy@163.com
FU This study was supported by the Joint construction Project of Henan
   Medical Science and Technology Research Plan [LHGJ20230966]; Joint
   construction Project of Henan Medical Science and Technology Research
   Plan
FX This study was supported by the Joint construction Project of Henan
   Medical Science and Technology Research Plan (LHGJ20230966).
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NR 47
TC 0
Z9 0
U1 1
U2 1
PU WILEY
PI HOBOKEN
PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA
SN 0272-4391
EI 1098-2299
J9 DRUG DEVELOP RES
JI Drug Dev. Res.
PD MAY
PY 2024
VL 85
IS 3
AR e22185
DI 10.1002/ddr.22185
PG 12
WC Chemistry, Medicinal; Pharmacology & Pharmacy
WE Science Citation Index Expanded (SCI-EXPANDED)
SC Pharmacology & Pharmacy
GA OL3H2
UT WOS:001207383800001
PM 38657094
DA 2025-03-13
ER

PT J
AU Sun, CX
   Wang, SW
   Zhang, YC
   Yang, F
   Zeng, TY
   Meng, FC
   Yang, MZ
   Yang, YQ
   Hua, YJ
   Fu, ZY
   Li, J
   Huang, X
   Wu, H
   Yin, YM
   Li, W
AF Sun, Chunxiao
   Wang, Siwei
   Zhang, Yuchen
   Yang, Fan
   Zeng, Tianyu
   Meng, Fanchen
   Yang, Mengzhu
   Yang, Yiqi
   Hua, Yijia
   Fu, Ziyi
   Li, Jun
   Huang, Xiang
   Wu, Hao
   Yin, Yongmei
   Li, Wei
TI Risk Signature of Cancer-Associated Fibroblast-Secreted Cytokines
   Associates With Clinical Outcomes of Breast Cancer
SO FRONTIERS IN ONCOLOGY
LA English
DT Article
DE breast cancer; prognostic signature; cancer-associated fibroblast;
   cytokine; tumor microenvironment
ID GENE-EXPRESSION SIGNATURE; HETEROGENEITY; EVOLUTION; PATTERNS
AB Cancer-associated fibroblasts (CAFs) are key components in tumor microenvironment (TME). The secreted products of CAFs play important roles in regulating tumor cells and further impacting clinical prognosis. This study aims to reveal the relationship between CAF-secreted cytokines and breast cancer (BC) by constructing the risk signature. We performed three algorithms to reveal CAF-related cytokines in the TCGA BC dataset and identified five prognosis-related cytokines. Then we used single-cell RNA sequencing (ScRNA-Seq) datasets of BC to confirm the expression level of these five cytokines in CAFs. METABRIC and other independent datasets were utilized to validate the findings in further analyses. Based on the identified five-cytokine signature derived from CAFs, BC patients with high-risk score (RS) had shorter overall survival than low-RS cases. Further analysis suggested that the high-RS level correlated with cell proliferation and mast cell infiltration in BCs of the Basal-like subtype. The results also indicated that the level of RS could discriminate the high-risk BC cases harboring driver mutations (i.e., PI3KCA, CDH1, and TP53). Additionally, the status of five-cytokine signature was associated with the frequency and molecular timing of whole genome duplication (WGD) events. Intratumor heterogeneity (ITH) analysis among BC samples indicated that the high-RS level was associated with the increase of tumor subclones. This work demonstrated that the prognostic signature based on CAF-secreted cytokines was associated with clinical outcome, tumor progression, and genetic alteration. Our findings may provide insights to develop novel strategies for early intervention and prognostic prediction of BC.
C1 [Sun, Chunxiao; Zhang, Yuchen; Yang, Fan; Zeng, Tianyu; Yang, Mengzhu; Yang, Yiqi; Hua, Yijia; Fu, Ziyi; Li, Jun; Huang, Xiang; Wu, Hao; Yin, Yongmei; Li, Wei] Nanjing Med Univ, Dept Oncol, Affiliated Hosp 1, Nanjing, Peoples R China.
   [Wang, Siwei; Meng, Fanchen] Nanjing Med Univ, Jiangsu Key Lab Mol & Translat Canc Res, Dept Thorac Surg, Affiliated Canc Hosp, Nanjing, Peoples R China.
   [Wang, Siwei; Meng, Fanchen] Jiangsu Canc Hosp, Nanjing, Peoples R China.
   [Wang, Siwei; Meng, Fanchen] Jiangsu Inst Canc Res, Nanjing, Peoples R China.
   [Yin, Yongmei] Nanjing Med Univ, Collaborat Innovat Ctr Personalized Canc Med, Jiangsu Key Lab Canc Biomarkers Prevent & Treatme, Nanjing, Peoples R China.
   [Li, Wei] Nanjing Med Univ, Dept Oncol, Sir Run Run Hosp, Nanjing, Peoples R China.
C3 Nanjing Medical University; Nanjing Medical University; Nanjing Medical
   University; Nanjing Medical University; Nanjing Medical University;
   Nanjing Medical University
RP Yin, YM; Li, W (corresponding author), Nanjing Med Univ, Dept Oncol, Affiliated Hosp 1, Nanjing, Peoples R China.; Yin, YM (corresponding author), Nanjing Med Univ, Collaborat Innovat Ctr Personalized Canc Med, Jiangsu Key Lab Canc Biomarkers Prevent & Treatme, Nanjing, Peoples R China.; Li, W (corresponding author), Nanjing Med Univ, Dept Oncol, Sir Run Run Hosp, Nanjing, Peoples R China.
EM ymyin@njmu.edu.cn; real.lw@163.com
RI Meng, Fanchen/AAZ-5904-2020; Fu, Ziyi/ABB-8091-2022; yin,
   yongmei/KVZ-0566-2024; Zeng, Tianyu/JJD-5741-2023; Wang,
   Yijun/GXW-1763-2022
FU National Science Foundation of China [81972484, 81772475, 81902704];
   Youth medical talent project in science and education of Jiangsu
   Province [QNRC2016855]; Collaborative innovation center for tumor
   individualization focuses on open topics of Nanjing Medical University
   [JX21817902/008]; Highlevel innovation team of Nanjing Medical
   University [JX102GSP201727]; Project of China Key Research and
   Development Program Precision Medicine Research [2016YFC0905901]; Key
   Medical Talents of Jiangsu Province [ZDRCA2016023]
FX This work was supported by the National Science Foundation of China
   (81972484, 81772475, 81972484, 81902704), Youth medical talent project
   in science and education of Jiangsu Province (QNRC2016855),
   Collaborative innovation center for tumor individualization focuses on
   open topics of Nanjing Medical University (JX21817902/008), Highlevel
   innovation team of Nanjing Medical University (JX102GSP201727), Project
   of China Key Research and Development Program Precision Medicine
   Research (2016YFC0905901), and Key Medical Talents of Jiangsu Province
   (ZDRCA2016023).
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NR 50
TC 10
Z9 10
U1 0
U2 22
PU FRONTIERS MEDIA SA
PI LAUSANNE
PA AVENUE DU TRIBUNAL FEDERAL 34, LAUSANNE, CH-1015, SWITZERLAND
SN 2234-943X
J9 FRONT ONCOL
JI Front. Oncol.
PD JUL 28
PY 2021
VL 11
AR 628677
DI 10.3389/fonc.2021.628677
PG 11
WC Oncology
WE Science Citation Index Expanded (SCI-EXPANDED)
SC Oncology
GA TY6FN
UT WOS:000683878100001
PM 34395236
OA Green Published, gold
DA 2025-03-13
ER

PT J
AU Yoshikawa, K
   Ishida, M
   Yanai, H
   Tsuta, K
   Sekimoto, M
   Sugie, T
AF Yoshikawa, Katsuhiro
   Ishida, Mitsuaki
   Yanai, Hirotsugu
   Tsuta, Koji
   Sekimoto, Mitsugu
   Sugie, Tomoharu
TI Prognostic significance of PD-L1-positive cancer-associated fibroblasts
   in patients with triple-negative breast cancer
SO BMC CANCER
LA English
DT Article
DE Triple-negative breast cancer; Programmed death ligand 1;
   Cancer-associated fibroblasts; Overall survival
AB BackgroundCancer-associated fibroblasts (CAFs) are some of the most abundant components of the tumour microenvironment. A recent study suggested that in some cancers, CAFs express programmed death ligand 1 (PD-L1), which can act as a prognostic marker. The aim of this study was to investigate the clinicopathological significance of CAF PD-L1 expression in patients with triple-negative breast cancer (TNBC) and to identify the most suitable primary antibody for immunostaining for CAF PD-L1.MethodsImmunohistochemical staining (primary antibodies of 73-10, SP142, and E1L3N) and tissue microarrays were used to analyse the expression profiles of PD-L1 in CAF in 61 patients with TNBC who underwent surgery. Overall survival (OS) was compared based on CAF PD-L1 expression, and the risk factors for OS were analysed. The relationship between clinicopathological parameters and survival was also examined.ResultsThirty-four (55.7%) patients were positive for CAF PD-L1 (73-10) expression. Compared with CAF PD-L1 negativity, there was a significant correlation between CAF PD-L1 positivity and better OS (p=0.029). CAF PD-L1 expression, evaluated using SP-142 or E1L3N, did not correlate with OS. CAF PD-L1-positivity (73-10) correlated significantly with better prognosis in multivariate analyses (hazard ratio: 0.198; 95% confidence interval: 0.044-0.891; p=0.035).ConclusionsCAF PD-L1 expression is a novel marker for a better prognosis of patients with TNBC, and the 73-10 assay may be suitable for immunostaining CAF PD-L1.
C1 [Yoshikawa, Katsuhiro; Ishida, Mitsuaki; Tsuta, Koji] Kansai Med Univ, Dept Pathol & Clin Lab, 2-5-1 Shinmachi, Hirakata, Osaka 5731010, Japan.
   [Yoshikawa, Katsuhiro; Yanai, Hirotsugu; Sekimoto, Mitsugu; Sugie, Tomoharu] Kansai Med Univ, Dept Surg, 2-5-1 Shinmachi, Hirakata, Osaka, Japan.
C3 Kansai Medical University; Kansai Medical University
RP Ishida, M (corresponding author), Kansai Med Univ, Dept Pathol & Clin Lab, 2-5-1 Shinmachi, Hirakata, Osaka 5731010, Japan.
EM ishidamt@hirakata.kmu.ac.jp
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NR 37
TC 29
Z9 31
U1 0
U2 8
PU BMC
PI LONDON
PA CAMPUS, 4 CRINAN ST, LONDON N1 9XW, ENGLAND
EI 1471-2407
J9 BMC CANCER
JI BMC Cancer
PD MAR 6
PY 2021
VL 21
IS 1
AR 239
DI 10.1186/s12885-021-07970-x
PG 10
WC Oncology
WE Science Citation Index Expanded (SCI-EXPANDED)
SC Oncology
GA QT4VS
UT WOS:000626587700013
PM 33676425
OA Green Published, gold
DA 2025-03-13
ER

PT J
AU Soon, PSH
   Kim, E
   Pon, CK
   Gill, AJ
   Moore, K
   Spillane, AJ
   Benn, DE
   Baxter, RC
AF Soon, Patsy S. H.
   Kim, Edward
   Pon, Cindy K.
   Gill, Anthony J.
   Moore, Katrina
   Spillane, Andrew J.
   Benn, Diana E.
   Baxter, Robert C.
TI Breast cancer-associated fibroblasts induce epithelial-to-mesenchymal
   transition in breast cancer cells
SO ENDOCRINE-RELATED CANCER
LA English
DT Article
ID STROMAL FIBROBLASTS; COLORECTAL-CANCER; CARCINOMA CELLS; STEM-CELLS;
   PROGRESSION; EXPRESSION; LUNG
AB Cancer-associated fibroblasts (CAFs) play a role in tumour initiation and progression, possibly by inducing epithelial-to-mesenchymal transition (EMT), a series of cellular changes that is known to underlie the process of metastasis. The aim of this study was to determine whether CAFs and surrounding normal breast fibroblasts (NBFs) are able to induce EMT markers and functional changes in breast epithelial cancer cells. Matched pairs of CAFs and NBFs were established from fresh human breast cancer specimens and characterised by assessment of CXCL12 levels, alpha-smooth muscle actin (alpha-SMA) levels and response to doxorubicin. The fibroblasts were then co-cultured with MCF7 cells. Vimentin and E-cadherin expressions were determined in co-cultured MCF7 cells by immunofluorescence and confocal microscopy as well as by western blotting and quantitative PCR. Co-cultured MCF7 cells were also assessed functionally by invasion assay. CAFs secreted higher levels of CXCL12 and expressed higher levels of alpha-SMA compared with NBFs. CAFs were also less sensitive to doxorubicin as evidenced by less H2AX phosphorylation and reduced apoptosis on flow cytometric analysis of Annexin V compared with NBFs. When co-cultured with MCF7 cells, there was greater vimentin and less E-cadherin expression as well as greater invasiveness in MCF7 cells co-cultured with CAFs compared with those co-cultured with NBFs. CAFs have the ability to induce a greater degree of EMT in MCF7 cell lines, indicating that CAFs contribute to a more malignant breast cancer phenotype and their role in influencing therapy resistance should therefore be considered when treating breast cancer.
C1 [Soon, Patsy S. H.; Kim, Edward; Pon, Cindy K.; Benn, Diana E.; Baxter, Robert C.] Royal N Shore Hosp, Hormones & Canc Grp, Kolling Inst Med Res, Sydney, NSW, Australia.
   [Soon, Patsy S. H.; Kim, Edward; Pon, Cindy K.; Gill, Anthony J.; Moore, Katrina; Spillane, Andrew J.; Benn, Diana E.; Baxter, Robert C.] Univ Sydney, Northern Clin Sch, Sydney, NSW 2006, Australia.
   [Soon, Patsy S. H.] Univ New S Wales, South Western Sydney Clin Sch, Sydney, NSW, Australia.
   [Soon, Patsy S. H.] Bankstown Hosp, Dept Surg, Bankstown, NSW, Australia.
   [Gill, Anthony J.] Royal N Shore Hosp, Dept Anat Pathol, St Leonards, NSW 2065, Australia.
   [Moore, Katrina; Spillane, Andrew J.] Royal N Shore Hosp, Dept Endocrine & Oncol Surg, St Leonards, NSW 2065, Australia.
C3 Royal North Shore Hospital; University of Sydney; Kolling Institute of
   Medical Research; University of Sydney; University of New South Wales
   Sydney; NSW Health; Bankstown Lidcombe Hospital; Royal North Shore
   Hospital; Royal North Shore Hospital
RP Soon, PSH (corresponding author), Royal N Shore Hosp, Hormones & Canc Grp, Kolling Inst Med Res, Sydney, NSW, Australia.
EM patsy.soon@sydney.edu.au
RI Spillane, Andrew John/JCE-4975-2023; Gill, Anthony/D-4215-2015; Baxter,
   Robert/F-3927-2012
OI Spillane, Andrew John/0000-0002-8354-434X; Gill,
   Anthony/0000-0002-9447-1967; Baxter, Robert/0000-0001-5061-2142
FU University of Sydney Cancer Research Fund; National Health and Medical
   Research Council (Health Professional Research Training Fellowship)
   [511996]; New South Wales Cancer Institute (Clinical Research
   Fellowship) [09/CRF/2-05]
FX This work was funded by the University of Sydney Cancer Research Fund. P
   SHSoon was also funded by National Health and Medical Research Council
   (Health Professional Research Training Fellowship #511996) and New South
   Wales Cancer Institute (Clinical Research Fellowship #09/CRF/2-05).
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NR 28
TC 109
Z9 126
U1 0
U2 25
PU BIOSCIENTIFICA LTD
PI BRISTOL
PA EURO HOUSE, 22 APEX COURT WOODLANDS, BRADLEY STOKE, BRISTOL BS32 4JT,
   ENGLAND
SN 1351-0088
EI 1479-6821
J9 ENDOCR-RELAT CANCER
JI Endocr.-Relat. Cancer
PD FEB
PY 2013
VL 20
IS 1
BP 1
EP 12
DI 10.1530/ERC-12-0227
PG 12
WC Oncology; Endocrinology & Metabolism
WE Science Citation Index Expanded (SCI-EXPANDED)
SC Oncology; Endocrinology & Metabolism
GA 121RZ
UT WOS:000317263200003
PM 23111755
OA Bronze
DA 2025-03-13
ER

PT J
AU Takai, K
   Le, A
   Weaver, VM
   Werb, Z
AF Takai, Ken
   Le, Annie
   Weaver, Valerie M.
   Werb, Zena
TI Targeting the cancer-associated fibroblasts as a treatment in
   triple-negative breast cancer
SO ONCOTARGET
LA English
DT Article
DE pirfenidone; triple-negative breast cancer; fibrosis; cancer-associated
   fibroblast; transforming growth factor-beta
ID IDIOPATHIC PULMONARY-FIBROSIS; TGF-BETA; ACTIVATION PROTEIN; TUMOR
   MICROENVIRONMENT; PIRFENIDONE PREVENTS; RENAL-FUNCTION; GROWTH; CELLS;
   METASTASIS; THERAPY
AB Increased collagen expression in tumors is associated with increased risk of metastasis, and triple-negative breast cancer (TNBC) has the highest propensity to develop distant metastases when there is evidence of central fibrosis. Transforming growth factor-beta (TGF-beta) ligands regulated by cancer-associated fibroblasts (CAFs) promote accumulation of fibrosis and cancer progression. In the present study, we have evaluated TNBC tumors with enhanced collagen to determine whether we can reduce metastasis by targeting the CAFs with Pirfenidone (PFD), an anti-fibrotic agent as well as a TGF-beta antagonist. In patient-derived xenograft models, TNBC tumors exhibited accumulated collagen and activated TGF-beta signaling, and developed lung metastasis. Next, primary CAFs were established from 4T1 TNBC homograft tumors, TNBC xenograft tumors and tumor specimens of breast cancer patients. CAFs promoted primary tumor growth with more fibrosis and TGF-beta activation and lung metastasis in 4T1 mouse model. We then examined the effects of PFD in vitro and in vivo. We found that PFD had inhibitory effects on cell viability and collagen production of CAFs in 2D culture. Furthermore, CAFs enhanced tumor growth and PFD inhibited the tumor growth induced by CAFs by causing apoptosis in the 3D co-culture assay of 4T1 tumor cells and CAFs. In vivo, PFD alone inhibited tumor fibrosis and TGF-beta signaling but did not inhibit tumor growth and lung metastasis. However, PFD inhibited tumor growth and lung metastasis synergistically in combination with doxorubicin. Thus, PFD has great potential for a novel clinically applicable TNBC therapy that targets tumor-stromal interaction.
C1 [Takai, Ken; Le, Annie; Werb, Zena] Univ Calif San Francisco, Dept Anat, San Francisco, CA 94143 USA.
   [Weaver, Valerie M.] Univ Calif San Francisco, Dept Surg, San Francisco, CA 94143 USA.
   [Weaver, Valerie M.] Univ Calif San Francisco, Ctr Bioengn & Tissue Regenerat, San Francisco, CA 94143 USA.
   [Takai, Ken] Saitama Canc Ctr, Div Breast Oncol, Saitama, Japan.
   [Le, Annie] St Georges Univ, Sch Med, True Blue, Grenada.
C3 University of California System; University of California San Francisco;
   University of California System; University of California San Francisco;
   University of California System; University of California San Francisco
RP Werb, Z (corresponding author), Univ Calif San Francisco, Dept Anat, San Francisco, CA 94143 USA.
EM zena.werb@ucsf.edu
OI Takai, Ken/0009-0009-3022-9950; Weaver, Valerie
   marie/0000-0003-4786-6752
FU UCSF Breast Oncology Program/Breast SPORE grant [P01 CA058207]; NCI [R01
   CA057621, R01 CA138818]
FX This work was supported by UCSF Breast Oncology Program/Breast SPORE
   grant (P01 CA058207) and NCI grants (R01 CA057621 to Z.W. and R01
   CA138818 to V.W.).
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NR 72
TC 151
Z9 167
U1 6
U2 57
PU IMPACT JOURNALS LLC
PI ORCHARD PARK
PA 6666 E QUAKER ST, STE 1, ORCHARD PARK, NY 14127 USA
EI 1949-2553
J9 ONCOTARGET
JI Oncotarget
PD DEC 13
PY 2016
VL 7
IS 50
BP 82889
EP 82901
DI 10.18632/oncotarget.12658
PG 13
WC Oncology; Cell Biology
WE Science Citation Index Expanded (SCI-EXPANDED)
SC Oncology; Cell Biology
GA EG9BQ
UT WOS:000391352800077
PM 27756881
OA Green Submitted, Green Published, gold
DA 2025-03-13
ER

PT J
AU Song, J
   Liao, HF
   Li, HY
   Chen, HY
   Si, HY
   Wang, JD
   Bai, X
AF Song, Jin
   Liao, Huifeng
   Li, Huayan
   Chen, Hongye
   Si, Huiyan
   Wang, Jiandong
   Bai, Xue
TI Identification of a novel cancer-associated fibroblasts gene signature
   based on bioinformatics analysis to predict prognosis and therapeutic
   responses in breast cancer
SO HELIYON
LA English
DT Article
DE Cancer -associated fibroblasts; WGCNA; Breast cancer; Tumor
   microenvironment; Prognosis
ID MIGRATION; INDUCTION; CELLS
AB Cancer-associated fibroblasts (CAFs) provide suitable conditions for growth of tumor cell and facilitate tumor progression. Hence, we aimed to identify a CAFs-related gene signature associated with the prognosis of patients with breast cancer (BRCA). We downloaded datasets from Gene Expression Omnibus (GEO) and confirmed the correlation between CAFs infiltration scores and prognosis. By performing weighted gene co-expression network analysis (WGCNA) and Lasso Cox regression analysis, we constructed a four-gene (COL5A3, FN1, POSTN, and RARRES2) prognostic CAFs signature model. Based on the median risk score of CAFs, patients with BRCA were divided into high- and low-risk groups. Compared with low-risk group, patients in high-risk group exhibited a poor prognosis and limited response to immunotherapy. Furthermore, patients with high CAFs risk scores were found to have a detrimental prognosis due to the induction of immunosuppressive cell infiltration, resulting in an immunosuppressive tumor microenvironment. Importantly, we found that CAFs overexpressing FN1 and POSTN significantly promoted the wound healing and invasion ability of tumor cells in vitro validation. Taking together, we identified a four-gene prognostic CAFs signature, which was proven to be a reliable indicator for prognosis and therapeutic efficacy in patients with BRCA. This study provided evidence for novel CAFs-based stromal therapy.
C1 [Song, Jin; Chen, Hongye; Si, Huiyan; Wang, Jiandong; Bai, Xue] Chinese Peoples Liberat Army Gen Hosp, Dept Gen Surg, Med Ctr 1, Beijing 100853, Peoples R China.
   [Liao, Huifeng] Chinese Peoples Liberat Army Gen Hosp, Dept Gen Surg, Med Ctr 7, Beijing 100700, Peoples R China.
   [Liao, Huifeng] Southern Med Univ, Sch Clin Med 2, Guangzhou 510515, Peoples R China.
   [Li, Huayan] Southern Med Univ, Zhujiang Hosp, Dept Gynecol, Guangzhou 510280, Peoples R China.
C3 Chinese People's Liberation Army General Hospital; Seventh Medical
   Center of Chinese PLA General Hospital; Chinese People's Liberation Army
   General Hospital; Southern Medical University - China; Southern Medical
   University - China
RP Wang, JD; Bai, X (corresponding author), Chinese Peoples Liberat Army Gen Hosp, Dept Gen Surg, Med Ctr 1, Beijing 100853, Peoples R China.
EM Vicky1968@163.com; drbaixue@126.com
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NR 55
TC 1
Z9 1
U1 1
U2 10
PU CELL PRESS
PI CAMBRIDGE
PA 50 HAMPSHIRE ST, FLOOR 5, CAMBRIDGE, MA 02139 USA
EI 2405-8440
J9 HELIYON
JI Heliyon
PD APR 15
PY 2024
VL 10
IS 7
AR e29216
DI 10.1016/j.heliyon.2024.e29216
EA APR 2024
PG 14
WC Multidisciplinary Sciences
WE Science Citation Index Expanded (SCI-EXPANDED)
SC Science & Technology - Other Topics
GA RD0Q4
UT WOS:001225619400001
PM 38601538
OA gold
DA 2025-03-13
ER

PT J
AU Li, QL
   Li, MH
   Zheng, KX
   Tang, S
   Ma, SL
AF Li, Qilong
   Li, Mohan
   Zheng, Kexin
   Tang, Shuang
   Ma, Shiliang
TI Expression pattern analysis and drug differential sensitivity of
   cancer-associated fibroblasts in triple-negative breast cancer
SO TRANSLATIONAL ONCOLOGY
LA English
DT Article
DE Stromal microenvironment; Intratumoral fibrosis; Drug resistance;
   Triple-negative breast cancer; alpha-Smooth muscle actin
ID TUMOR-GROWTH; METASTASIS; MICROENVIRONMENT; PROGRESSION; FIBROSIS;
   TARGET
AB Triple-negative breast cancer (TNBC) has the characteristics of a complex molecular landscape, aggressive or high proliferation leading to poor prognosis, and behavioral heterogeneity. The purpose of the present study was to determine the spatiotemporal expression of alpha-smooth muscle actin (alpha-SMA)-positive cancer-associated fibroblasts (CAFs) at histological level in 4T1 tumors and to predict the sensitivity to 138 drugs in patients with TNBC according to alpha-SMA expression. The quantitative results of fibrosis showed that the volume of 4T1 tumors correlated positively with the area of tumor fibrosis. Furthermore, we divided 4T1 tumors according to the degree of fibrosis and characterized the molecular characteristics of the four regions. Finally, the difference in the signaling pathways and sensitivity to 138 drugs was analyzed in patients with TNBC according to alpha-SMA expression combined with The Cancer Genome Atlas (TOGA) database. The myogenesis, TGF-beta, and Notch signaling pathways were upregulated and the patients with TNBC were significantly differentially sensitive to 25 drugs. The results of in vivo experiments showed that the inhibitory effect of embelin on 4T1 tumors with high alpha-SMA expression was greater than that on 4TO7 tumors with low alpha-SMA expression. At the same time, embelin significantly decreased alpha-SMA and PDGFRA expression in 4T1 tumors compared with the control group. Our findings add to understanding of CAP distribution in the 4T1 tumor microenvironment and its possible role in treating cancer.
C1 [Li, Qilong; Tang, Shuang; Ma, Shiliang] Shenyang Agr Univ, Coll Biosci & Biotechnol, Shenyang 110866, Liaoning, Peoples R China.
   [Li, Mohan; Zheng, Kexin; Ma, Shiliang] Shenyang Agr Univ, Coll Food Sci, Shenyang 110866, Liaoning, Peoples R China.
C3 Shenyang Agricultural University; Shenyang Agricultural University
RP Ma, SL (corresponding author), Shenyang Agr Univ, Coll Biosci & Biotechnol, Shenyang 110866, Liaoning, Peoples R China.
EM msl@syau.edu.cn
RI 唐, 爽/GXN-4370-2022; Li, Mohan/AAP-6057-2020
OI Tang, Shuang/0000-0002-7078-7289; Li, Mohan/0000-0002-0901-4615
FU "Financial Support for Selected Researchers Back from Abroad (2012)"
   from Liaoning Province [88030312004]; China Scholarship Council
   [202008210391]; Doctoral Start-up Foundation of Shenyang Agricultural
   University [880418073]
FX This work was supported by the "Financial Support for Selected
   Researchers Back from Abroad (2012)" from Liaoning Province (Grant No.
   88030312004), China Scholarship Council (stipend to MH. Li, Grant No.
   202008210391), and Doctoral Start-up Foundation of Shenyang Agricultural
   University (grant number 880418073).
CR [Anonymous], DRUGS CONTEXT
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NR 44
TC 15
Z9 15
U1 0
U2 10
PU ELSEVIER SCIENCE INC
PI NEW YORK
PA STE 800, 230 PARK AVE, NEW YORK, NY 10169 USA
SN 1936-5233
J9 TRANSL ONCOL
JI Transl. Oncol.
PD JAN
PY 2021
VL 14
IS 1
AR 100891
DI 10.1016/j.tranon.2020.100891
PG 10
WC Oncology
WE Science Citation Index Expanded (SCI-EXPANDED)
SC Oncology
GA PT2AR
UT WOS:000608422100009
PM 33069102
OA gold, Green Published
DA 2025-03-13
ER

PT J
AU Li, Q
   Lv, XJ
   Han, CY
   Kong, Y
   Dai, ZY
   Huo, DW
   Li, T
   Li, DP
   Li, W
   Wang, X
   Zhao, Q
   Ming, J
   Yang, W
   Chen, Y
   Wu, XD
AF Li, Qian
   Lv, Xuejiao
   Han, Chunyong
   Kong, Yu
   Dai, Zhongye
   Huo, Dawei
   Li, Ting
   Li, Dapeng
   Li, Wei
   Wang, Xing
   Zhao, Qian
   Ming, Jie
   Yang, Wen
   Chen, Yang
   Wu, Xudong
TI Enhancer reprogramming promotes the activation of cancer-associated
   fibroblasts and breast cancer metastasis
SO THERANOSTICS
LA English
DT Article
DE cancer-associated fibroblasts; metastasis; enhancers; transcription
   factors; JUN
ID COLORECTAL-CANCER; TUMOR-GROWTH; STEM-CELLS; TRANSCRIPTION;
   PHOSPHORYLATION; IDENTIFICATION; ALIGNMENT; PACKAGE; POTENT; AP-1
AB Rationale: Cancer associated fibroblasts (CAFs) are a subpopulation of cells within the tumor microenvironment that usually promote cancer progression and metastasis. Hence it is critical to find out the driving factors and mechanisms for the development of CAFs from normal fibroblasts (NFs) in response to sustained stimulation of cancer cells. Here we perform transcriptomic and epigenomic analyses in paired NFs and CAFs associated with breast cancer metastasis to investigate the molecular mechanisms for stromal fibroblasts reprogramming. Methods: We conducted transcriptomic analyses in paired NFs and CAFs isolated from clinical specimens of breast cancer patients with metastasis. Meanwhile, genome-wide mapping of histone marks H3K4me1 and H3K27ac was also performed to characterize CAF-specific enhancer landscape. The function and mechanisms of activated JUN in stromal fibroblasts were studied using in vitro and in vivo models. Results: We have identified CAF-specific signature genes and activated enhancers, which are significantly associated with pro-metastatic programs. Among the CAF activated enhancers, FOS and JUN family of transcription factors are enriched. In line with this, we find that JUN protein is highly activated in the stroma of metastatic breast cancers. And through gain and loss-of-function studies, we demonstrate that activated JUN is necessary and sufficient to remodel enhancers and maintain the activation of CAF-specific enhancers, and thereby promotes breast cancer invasiveness in a non-cell-autonomous manner. Conclusions: Our study gets an insight into the transcriptomic features of invasive breast stroma and transcription regulatory mechanisms for stroma cell transformation, providing a proof-of-concept of stroma-targeting strategy in cancer treatment.
C1 [Li, Qian; Lv, Xuejiao; Kong, Yu; Dai, Zhongye; Huo, Dawei; Li, Ting; Wang, Xing; Zhao, Qian; Wu, Xudong] Tianjin Med Univ, Prov & Minist Cosponsored Collaborat Innovat Ctr M, Sch Basic Med Sci, Dept Cell Biol,State Key Lab Expt Hematol,Key Lab, Tianjin 300070, Peoples R China.
   [Han, Chunyong] Tianjin Med Univ, Canc Inst & Hosp, Key Lab Breast Canc Prevent & Therapy, Dept Breast Reconstruct,Minist Educ, Tianjin 300060, Peoples R China.
   [Han, Chunyong; Li, Dapeng] Natl Clin Res Ctr Canc, Tianjin Clin Res Ctr Canc, Key Lab Canc Prevent & Treatment Tianjin, Tianjin, Peoples R China.
   [Li, Dapeng] Tianjin Med Univ, Canc Inst & Hosp, Dept Thyroid & Neck Tumor, Tianjin 300060, Peoples R China.
   [Li, Wei] Tianjin First Ctr Hosp, Dept Pathol, Tianjin 300192, Peoples R China.
   [Ming, Jie; Yang, Wen] Huazhong Univ Sci & Technol, Union Hosp, Dept Breast & Thyroid Surg, Wuhan 430022, Hubei, Peoples R China.
   [Chen, Yang] Chinese Acad Med Sci, Inst Basic Med Sci, State Key Lab Med Mol Biol, 5 Dong Dan San Tiao, Beijing 100005, Peoples R China.
   [Chen, Yang] Peking Union Med Coll, Sch Basic Med, 5 Dong Dan San Tiao, Beijing 100005, Peoples R China.
   [Wu, Xudong] Tianjin Med Univ Gen Hosp, Dept Neurosurg, Tianjin 300052, Peoples R China.
   [Wu, Xudong] Tianjin Med Univ, Sch Basic Med Sci, Dept Cell Biol, Tianjin 300070, Peoples R China.
C3 Tianjin Medical University; Tianjin Medical University; Tianjin Medical
   University; Huazhong University of Science & Technology; Institute of
   Basic Medical Sciences - CAMS; Chinese Academy of Medical Sciences -
   Peking Union Medical College; Chinese Academy of Medical Sciences -
   Peking Union Medical College; Peking Union Medical College; Tianjin
   Medical University; Tianjin Medical University
RP Wu, XD (corresponding author), Tianjin Med Univ, Prov & Minist Cosponsored Collaborat Innovat Ctr M, Sch Basic Med Sci, Dept Cell Biol,State Key Lab Expt Hematol,Key Lab, Tianjin 300070, Peoples R China.; Wu, XD (corresponding author), Tianjin Med Univ, Sch Basic Med Sci, Dept Cell Biol, Tianjin 300070, Peoples R China.
EM wuxudong@tmu.edu.cn
RI MING, JIE/HGU-2555-2022; huo, dawei/GXZ-9955-2022; wu,
   xudong/KGL-1857-2024
OI Wu, Xudong/0000-0001-9594-479X
FU National key research and development program [2017YFA0504102]; National
   Natural Science Foundation of China [81772676, 31970579, 82073138,
   82072942, 31900464]; Natural Science Foundation of Tianjin Municipal
   Science and Technology Commission [18JCJQJC48200]; Key Research Project
   of Tianjin Education Commission [2020ZD13]; national youth talent
   support program
FX We thank Prof. Yuhui Huang for EO771 cell line, thank Prof. Lijian Hui
   and Prof. Feifan Guo for kindly providing Jun<SUP>fl/fl</SUP> mice. This
   study was supported by National key research and development program
   (2017YFA0504102 to X.W.), the National Natural Science Foundation of
   China (81772676, 31970579 to X.W., 82073138 to Q.L., 82072942 to C.H.,
   31900464 to T.L.), the Natural Science Foundation of Tianjin Municipal
   Science and Technology Commission (18JCJQJC48200 to X.W.), Key Research
   Project of Tianjin Education Commission (2020ZD13 to X.W.), and the
   national youth talent support program to X.W.
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NR 73
TC 13
Z9 13
U1 1
U2 15
PU IVYSPRING INT PUBL
PI LAKE HAVEN
PA PO BOX 4546, LAKE HAVEN, NSW 2263, AUSTRALIA
SN 1838-7640
J9 THERANOSTICS
JI Theranostics
PY 2022
VL 12
IS 17
BP 7491
EP 7508
DI 10.7150/thno.75853
PG 18
WC Medicine, Research & Experimental
WE Science Citation Index Expanded (SCI-EXPANDED)
SC Research & Experimental Medicine
GA 5W3QV
UT WOS:000877833900007
PM 36438487
OA Green Published, gold
DA 2025-03-13
ER

PT J
AU Guido, C
   Whitaker-Menezes, D
   Capparelli, C
   Balliet, R
   Lin, Z
   Pestell, RG
   Howell, A
   Aquila, S
   Andò, S
   Martinez-Outschoorn, U
   Sotgia, F
   Lisanti, MP
AF Guido, Carmela
   Whitaker-Menezes, Diana
   Capparelli, Claudia
   Balliet, Renee
   Lin, Zhao
   Pestell, Richard G.
   Howell, Anthony
   Aquila, Saveria
   Ando, Sebastiano
   Martinez-Outschoorn, Ubaldo
   Sotgia, Federica
   Lisanti, Michael P.
TI Metabolic reprogramming of cancer-associated fibroblasts by TGF-β drives
   tumor growth Connecting TGF-β signaling with "Warburg-like" cancer
   metabolism and L-lactate production
SO CELL CYCLE
LA English
DT Article
DE TGF- beta; myofibroblast; oxidative stress; tumor stroma; cancer
   associated fibroblast; aerobic glycolysis; autophagy; mitophagy; cancer
   metabolism; autocrine signaling; paracrine signaling; the field effect;
   "Pied-Piper of Hamelin"
ID SMOOTH MUSCLE ACTIN; BREAST-CANCER; TRANSFORMING GROWTH-FACTOR-BETA-1;
   OXIDATIVE STRESS; CAVEOLIN-1 EXPRESSION; AEROBIC GLYCOLYSIS;
   EPITHELIAL-CELLS; AUTOPHAGY; MICROENVIRONMENT; METASTASIS
AB We have previously shown that a loss of stromal Cav-1 is a biomarker of poor prognosis in breast cancers. Mechanistically, a loss of Cav-1 induces the metabolic reprogramming of stromal cells, with increased autophagy/mitophagy, mitochondrial dysfunction and aerobic glycolysis. As a consequence, Cav-1-low CAFs generate nutrients (such as L-lactate) and chemical building blocks that fuel mitochondrial metabolism and the anabolic growth of adjacent breast cancer cells. It is also known that a loss of Cav-1 is associated with hyperactive TGF-beta signaling. However, it remains unknown whether hyperactivation of the TGF-beta signaling pathway contributes to the metabolic reprogramming of Cav-1-low CAFs. To address these issues, we overexpressed TGF-beta ligands and the TGF-beta receptor I (TGF-beta-RI) in stromal fibroblasts and breast cancer cells. Here, we show that the role of TGF-beta in tumorigenesis is compartment-specific, and that TGF-beta promotes tumorigenesis by shifting cancer-associated fibroblasts toward catabolic metabolism. Importantly, the tumor-promoting effects of TGF-beta are independent of the cell type generating TGF-beta. Thus, stromal-derived TGF-beta activates signaling in stromal cells in an autocrine fashion, leading to fibroblast activation, as judged by increased expression of myofibroblast markers, and metabolic reprogramming, with a shift toward catabolic metabolism and oxidative stress. We also show that TGF-beta-activated fibroblasts promote the mitochondrial activity of adjacent cancer cells, and in a xenograft model, enhancing the growth of breast cancer cells, independently of angiogenesis. Conversely, activation of the TGF-beta pathway in cancer cells does not influence tumor growth, but cancer cell-derived-TGF-beta ligands affect stromal cells in a paracrine fashion, leading to fibroblast activation and enhanced tumor growth. In conclusion, ligand-dependent or cell-autonomous activation of the TGF-beta pathway in stromal cells induces their metabolic reprogramming, with increased oxidative stress, autophagy/mitophagy and glycolysis, and downregulation of Cav-1. These metabolic alterations can spread among neighboring fibroblasts and greatly sustain the growth of breast cancer cells. Our data provide novel insights into the role of the TGF-beta pathway in breast tumorigenesis, and establish a clear causative link between the tumor-promoting effects of TGF-beta signaling and the metabolic reprogramming of the tumor microenvironment.
C1 [Guido, Carmela; Whitaker-Menezes, Diana; Capparelli, Claudia; Balliet, Renee; Lin, Zhao; Pestell, Richard G.; Martinez-Outschoorn, Ubaldo; Sotgia, Federica; Lisanti, Michael P.] Thomas Jefferson Univ, Jefferson Stem Cell Biol & Regenerat Med Ctr, Kimmel Canc Ctr, Philadelphia, PA 19107 USA.
   [Guido, Carmela; Whitaker-Menezes, Diana; Capparelli, Claudia; Balliet, Renee; Lin, Zhao; Pestell, Richard G.; Martinez-Outschoorn, Ubaldo; Sotgia, Federica; Lisanti, Michael P.] Thomas Jefferson Univ, Kimmel Canc Ctr, Dept Stem Cell Biol & Regenerat Med, Philadelphia, PA 19107 USA.
   [Guido, Carmela; Whitaker-Menezes, Diana; Capparelli, Claudia; Balliet, Renee; Lin, Zhao; Pestell, Richard G.; Martinez-Outschoorn, Ubaldo; Sotgia, Federica; Lisanti, Michael P.] Thomas Jefferson Univ, Kimmel Canc Ctr, Dept Canc Biol, Philadelphia, PA 19107 USA.
   [Guido, Carmela; Capparelli, Claudia; Aquila, Saveria; Ando, Sebastiano] Univ Calabria, Dept Pharmacobiol, I-87036 Cosenza, Italy.
   [Guido, Carmela; Capparelli, Claudia; Aquila, Saveria; Ando, Sebastiano] Univ Calabria, Fac Pharm, I-87036 Cosenza, Italy.
   [Pestell, Richard G.; Martinez-Outschoorn, Ubaldo; Lisanti, Michael P.] Thomas Jefferson Univ, Dept Med Oncol, Kimmel Canc Ctr, Philadelphia, PA 19107 USA.
   [Howell, Anthony; Sotgia, Federica; Lisanti, Michael P.] Univ Manchester, Manchester Breast Ctr, Manchester, Lancs, England.
   [Howell, Anthony; Sotgia, Federica; Lisanti, Michael P.] Univ Manchester, Breakthrough Breast Canc Res Unit, Manchester Acad Hlth Sci Ctr, Paterson Inst Canc Res,Sch Canc Enabling Sci & Te, Manchester, Lancs, England.
C3 Thomas Jefferson University; Thomas Jefferson University; Thomas
   Jefferson University; University of Calabria; University of Calabria;
   Thomas Jefferson University; University of Manchester; University of
   Manchester; Paterson Institute for Cancer Research
RP Sotgia, F (corresponding author), Thomas Jefferson Univ, Jefferson Stem Cell Biol & Regenerat Med Ctr, Kimmel Canc Ctr, Philadelphia, PA 19107 USA.
EM fsotgia@gmail.com; michaelp.lisanti@gmail.com
RI Pestell, Richard/JQW-3484-2023; Martinet, Wim/I-7375-2015; Lisanti,
   Michael/C-6866-2013
OI Lisanti, Michael/0000-0003-2034-1382; Howell,
   Anthony/0000-0002-6233-719X; Sotgia, Federica/0000-0003-2826-4529;
   AQUILA, Saveria/0000-0003-4738-6927; Guido, Carmela/0000-0002-4225-8208;
   Martinez-Outschoorn, Ubaldo/0000-0003-1483-4551
FU Breast Cancer Alliance (BCA); American Cancer Society (ACS); Margaret Q.
   Landenberger Research Foundation; NIH/NCI [R01-CA-080250, R01-CA-098779,
   R01-CA-120876, R01-AR-055660, R01-CA-70896, R01-CA-75503, R01-CA-86072,
   R01-CA-107382]; Susan G. Komen Breast Cancer Foundation; Dr. Ralph and
   Marian C. Falk Medical Research Trust; NIH/NCI Cancer Center Core grant
   [P30-CA-56036]; Pennsylvania Department of Health; Centre grant in
   Manchester from Breakthrough Breast Cancer in the UK; Advanced ERC Grant
   from the European Research Council
FX F.S. and her laboratory were supported by grants from the Breast Cancer
   Alliance (BCA) and the American Cancer Society (ACS). U. E. M. was
   supported by a Young Investigator Award from the Margaret Q.
   Landenberger Research Foundation. M. P. L. was supported by grants from
   the NIH/NCI (R01-CA-080250; R01-CA-098779; R01-CA-120876;
   R01-AR-055660), and the Susan G. Komen Breast Cancer Foundation. R. G.
   P. was supported by grants from the NIH/NCI (R01-CA-70896, R01-CA-75503,
   R01-CA-86072 and R01-CA-107382) and the Dr. Ralph and Marian C. Falk
   Medical Research Trust. The Kimmel Cancer Center was supported by the
   NIH/NCI Cancer Center Core grant P30-CA-56036 (to R. G. P.). Funds were
   also contributed by the Margaret Q. Landenberger Research Foundation (to
   M. P. L.). This project is funded, in part, under a grant with the
   Pennsylvania Department of Health (to M. P. L. and F. S.). The
   Department specifically disclaims responsibility for any analyses,
   interpretations or conclusions. This work was also supported, in part by
   a Centre grant in Manchester from Breakthrough Breast Cancer in the UK
   (to A. H.) and an Advanced ERC Grant from the European Research Council.
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NR 49
TC 258
Z9 288
U1 2
U2 37
PU LANDES BIOSCIENCE
PI AUSTIN
PA 1806 RIO GRANDE ST, AUSTIN, TX 78702 USA
SN 1538-4101
J9 CELL CYCLE
JI Cell Cycle
PD AUG 15
PY 2012
VL 11
IS 16
BP 3019
EP 3035
DI 10.4161/cc.21384
PG 17
WC Cell Biology
WE Science Citation Index Expanded (SCI-EXPANDED)
SC Cell Biology
GA 995JJ
UT WOS:000308004000020
PM 22874531
OA Green Published, Bronze
DA 2025-03-13
ER

PT J
AU Olazaba, OL
   Farrow, J
   Monkkonen, T
AF Olazaba, Omar Lujano
   Farrow, Jeffrey
   Monkkonen, Teresa
TI Fibroblast heterogeneity and functions: insights from single-cell
   sequencing in wound healing, breast cancer, ovarian cancer and melanoma
SO FRONTIERS IN GENETICS
LA English
DT Review
DE wound healing; cancer associated fibroblast; single-cell multiomics;
   breast cancer; ovarian cancer; melanoma
ID ACTIVATION PROTEIN-ALPHA; STROMAL CELLS; IN-VITRO; EXPRESSION; TISSUE;
   MICROENVIRONMENT; REVEALS; PHENOTYPES; RESISTANCE; CARCINOMA
AB Cancer has been described as the wound that does not heal, in large part due to fibroblast involvement. Activation of cancer-associated fibroblasts (CAFs) contributes to critical features of the tumor microenvironment, including upregulation of key marker proteins, recruitment of immune cells, and deposition of extracellular matrix (ECM)-similar to fibroblast activation in injury-induced wound healing. Prior to the widespread availability of single-cell RNA sequencing (scRNA seq), studies of CAFs or fibroblasts in wound healing largely relied on models guided by individual fibroblast markers, or methods with less resolution to unravel the heterogeneous nature of CAFs and wound healing fibroblasts (especially regarding scarring outcome). Here, insights from the enhanced resolution provided by scRNA sequencing of fibroblasts in normal wound healing, breast cancer, ovarian cancer, and melanoma are discussed. These data have revealed differences in expression of established canonical activation marker genes, epigenetic modifications, fibroblast lineages, new gene and proteins of clinical interest for further experimentation, and novel signaling interactions with other cell types that include spatial information.
C1 [Olazaba, Omar Lujano; Farrow, Jeffrey; Monkkonen, Teresa] San Diego State Univ, Dept Biol, San Diego, CA 92182 USA.
C3 California State University System; San Diego State University
RP Monkkonen, T (corresponding author), San Diego State Univ, Dept Biol, San Diego, CA 92182 USA.
EM tmonkkonen@sdsu.edu
RI Monkkonen, Teresa/ABG-5706-2020
OI Monkkonen, Teresa/0000-0001-6245-7610
FU SDSU University Graduate Fellowship [R01CA260281, U54CA267789];
   UCSD/Moore's Cancer Center Recruitment and SDSU
FX This work was supported by SDSU FUERTE/NIH FIRST program recruitment
   funds to TM, UCSD/MCC recruitment funds to TM, and the SDSU University
   Graduate Fellowship to OO. There are no disclosures on behalf of OO, JF,
   or TM related to this work.r The author(s) declare that financial
   support was received for the research, authorship, and/or publication of
   this article. This work was supported by the SDSU University Graduate
   Fellowship to OLO; R01CA260281 to Dr. Carrie House supporting OLO; SDSU
   FUERTE/ NIH FIRST program recruitment funds supporting TM (U54CA267789),
   and UCSD/Moore's Cancer Center Recruitment and SDSU seed funding to TM.
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NR 95
TC 5
Z9 5
U1 8
U2 9
PU FRONTIERS MEDIA SA
PI LAUSANNE
PA AVENUE DU TRIBUNAL FEDERAL 34, LAUSANNE, CH-1015, SWITZERLAND
EI 1664-8021
J9 FRONT GENET
JI Front. Genet.
PD MAR 8
PY 2024
VL 15
AR 1304853
DI 10.3389/fgene.2024.1304853
PG 19
WC Genetics & Heredity
WE Science Citation Index Expanded (SCI-EXPANDED)
SC Genetics & Heredity
GA LR6P2
UT WOS:001188571000001
PM 38525245
OA Green Published, gold
DA 2025-03-13
ER

PT J
AU Andreucci, E
   Fioretto, BS
   Rosa, I
   Matucci-Cerinic, M
   Biagioni, A
   Romano, E
   Calorini, L
   Manetti, M
AF Andreucci, Elena
   Fioretto, Bianca Saveria
   Rosa, Irene
   Matucci-Cerinic, Marco
   Biagioni, Alessio
   Romano, Eloisa
   Calorini, Lido
   Manetti, Mirko
TI Extracellular Lactic Acidosis of the Tumor Microenvironment Drives
   Adipocyte-to-Myofibroblast Transition Fueling the Generation of
   Cancer-Associated Fibroblasts
SO CELLS
LA English
DT Article
DE adipocytes; adipose-derived stem cells; cell differentiation;
   extracellular acidosis; lactate; myofibroblasts; cancer-associated
   fibroblasts; breast cancer cells
ID MESENCHYMAL STEM-CELLS; BREAST-CANCER
AB Lactic acidosis characterizes the tumor microenvironment (TME) and is involved in the mechanisms leading to cancer progression and dissemination through the reprogramming of tumor and local host cells (e.g., endothelial cells, fibroblasts, and immune cells). Adipose tissue also represents a crucial component of the TME which is receiving increasing attention due to its pro-tumoral activity, however, to date, it is not known whether it could be affected by the acidic TME. Now, emerging evidence from chronic inflammatory and fibrotic diseases underlines that adipocytes may give rise to pathogenic myofibroblast-like cells through the adipocyte-to-myofibroblast transition (AMT). Thus, our study aimed to investigate whether extracellular acidosis could affect the AMT process, sustaining the acquisition by adipocytes of a cancer-associated fibroblast (CAF)-like phenotype with a pro-tumoral activity. To this purpose, human subcutaneous adipose-derived stem cells committed to adipocytes (acADSCs) were cultured under basal (pH 7.4) or lactic acidic (pH 6.7, 10 mM lactate) conditions, and AMT was evaluated with quantitative PCR, immunoblotting, and immunofluorescence analyses. We observed that lactic acidosis significantly impaired the expression of adipocytic markers while inducing myofibroblastic, pro-fibrotic, and pro-inflammatory phenotypes in acADSCs, which are characteristic of AMT reprogramming. Interestingly, the conditioned medium of lactic acidosis-exposed acADSC cultures was able to induce myofibroblastic activation in normal fibroblasts and sustain the proliferation, migration, invasion, and therapy resistance of breast cancer cells in vitro. This study reveals a previously unrecognized relationship between lactic acidosis and the generation of a new CAF-like cell subpopulation from adipocytic precursor cells sustaining tumor malignancy.
C1 [Andreucci, Elena; Biagioni, Alessio; Calorini, Lido] Univ Florence, Dept Expt & Clin Biomed Sci Mario Serio, Sect Expt Pathol & Oncol, I-50134 Florence, Italy.
   [Fioretto, Bianca Saveria; Rosa, Irene; Manetti, Mirko] Univ Florence, Dept Expt & Clin Med, Sect Anat & Histol, I-50134 Florence, Italy.
   [Matucci-Cerinic, Marco; Romano, Eloisa] Univ Florence, Dept Expt & Clin Med, Sect Internal Med, I-50134 Florence, Italy.
   [Manetti, Mirko] Univ Florence, Dept Expt & Clin Med Imaging Platform, I-50134 Florence, Italy.
C3 University of Florence; University of Florence; University of Florence;
   University of Florence
RP Manetti, M (corresponding author), Univ Florence, Dept Expt & Clin Med, Sect Anat & Histol, I-50134 Florence, Italy.; Manetti, M (corresponding author), Univ Florence, Dept Expt & Clin Med Imaging Platform, I-50134 Florence, Italy.
EM mirko.manetti@unifi.it
RI Manetti, Mirko/AEH-9944-2022; Romano, Eloisa/AEZ-7072-2022; Andreucci,
   Elena/AAB-2301-2019; Rosa, Irene/ABD-1854-2020; Fioretto, Bianca
   Saveria/AIE-4205-2022; Biagioni, Alessio/J-8310-2018
OI Calorini, Lido/0000-0002-5508-4200; ANDREUCCI,
   Elena/0000-0003-3980-3073; Fioretto, Bianca Saveria/0000-0001-9275-7593;
   Biagioni, Alessio/0000-0002-6193-7417; Rosa, Irene/0000-0001-6352-0175;
   Manetti, Mirko/0000-0003-3956-8480; Romano, Eloisa/0000-0003-2744-8625
FU Italian Ministry of University and Research; Associazione Italiana per
   la Ricerca sul Cancro (AIRC)
FX This research was supported by the Italian Ministry of University and
   Research (RICATEN2022 to L.C. and M.M.). E.A. was supported by a
   research fellowship granted by Associazione Italiana per la Ricerca sul
   Cancro (AIRC).
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NR 47
TC 14
Z9 14
U1 2
U2 10
PU MDPI
PI BASEL
PA ST ALBAN-ANLAGE 66, CH-4052 BASEL, SWITZERLAND
EI 2073-4409
J9 CELLS-BASEL
JI Cells
PD MAR
PY 2023
VL 12
IS 6
AR 939
DI 10.3390/cells12060939
PG 20
WC Cell Biology
WE Science Citation Index Expanded (SCI-EXPANDED)
SC Cell Biology
GA A8FT8
UT WOS:000957429000001
PM 36980280
OA Green Published, gold
DA 2025-03-13
ER

PT J
AU Bartoschek, M
   Oskolkov, N
   Bocci, M
   Lövrot, J
   Larsson, C
   Sommarin, M
   Madsen, CD
   Lindgren, D
   Pekar, G
   Karlsson, G
   Ringnér, M
   Bergh, J
   Björklund, Å
   Pietras, K
AF Bartoschek, Michael
   Oskolkov, Nikolay
   Bocci, Matteo
   Lovrot, John
   Larsson, Christer
   Sommarin, Mikael
   Madsen, Chris D.
   Lindgren, David
   Pekar, Gyula
   Karlsson, Goran
   Ringner, Markus
   Bergh, Jonas
   Bjorklund, Asa
   Pietras, Kristian
TI Spatially and functionally distinct subclasses of breast
   cancer-associated fibroblasts revealed by single cell RNA sequencing
SO NATURE COMMUNICATIONS
LA English
DT Article
ID EXPRESSION; MYOFIBROBLASTS; HETEROGENEITY; ORIGIN
AB Cancer-associated fibroblasts (CAFs) are a major constituent of the tumor microenvironment, although their origin and roles in shaping disease initiation, progression and treatment response remain unclear due to significant heterogeneity. Here, following a negative selection strategy combined with single-cell RNA sequencing of 768 transcriptomes of mesenchymal cells from a genetically engineered mouse model of breast cancer, we define three distinct subpopulations of CAFs. Validation at the transcriptional and protein level in several experimental models of cancer and human tumors reveal spatial separation of the CAF subclasses attributable to different origins, including the peri-vascular niche, the mammary fat pad and the transformed epithelium. Gene profiles for each CAF subtype correlate to distinctive functional programs and hold independent prognostic capability in clinical cohorts by association to metastatic disease. In conclusion, the improved resolution of the widely defined CAF population opens the possibility for biomarker-driven development of drugs for precision targeting of CAFs.
C1 [Bartoschek, Michael; Bocci, Matteo; Larsson, Christer; Madsen, Chris D.; Lindgren, David; Pietras, Kristian] Lund Univ, Dept Lab Med, Div Translat Canc Res, BioCARE, S-22381 Lund, Sweden.
   [Oskolkov, Nikolay; Ringner, Markus] Lund Univ, Sci Life Lab, Natl Bioinformat Infrastruct Sweden, Dept Biol, Solvegatan 35, S-22362 Lund, Sweden.
   [Lovrot, John; Bergh, Jonas] Karolinska Inst, Dept Oncol & Pathol, Karolinska Univ Sjukhuset Z1 01, S-17176 Stockholm, Sweden.
   [Sommarin, Mikael; Karlsson, Goran] Lund Univ, Lund Stem Cell Ctr, Div Mol Hematol, BMC B12, S-22184 Lund, Sweden.
   [Pekar, Gyula] Lund Univ, Dept Clin Sci, Div Oncol & Pathol, Skane Univ Hosp, S-22185 Lund, Sweden.
   [Bjorklund, Asa] Uppsala Univ, Natl Bioinformat Infrastruct Sweden, Sci Life Lab, Dept Cell & Mol Biol, Husargatan 3, S-75237 Uppsala, Sweden.
C3 Lund University; Lund University; Karolinska Institutet; Lund
   University; Lund University; Skane University Hospital; Uppsala
   University
RP Pietras, K (corresponding author), Lund Univ, Dept Lab Med, Div Translat Canc Res, BioCARE, S-22381 Lund, Sweden.
EM Kristian.Pietras@med.lu.se
RI Oskolkov, Nikolay/AAH-2349-2019; Pietras, Kristian/ABE-8727-2020;
   Ringnér, Markus/G-3641-2011; Bocci, Matteo/AAB-5016-2021; Lövrot,
   John/K-8559-2012; Bjorklund, Asa K/J-4587-2013
OI Sommarin, Mikael/0000-0002-2581-5543; Bartoschek,
   Michael/0000-0002-1567-795X; Ringner, Markus/0000-0001-5469-8940; Bocci,
   Matteo/0000-0002-8774-0006; Bjorklund, Asa K/0000-0003-2224-7090;
   Lovrot, John/0000-0002-9339-8059; Bergh, Jonas/0000-0001-5526-1847;
   Madsen, Chris D/0000-0001-6838-2103; Pietras,
   Kristian/0000-0001-6738-4705; Pekar, Gyula/0000-0002-0667-0270
FU European Research Council (the TUMORGAN project) [309322]; Swedish
   Research Council; Swedish Cancer Society; STARGET consortium (Swedish
   Research Council Linnaeus network); Biltema foundation; BioCARE;
   SciLifeLab WABI; Sydsvenska Brostcancergruppen; Fru Berta Kamprads
   stiftelse; Region Skane ALF; Lund University; European Research Council
   (ERC) [309322] Funding Source: European Research Council (ERC)
FX K.P. is the Goran & Birgitta Grosskopf Professor at Lund University. The
   research presented herein was supported by grants from the following
   agencies to K.P.: a Consolidator Grant from the European Research
   Council (the TUMORGAN project, grant 309322), the Swedish Research
   Council, the Swedish Cancer Society, the STARGET consortium (a Swedish
   Research Council Linnaeus network), the Biltema foundation, BioCARE,
   Region Skane ALF-funding, and Lund University. The bioinformatic
   analysis was supported by SciLifeLab WABI. Human breast cancer tissue
   was kindly provided by the Sweden Cancerome Network-Breast Cancer
   Initiative Community supported by grants from Sydsvenska
   Brostcancergruppen and Fru Berta Kamprads stiftelse.
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NR 49
TC 524
Z9 565
U1 7
U2 98
PU NATURE PORTFOLIO
PI BERLIN
PA HEIDELBERGER PLATZ 3, BERLIN, 14197, GERMANY
EI 2041-1723
J9 NAT COMMUN
JI Nat. Commun.
PD DEC 4
PY 2018
VL 9
AR 5150
DI 10.1038/s41467-018-07582-3
PG 13
WC Multidisciplinary Sciences
WE Science Citation Index Expanded (SCI-EXPANDED)
SC Science & Technology - Other Topics
GA HC8HG
UT WOS:000452042500001
PM 30514914
OA gold, Green Published
HC Y
HP N
DA 2025-03-13
ER

PT J
AU Shah, SH
   Miller, P
   Garcia-Contreras, M
   Ao, Z
   Machlin, L
   Issa, E
   El-Ashry, D
AF Shah, Sanket H.
   Miller, Philip
   Garcia-Contreras, Marta
   Ao, Zheng
   Machlin, Leah
   Issa, Emilio
   El-Ashry, Dorraya
TI Hierarchical paracrine interaction of breast cancer associated
   fibroblasts with cancer cells via hMAPK-microRNAs to drive ER-negative
   breast cancer phenotype
SO CANCER BIOLOGY & THERAPY
LA English
DT Article
DE CAFs; Estrogen receptor; exosomes; MAPK; microRNA; TME
ID ESTROGEN-RECEPTOR-ALPHA; ACTIVATED PROTEIN-KINASE;
   EPITHELIAL-MESENCHYMAL TRANSITION; PROMOTE TUMOR-GROWTH; STROMAL
   FIBROBLASTS; TAMOXIFEN RESISTANCE; EXTRACELLULAR-MATRIX;
   GENE-EXPRESSION; TGF-BETA; MICROENVIRONMENT
AB Multiple juxtacrine and paracrine interactions occur between cancer cells and non-cancer cells of the tumor microenvironment (TME) that direct tumor progression. Cancer Associated Fibroblasts (CAFs) are an integral component of the TME, and the majority of breast tumor stroma is comprised of CAFs. Heterotypic interactions between cancer cells and non-cancer cells of the TME occur via soluble agents, including cytokines, hormones, growth factors, and secreted microRNAs. We previously identified a microRNA signature indicative of hyperactive MAPK signaling (hMAPK-miRNA signature) that significantly associated with reduced recurrence-free and overall survival. Here we report that the hMAPK-miRNA signature associates with a high metric of stromal cell infiltrate, and we investigate the role of microRNAs, particularly hMAPK-microRNAs, secreted by CAFs on estrogen receptor (ER) expression in breast cancer cells. ER-positive MCF-7/ltE2- cells were treated with conditioned media (CM) from CAFs derived from breast cancers of different PAM50 subtypes (CAF(BAS), CAF(HER2), and CAF(LA)). CAF CM isolated specifically from ER-negative primary breast tumors led to ER repression in vitro. Nanoparticle tracking analysis and transmission electron microscopy confirmed the presence of CAF-secreted exosomes in CM and the uptake of these exosomes by the ER+ MCF-7/ltE2- cells. Differentially expressed microRNAs in CAF CM as well as in MCF-7/ltE2- cells treated with this CM were identified. Knockdown of miR-221/222 in CAF(BAS) resulted in knockdown of miR221/222 levels in the conditioned media and the CM from CAF(BAS); miR221/222 knockdown rescued ER repression in ER-positive cell lines treated with CAF(BAS)-CM. Collectively, our results demonstrate that CAF-secreted microRNAs are directly involved in ER-repression, and may contribute to the MAPK-induced ER repression in breast cancer cells.
C1 [Shah, Sanket H.; Ao, Zheng] Univ Miami, Canc Biol, Miami, FL USA.
   [El-Ashry, Dorraya] Univ Miami, Miller Sch Med, Dept Internal Med, Miami, FL 33136 USA.
   [Miller, Philip; Machlin, Leah] Univ Miami, Miller Sch Med, Sylvester Comprehens Canc Ctr, Miami, FL 33136 USA.
   [Garcia-Contreras, Marta] Univ Miami, Miller Sch Med, Diabet Res Inst, Miami, FL 33136 USA.
   [Issa, Emilio] Univ Miami, Dept Biol, Miami, FL USA.
C3 University of Miami; University of Miami; University of Miami;
   University of Miami; University of Miami
RP El-Ashry, D (corresponding author), Univ Miami, Miller Sch Med, Dept Internal Med, Miami, FL 33136 USA.
EM del-ashry@med.miami.edu
RI ao, zheng/A-7890-2018; Garcia-Contreras, Marta/KJL-9181-2024; Shah,
   Sanket/I-1665-2019
OI Garcia-Contreras, Marta/0000-0001-8014-7966
FU School of Medicine and Dentistry, Catholic University of Valencia,
   Valencia, Spain; Ri.Med Foundation, Palermo, Italy; Sylvester
   Comprehensive Cancer Center development funds
FX The authors would like to thank Dr. Marc E. Lippman and members of Dr.
   El-Ashry and Dr. Lippman laboratory group, Drs. Bal Lokeshwar, Kerry
   Burnstein, Ram Datar and Sharon Elliot for thoughtful discussions.
   Sanket H. Shah would like to thank partial support and assistance from
   the Sheila and David Fuente Graduate Program in Cancer Biology,
   University of Miami. Marta Garcia-Contreras would like to thank partial
   support and assistance from School of Medicine and Dentistry, Catholic
   University of Valencia, Valencia, Spain and Ri.Med Foundation, Palermo,
   Italy. We thank Sylvester Comprehensive Cancer Center development funds
   for partial support to DEA. We would like to thank Sion Williams at
   Oncogenomics Core Facility of University of Miami for their technical
   support with the Nanostring analysis. We would like to acknowledge Mario
   Soriano-Navarro for his technical support at the Electron Microscopy
   Service of Centro de Investigacion Principe Felipe, Valencia, Spain.
   Also we thank the Microvesicles and Exosomes core at Diabetes Research
   Institute, University of Miami for the nano-particle tracking analysis
   technical support. And Maria Boulina for technical support at the
   Analytical Imaging Core Facility core of University of Miami.
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NR 84
TC 56
Z9 60
U1 1
U2 15
PU TAYLOR & FRANCIS INC
PI PHILADELPHIA
PA 530 WALNUT STREET, STE 850, PHILADELPHIA, PA 19106 USA
SN 1538-4047
EI 1555-8576
J9 CANCER BIOL THER
JI Cancer Biol. Ther.
PD NOV
PY 2015
VL 16
IS 11
BP 1671
EP 1681
DI 10.1080/15384047.2015.1071742
PG 11
WC Oncology
WE Science Citation Index Expanded (SCI-EXPANDED)
SC Oncology
GA CX5SF
UT WOS:000365762100011
PM 26186233
OA Bronze, Green Published
DA 2025-03-13
ER

PT J
AU Naito, K
   Sangai, T
   Yamashita, K
AF Naito, Kanako
   Sangai, Takafumi
   Yamashita, Keishi
TI CAF-Associated Genes in Breast Cancer for Novel Therapeutic Strategies
SO BIOMEDICINES
LA English
DT Review
DE tumor microenvironment (TME); cancer-associated fibroblasts (CAFs);
   SPARC; breast cancer; colorectal cancer; triple-negative breast cancer
ID STROMAL FIBROBLASTS; TGF-BETA; CELLS; REVEALS; TUMORS
AB Breast cancer (BC) is the most common cancer in women, and therapeutic strategies for it are based on the molecular subtypes of luminal BC, HER2 BC, and triple-negative BC (TNBC) because each subtype harbors different unique genetic aberrations. Recently, features of the tumor microenvironment (TME), especially cancer-associated fibroblasts (CAFs), have been demonstrated to play a critical role in BC progression, and we would like to understand the molecular features of BC CAFs for novel therapeutic strategies. In a recent study, 115 CAF-associated genes (CAFGs) were identified in a public database of microdissection and microarray data (GSE35602) from 13 colorectal cancer (CRC) tumors. Using a public database (GSE10797) of 28 BC tumors, a similar analysis was performed. In BC, 59 genes from the 115 CAFGs identified in CRC (CRC CAFGs) were also closely associated with a CAFs marker, SPARC (R = 0.6 or beyond), and POSTN was of particular interest as one of the BC CAFGs with the highest expression levels and a close association with SPARC expression (R = 0.94) in the cancer stroma of BC tumors. In BC stroma, POSTN was followed in expression levels by DKK3, MMP2, PDPN, and ACTA2. Unexpectedly, FAP and VIM were not as highly associated with SPARC expression in the cancer stroma of BC tumors and exhibited low expression. These findings suggested that ACTA2 might be the most relevant conventional CAFs marker in BC, and ACTA2 was actually correlated in expression with many CRC CAFGs, such as SPARC. Surprisingly, the SE ratio values of the BC CAFGs were much lower (average SE = 3.8) than those of the CRC CAFGs (SE = 10 or beyond). We summarized the current understanding of BC CAFs from the literature. Finally, in triple-negative BC (TNBC) (n = 5), SPARC expression uniquely showed a close association with COL11A1 and TAGLN expression, representing a myofibroblast (myCAFs) marker in the cancer stroma of the BC tumors, suggesting that myCAFs may be molecularly characterized by TNBC in contrast to other BC phenotypes. In summary, CAFs could have unique molecular characteristics in BC, and such TME uniqueness could be therapeutically targeted in BC.
C1 [Naito, Kanako; Yamashita, Keishi] Kitasato Univ, Res & Dev Ctr New Med Frontiers, Sch Med, Div Adv Surg Oncol, Sagamihara 2520374, Japan.
   [Sangai, Takafumi] Kitasato Univ, Sch Med, Dept Breast & Thyroid Surg, Sagamihara 2520374, Japan.
C3 Kitasato University; Kitasato University
RP Naito, K; Yamashita, K (corresponding author), Kitasato Univ, Res & Dev Ctr New Med Frontiers, Sch Med, Div Adv Surg Oncol, Sagamihara 2520374, Japan.
EM naito.kanako@st.kitasato-u.ac.jp; sangai@med.kitasato-u.ac.jp;
   keishi23@med.kitasato-u.ac.jp
OI Yamashita, Keishi/0000-0002-8492-0300
FX This research received no external funding.
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NR 66
TC 0
Z9 0
U1 3
U2 3
PU MDPI
PI BASEL
PA ST ALBAN-ANLAGE 66, CH-4052 BASEL, SWITZERLAND
EI 2227-9059
J9 BIOMEDICINES
JI Biomedicines
PD SEP
PY 2024
VL 12
IS 9
AR 1964
DI 10.3390/biomedicines12091964
PG 18
WC Biochemistry & Molecular Biology; Medicine, Research & Experimental;
   Pharmacology & Pharmacy
WE Science Citation Index Expanded (SCI-EXPANDED)
SC Biochemistry & Molecular Biology; Research & Experimental Medicine;
   Pharmacology & Pharmacy
GA H5E4J
UT WOS:001323669500001
PM 39335478
OA Green Published, gold
DA 2025-03-13
ER

PT J
AU Balliet, RM
   Capparelli, C
   Guido, C
   Pestell, TG
   Martinez-Outschoorn, UE
   Lin, Z
   Whitaker-Menezes, D
   Chiavarina, B
   Pestell, RG
   Howell, A
   Sotgia, F
   Lisanti, MP
AF Balliet, Renee M.
   Capparelli, Claudia
   Guido, Carmela
   Pestell, Timothy G.
   Martinez-Outschoorn, Ubaldo E.
   Lin, Zhao
   Whitaker-Menezes, Diana
   Chiavarina, Barbara
   Pestell, Richard G.
   Howell, Anthony
   Sotgia, Federica
   Lisanti, Michael P.
TI Mitochondrial oxidative stress in cancer-associated fibroblasts drives
   lactate production, promoting breast cancer tumor growth Understanding
   the aging and cancer connection
SO CELL CYCLE
LA English
DT Article
DE caveolin-1; mitochondria; oxidative phosphorylation (OXPHOS); electron
   transport; respiratory chain; reverse Warburg effect; aerobic
   glycolysis; hydrogen peroxide; lactate; cancer metabolism; TFAM; aging;
   cancer associated fibroblasts
ID STROMAL CAVEOLIN-1; HYDROGEN-PEROXIDE; CELL METABOLISM; LIFE-SPAN;
   MICROENVIRONMENT; EXPRESSION; AUTOPHAGY; DNA; METASTASIS; PROTEIN
AB Increasing chronological age is the most significant risk factor for cancer. Recently, we proposed a new paradigm for understanding the role of the aging and the tumor microenvironment in cancer onset. In this model, cancer cells induce oxidative stress in adjacent stromal fibroblasts. This, in turn, causes several changes in the phenotype of the fibroblast including mitochondrial dysfunction, hydrogen peroxide production and aerobic glycolysis, resulting in high levels of L-lactate production. L-lactate is then transferred from these glycolytic fibroblasts to adjacent epithelial cancer cells and used as "fuel" for oxidative mitochondrial metabolism. Here, we created a new pre-clinical model system to directly test this hypothesis experimentally. To synthetically generate glycolytic fibroblasts, we genetically-induced mitochondrial dysfunction by knocking down TFAM using an sh-RNA approach. TFAM is mitochondrial transcription factor A, which is important in functionally maintaining the mitochondrial respiratory chain. Interestingly, TFAM-deficient fibroblasts showed evidence of mitochondrial dysfunction and oxidative stress, with the loss of certain mitochondrial respiratory chain components, and the over-production of hydrogen peroxide and L-lactate. Thus, TFAM-deficient fibroblasts underwent metabolic reprogramming towards aerobic glycolysis. Most importantly, TFAM-deficient fibroblasts significantly promoted tumor growth, as assayed using a human breast cancer (MDA-MB-231) xenograft model. These increases in glycolytic fibroblast driven tumor growth were independent of tumor angiogenesis. Mechanistically, TFAM-deficient fibroblasts increased the mitochondrial activity of adjacent epithelial cancer cells in a co-culture system, as seen using MitoTracker. Finally, TFAM-deficient fibroblasts also showed a loss of caveolin-1 (Cav-1), a known breast cancer stromal biomarker. Loss of stromal fibroblast Cav-1 is associated with early tumor recurrence, metastasis and treatment failure, resulting in poor clinical outcome in breast cancer patients. Thus, this new experimental model system, employing glycolytic fibroblasts, may be highly clinically relevant. These studies also have implications for understanding the role of hydrogen peroxide production in oxidative damage and "host cell aging," in providing a permissive metabolic microenvironment for promoting and sustaining tumor growth.
C1 [Balliet, Renee M.; Capparelli, Claudia; Guido, Carmela; Pestell, Timothy G.; Martinez-Outschoorn, Ubaldo E.; Lin, Zhao; Whitaker-Menezes, Diana; Chiavarina, Barbara; Pestell, Richard G.; Sotgia, Federica; Lisanti, Michael P.] Thomas Jefferson Univ, Jefferson Stem Cell Biol & Regenerat Med Ctr, Philadelphia, PA 19107 USA.
   [Balliet, Renee M.; Capparelli, Claudia; Guido, Carmela; Pestell, Timothy G.; Martinez-Outschoorn, Ubaldo E.; Lin, Zhao; Whitaker-Menezes, Diana; Chiavarina, Barbara; Pestell, Richard G.; Sotgia, Federica; Lisanti, Michael P.] Thomas Jefferson Univ, Dept Stem Cell Biol & Regenerat Med, Philadelphia, PA 19107 USA.
   [Martinez-Outschoorn, Ubaldo E.; Lisanti, Michael P.] Thomas Jefferson Univ, Dept Med Oncol, Kimmel Canc Ctr, Philadelphia, PA 19107 USA.
   [Howell, Anthony; Sotgia, Federica; Lisanti, Michael P.] Univ Manchester, Manchester Acad Hlth Sci Ctr, Manchester Breast Ctr, Paterson Inst Canc Res,Sch Canc, Manchester M13 9PL, Lancs, England.
   [Pestell, Richard G.; Howell, Anthony; Sotgia, Federica; Lisanti, Michael P.] Univ Manchester, Manchester Acad Hlth Sci Ctr, Breakthrough Breast Canc Res Unit, Paterson Inst Canc Res,Sch Canc, Manchester M13 9PL, Lancs, England.
C3 Thomas Jefferson University; Thomas Jefferson University; Thomas
   Jefferson University; Paterson Institute for Cancer Research; University
   of Manchester; University of Manchester; Paterson Institute for Cancer
   Research
RP Lisanti, MP (corresponding author), Thomas Jefferson Univ, Jefferson Stem Cell Biol & Regenerat Med Ctr, Philadelphia, PA 19107 USA.
EM federica.sotgia@jefferson.edu; michael.lisanti@kimmelcancercenter.org
RI Lisanti, Michael/C-6866-2013; Pestell, Richard/JQW-3484-2023; Martinet,
   Wim/I-7375-2015
OI Lisanti, Michael/0000-0003-2034-1382; Martinez-Outschoorn,
   Ubaldo/0000-0003-1483-4551; Guido, Carmela/0000-0002-4225-8208; Howell,
   Anthony/0000-0002-6233-719X; Sotgia, Federica/0000-0003-2826-4529
FU Breast Cancer Alliance (BCA); American Cancer Society (ACS); Margaret Q.
   Landenberger Research Foundation; NIH/NCI [R01-CA-080250, R01-CA-098779,
   R01-CA-120876, R01-AR-055660, R01-CA-70896, R01-CA-75503, R01-CA-86072,
   R01-CA-107382]; Susan G. Komen Breast Cancer Foundation; Dr. Ralph and
   Marian C. Falk Medical Research Trust; NIH/NCI Cancer Center
   [P30-CA-56036]; Pennsylvania Department of Health; Breakthrough Breast
   Cancer in the UK; European Research Council
FX F. S. and her laboratory were supported by grants from the Breast Cancer
   Alliance (BCA) and the American Cancer Society (ACS). U. E. M. was
   supported by a Young Investigator Award from the Margaret Q.
   Landenberger Research Foundation. M. P. L. was supported by grants from
   the NIH/NCI (R01-CA-080250; R01-CA-098779; R01-CA-120876; R01-AR-055660)
   and the Susan G. Komen Breast Cancer Foundation. R. G. P. was supported
   by grants from the NIH/NCI (R01-CA-70896, R01-CA-75503, R01-CA-86072 and
   R01-CA-107382) and the Dr. Ralph and Marian C. Falk Medical Research
   Trust. The Kimmel Cancer Center was supported by the NIH/NCI Cancer
   Center Core grant P30-CA-56036 (to R. G. P.). Funds were also
   contributed by the Margaret Q. Landenberger Research Foundation (to M.
   P. L.). This project is funded, in part, under a grant with the
   Pennsylvania Department of Health (to M. P. L. and F. S.). The
   Department specifically disclaims responsibility for any analyses,
   interpretations or conclusions. This work was also supported, in part,
   by a Centre grant in Manchester from Breakthrough Breast Cancer in the
   UK (to A. H.) and an Advanced ERC Grant from the European Research
   Council.
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NR 60
TC 102
Z9 119
U1 0
U2 27
PU TAYLOR & FRANCIS INC
PI PHILADELPHIA
PA 530 WALNUT STREET, STE 850, PHILADELPHIA, PA 19106 USA
SN 1538-4101
EI 1551-4005
J9 CELL CYCLE
JI Cell Cycle
PD DEC 1
PY 2011
VL 10
IS 23
BP 4065
EP 4073
DI 10.4161/cc.10.23.18254
PG 9
WC Cell Biology
WE Science Citation Index Expanded (SCI-EXPANDED)
SC Cell Biology
GA 863IT
UT WOS:000298156700018
PM 22129993
OA Bronze, Green Published
DA 2025-03-13
ER

PT J
AU Angelucci, C
   Maulucci, G
   Colabianchi, A
   Iacopino, F
   D'Alessio, A
   Maiorana, A
   Palmieri, V
   Papi, M
   De Spirito, M
   Di Leone, A
   Masetti, R
   Sica, G
AF Angelucci, C.
   Maulucci, G.
   Colabianchi, A.
   Iacopino, F.
   D'Alessio, A.
   Maiorana, A.
   Palmieri, V.
   Papi, M.
   De Spirito, M.
   Di Leone, A.
   Masetti, R.
   Sica, G.
TI Stearoyl-CoA desaturase 1 and paracrine diffusible signals have a major
   role in the promotion of breast cancer cell migration induced by
   cancer-associated fibroblasts
SO BRITISH JOURNAL OF CANCER
LA English
DT Article
DE breast cancer cells; fibroblasts; SCD1; SREBP1; cell migration
ID ELEMENT-BINDING PROTEINS; MAMMARY-TUMOR GROWTH; MEMBRANE-FLUIDITY;
   STROMAL FIBROBLASTS; PROSTATE-CANCER; EXPRESSION; CARCINOMA; INVASION;
   ACID; MICE
AB Background: Despite the recognised contribution of the stroma to breast cancer development and progression, the effective targeting of the tumor microenvironment remains a challenge to be addressed. We previously reported that normal fibroblasts (NFs) and, notably, breast cancer-associated fibroblasts (CAFs) induced epithelial-to-mesenchymal transition and increases in cell membrane fluidity and migration in well-(MCF-7) and poorly-differentiated (MDA-MB-231) breast cancer cells. This study was designed to better define the role played, especially by CAFs, in promoting breast tumor cell migration.
   Methods: Fibroblast/breast cancer cell co-cultures were set up to investigate the influence of NFs and CAFs on gene and protein expression of Stearoyl-CoA desaturase 1 (SCD1), the main enzyme regulating membrane fluidity, as well as on the protein level and activity of its transcription factor, the sterol regulatory element-binding protein 1 (SREBP1), in MCF-7 and MDA-MB-231 cells. To assess the role of SREBP1 in the regulation of SCD1 expression, the desaturase levels were also determined in tumor cells treated with an SREBP1 inhibitor. Migration was evaluated by wound-healing assay in SCD1inhibited (by small-interfering RNA (siRNA) or pharmacologically) cancer cells and the effect of CAF-conditioned medium was also assessed. To define the role of stroma-derived signals in cancer cell migration speed, cell-tracking analysis was performed in the presence of neutralising antibodies to hepatocyte growth factor, transforming growth factor-beta or basic fibroblast growth factor.
   Results: A two to three fold increase in SCD1 mRNA and protein expression has been induced, particularly by CAFs, in the two cancer cell lines that appear to be dependent on SREBP1 activity in MCF-7 but not in MDA-MB-231 cells. Both siRNA-mediated and pharmacological inhibition of SCD1 impaired tumor cells migration, also when promoted by CAF-released soluble factors. Fibroblast-triggered increase in cancer cell migration speed was markedly reduced or abolished by neutralising the above growth factors.
   Conclusion: These results provide further insights in understanding the role of CAFs in promoting tumor cell migration, which may help to design new stroma-based therapeutic strategies.
C1 [Angelucci, C.; Colabianchi, A.; Iacopino, F.; D'Alessio, A.; Sica, G.] Univ Cattolica Sacro Cuore, Fac Med A Gemelli, Inst Histol & Embryol, I-00168 Rome, Italy.
   [Maulucci, G.; Maiorana, A.; Palmieri, V.; Papi, M.; De Spirito, M.] Univ Cattolica Sacro Cuore, Fac Med A Gemelli, Inst Phys, I-00168 Rome, Italy.
   [Di Leone, A.; Masetti, R.] Univ Cattolica Sacro Cuore, Fac Med A Gemelli, Dept Surg, Breast Unit, I-00168 Rome, Italy.
C3 Catholic University of the Sacred Heart; IRCCS Policlinico Gemelli;
   Catholic University of the Sacred Heart; IRCCS Policlinico Gemelli;
   Catholic University of the Sacred Heart; IRCCS Policlinico Gemelli
RP De Spirito, M (corresponding author), Univ Cattolica Sacro Cuore, Fac Med A Gemelli, Inst Histol & Embryol, I-00168 Rome, Italy.
EM m.despirito@rm.unicatt.it
RI D'Alessio, Alessio/F-3778-2010; Palmieri, Valentina/AAB-3564-2021; De
   Spirito, Marco/U-3817-2019; Maiorana, Alessandro/HQZ-8368-2023;
   Maulucci, Giuseppe/C-7400-2009; Papi, Massimiliano/AAC-3657-2022; Di
   Leone, Alba/AAD-2050-2022; De Spirito, Marco/C-5386-2008; Palmieri,
   Valentina/H-7836-2012
OI Maulucci, Giuseppe/0000-0002-2154-319X; Papi,
   Massimiliano/0000-0002-0029-1309; MASETTI, Riccardo/0000-0002-7520-9111;
   Di Leone, Alba/0000-0002-8219-5336; De Spirito,
   Marco/0000-0003-4260-5107; D'Alessio, Alessio/0000-0002-3340-2634;
   Palmieri, Valentina/0000-0002-6358-9647
FU Susan G Komen, Italian Affiliate (Rome, Italy)
FX This work was supported by the Susan G Komen, Italian Affiliate (Rome,
   Italy). Confocal microscopy experiments reported in this paper were
   performed at the LABCEMI (Laboratorio Centralizzato di Microscopia
   Ottica ed Elettronica) of the 'Universita Cattolica del Sacro Cuore'
   (Rome, Italy; http://www.rm.unicatt.it/).
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NR 50
TC 34
Z9 45
U1 0
U2 24
PU NATURE PUBLISHING GROUP
PI LONDON
PA MACMILLAN BUILDING, 4 CRINAN ST, LONDON N1 9XW, ENGLAND
SN 0007-0920
EI 1532-1827
J9 BRIT J CANCER
JI Br. J. Cancer
PD MAY 12
PY 2015
VL 112
IS 10
BP 1675
EP 1686
DI 10.1038/bjc.2015.135
PG 12
WC Oncology
WE Science Citation Index Expanded (SCI-EXPANDED)
SC Oncology
GA CH9SL
UT WOS:000354376500008
PM 25880005
OA hybrid, Green Published
DA 2025-03-13
ER

PT J
AU Zheng, SQ
   Zou, YT
   Tang, YH
   Yang, AL
   Liang, JY
   Wu, LY
   Tian, WW
   Xiao, WK
   Xie, XH
   Yang, L
   Xie, JD
   Wei, WD
   Xie, XM
AF Zheng, Shaoquan
   Zou, Yutian
   Tang, Yuhui
   Yang, Anli
   Liang, Jie-Ying
   Wu, Linyu
   Tian, Wenwen
   Xiao, Weikai
   Xie, Xinhua
   Yang, Lu
   Xie, Jindong
   Wei, Weidong
   Xie, Xiaoming
TI Landscape of cancer-associated fibroblasts identifies the secreted
   biglycan as a protumor and immunosuppressive factor in triple-negative
   breast cancer
SO ONCOIMMUNOLOGY
LA English
DT Article
DE Triple-negative breast cancer; cancer-associated fibroblast; biglycan;
   immune microenvironment; extracellular matrix
ID EXPRESSION; CELLS; MICROENVIRONMENT
AB Cancer-associated fibroblasts (CAFs) are essential for tumor microenvironment remodeling and correlate with tumor progression. However, interactions between CAFs and tumor cells and immune cells in triple-negative breast cancer (TNBC) are still poorly explored. Here, we investigate the role of CAFs in TNBC and potential novel mediators of their functions. The clustering of classic markers was applied to estimate the relative abundance of CAFs in TNBC cohorts. Primary fibroblasts were isolated from normal and tumor samples. The RNA and culture medium of fibroblasts were subjected to RNA sequencing and mass spectrometry to explore the upregulated signatures in CAFs. Microdissection and single-cell RNA sequencing datasets were used to examine the expression profiles. CAFs were associated with hallmark signalings and immune components in TNBC. Clustering based on CAF markers in the literature revealed different CAF infiltration groups in TNBC: low, medium and high. Most of the cancer hallmark signaling pathways were enriched in the high CAF infiltration group. Furthermore, RNA sequencing and mass spectrometry identified biglycan (BGN), a soluble secreted protein, as upregulated in CAFs compared to normal cancer-adjacent fibroblasts (NAFs). The expression of biglycan was negatively correlated with CD8 + T cells. Biglycan indicated poor prognostic outcomes and might be correlated with the immunosuppressive tumor microenvironment (TME). In conclusion, CAFs play an essential role in tumor progression and the TME. We identified an extracellular protein, biglycan, as a prognostic marker and potential therapeutic target in TNBC.
C1 [Zheng, Shaoquan; Zou, Yutian; Tang, Yuhui; Yang, Anli; Wu, Linyu; Tian, Wenwen; Xie, Xinhua; Xie, Jindong; Wei, Weidong; Xie, Xiaoming] Sun Yat Sen Univ, Dept Breast Oncol, Canc Ctr, Guangzhou, Peoples R China.
   [Zheng, Shaoquan; Zou, Yutian; Tang, Yuhui; Yang, Anli; Liang, Jie-Ying; Wu, Linyu; Tian, Wenwen; Xie, Xinhua; Xie, Jindong; Wei, Weidong; Xie, Xiaoming] Sun Yat Sen Univ, Collaborat Innovat Ctr Canc Med, Canc Ctr, State Key Lab Oncol South China, Guangzhou, Peoples R China.
   [Liang, Jie-Ying] Sun Yat Sen Univ, Dept Med Oncol, Canc Ctr, Guangzhou, Peoples R China.
   [Xiao, Weikai] Guangdong Prov Peoples Hosp, Dept Breast Canc, Guangzhou, Peoples R China.
   [Xiao, Weikai; Yang, Lu] Guangdong Acad Med Sci, Guangzhou, Peoples R China.
   [Yang, Lu] Guangdong Prov Peoples Hosp, Canc Ctr, Dept Radiotherapy, Guangzhou, Peoples R China.
C3 Sun Yat Sen University; Sun Yat Sen University; State Key Lab Oncology
   South China; Sun Yat Sen University; Guangdong Academy of Medical
   Sciences & Guangdong General Hospital; Guangdong Academy of Medical
   Sciences & Guangdong General Hospital; Guangdong Academy of Medical
   Sciences & Guangdong General Hospital
RP Wei, WD; Xie, XM (corresponding author), Sun Yat Sen Univ, Dept Breast Oncol, Canc Ctr, State Key Lab Oncol South China,Collaborat Innova, 651 Dongfeng East Rd, Guangzhou 510060, Peoples R China.
EM weiwd@sysucc.org.cn; xiexm@sysucc.org.cn
RI Xie, Jindong/AGL-8633-2022; Xie, Xinhua/LTC-9902-2024; Zheng,
   Shaoquan/GOK-1936-2022; Xie, Xiaoming/AAX-7439-2020; Tang,
   Yuhui/IWU-4174-2023; Liang, Jie-ying/HCH-2578-2022; Zou,
   Yutian/AAB-2820-2022
OI Xie, Xinhua/0000-0002-2775-0990; Liang, Jie-ying/0000-0002-9829-294X;
   Xie, Jindong/0000-0002-2482-7358; Zou, Yutian/0000-0002-5205-9923;
   Zheng, Shaoquan/0000-0003-1912-0216; Tang, Yuhui/0009-0001-2181-4068
FU National Natural Science Foundation of China [82003066]; Guangzhou Basic
   and Applied Basic Research Project [202102020168]; Guangdong Province
   Basic and Applied Basic Research Fund Project [2020A1515110034];
   Guangzhou Science and Technology Plan Project [202102020114]
FX This work was supported by the National Natural Science Foundation of
   China [82003066]; Guangzhou Basic and Applied Basic Research Project
   [202102020168]; Guangdong Province Basic and Applied Basic Research Fund
   Project [2020A1515110034]; Guangzhou Science and Technology Plan Project
   [202102020114].
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NR 72
TC 60
Z9 63
U1 1
U2 70
PU TAYLOR & FRANCIS INC
PI PHILADELPHIA
PA 530 WALNUT STREET, STE 850, PHILADELPHIA, PA 19106 USA
SN 2162-402X
J9 ONCOIMMUNOLOGY
JI OncoImmunology
PD DEC 31
PY 2022
VL 11
IS 1
AR 2020984
DI 10.1080/2162402X.2021.2020984
PG 16
WC Oncology; Immunology
WE Science Citation Index Expanded (SCI-EXPANDED)
SC Oncology; Immunology
GA XZ3LD
UT WOS:000737556200001
PM 35003899
OA gold, Green Published
DA 2025-03-13
ER

PT J
AU Timperi, E
   Gueguen, P
   Molgora, M
   Magagna, I
   Kieffer, Y
   Lopez-Lastra, S
   Sirven, P
   Baudrin, LG
   Baulande, S
   Nicolas, A
   Champenois, G
   Meseure, D
   Vincent-Salomon, A
   Tardivon, A
   Laas, E
   Soumelis, V
   Colonna, M
   Mechta-Grigoriou, F
   Amigorena, S
   Romano, E
AF Timperi, Eleonora
   Gueguen, Paul
   Molgora, Martina
   Magagna, Ilaria
   Kieffer, Yann
   Lopez-Lastra, Silvia
   Sirven, Philemon
   Baudrin, Laura G.
   Baulande, Sylvain
   Nicolas, Andre
   Champenois, Gabriel
   Meseure, Didier
   Vincent-Salomon, Anne
   Tardivon, Anne
   Laas, Enora
   Soumelis, Vassili
   Colonna, Marco
   Mechta-Grigoriou, Fatima
   Amigorena, Sebastian
   Romano, Emanuela
TI Lipid-Associated Macrophages Are Induced by Cancer-Associated
   Fibroblasts and Mediate Immune Suppression in Breast Cancer
SO CANCER RESEARCH
LA English
DT Article
ID POLARIZATION; CELLS
AB Tumor-associated macrophages (TAM) play a detrimental role in triple-negative breast cancer (TNBC). In-depth analysis of TAM characteristics and interactions with stromal cells, such as cancer-associated fibroblast (CAF), could provide important biological and therapeutic insights. Here we identify at the single-cell level a monocyte-derived STAB1+TREM2high lipid-associated macrophage (LAM) subpopulation with immune suppressive capacities that is expanded in patients resistant to immune checkpoint blockade (ICB). Genetic depletion of this LAM subset in mice suppressed TNBC tumor growth. Flow cytometry and bulk RNA sequencing data demonstrated that coculture with TNBC-derived CAFs led to reprogramming of blood monocytes towards immune suppressive STAB1+TREM2high LAMs, which inhibit T-cell activation and proliferation. Cell-to-cell interaction modeling and assays in vitro demonstrated the role of the inflammatory CXCL12-CXCR4 axis in CAF-myeloid cell cross-talk and recruitment of monocytes in tumor sites. Altogether, these data suggest an inflammation model whereby monocytes recruited to the tumor via the CAF-driven CXCL12-CXCR4 axis acquire protumorigenic LAM capacities to support an immunosuppressive microenvironment. Significance: This work identifies a novel lipid-associated macrophage subpopulation with immune suppressive functions, offering new leads for therapeutic interventions in triple-negative breast cancer.
C1 [Timperi, Eleonora; Gueguen, Paul; Lopez-Lastra, Silvia; Sirven, Philemon; Amigorena, Sebastian; Romano, Emanuela] PSL Res Univ, Inst Curie, Dept Immunol, INSERM U932, Paris, France.
   [Molgora, Martina; Colonna, Marco] Washington Univ, Dept Pathol & Immunol, Sch Med, St Louis, MO USA.
   [Magagna, Ilaria; Kieffer, Yann; Mechta-Grigoriou, Fatima] PSL Res Univ, Inst Curie, Stress & Canc Lab, INSERM U830,Equipe Labelisee La Ligue Natl Canc, Paris, France.
   [Baudrin, Laura G.; Baulande, Sylvain] Inst Curie, Inst Curie Genom Excellence ICGex NGS Platform, Paris, France.
   [Nicolas, Andre; Champenois, Gabriel; Meseure, Didier; Vincent-Salomon, Anne] Inst Curie, Dept Pathol, Paris, France.
   [Nicolas, Andre; Champenois, Gabriel; Meseure, Didier; Vincent-Salomon, Anne] Inst Curie, Ctr Invest Clin Biotherapie, Paris, France.
   [Tardivon, Anne] Inst Curie, Dept Radiol, Paris, France.
   [Laas, Enora] Inst Curie, Serv Breast & Gynecol Surg, Paris, France.
   [Soumelis, Vassili] Univ Paris, INSERM U976, Hop St Louis, Paris, France.
   [Soumelis, Vassili] Hop St Louis, AP HP, Lab Immunol & Histocompatibilite, Paris, France.
   [Romano, Emanuela] Inst Curie, Ctr Canc Immunotherapy, Dept Med Oncol, Paris, France.
   [Soumelis, Vassili] Owkin, 12 Rue Martel, Paris, France.
   [Gueguen, Paul] Univ Lausanne, Lausanne, Switzerland.
   [Magagna, Ilaria] Sanofi, Paris, France.
C3 Universite PSL; UNICANCER; Institut Curie; Institut National de la Sante
   et de la Recherche Medicale (Inserm); Washington University (WUSTL);
   Universite PSL; UNICANCER; Institut Curie; Institut National de la Sante
   et de la Recherche Medicale (Inserm); Universite Paris Cite; UNICANCER;
   Universite PSL; Institut Curie; UNICANCER; Universite PSL; Institut
   Curie; UNICANCER; Universite PSL; Institut Curie; Institut National de
   la Sante et de la Recherche Medicale (Inserm); UNICANCER; Universite
   PSL; Institut Curie; UNICANCER; Universite PSL; Institut Curie;
   Assistance Publique Hopitaux Paris (APHP); Universite Paris Cite;
   Hopital Universitaire Saint-Louis - APHP; Institut National de la Sante
   et de la Recherche Medicale (Inserm); Universite Paris Cite; Assistance
   Publique Hopitaux Paris (APHP); Hopital Universitaire Saint-Louis -
   APHP; UNICANCER; Universite PSL; Institut Curie; University of Lausanne;
   Sanofi-Aventis; Sanofi France
RP Romano, E (corresponding author), PSL Res Univ, INSERM U932, Dept Immunol & Med Oncol, Inst Curie, 26 Rue Ulm, F-75005 Paris, France.; Timperi, E (corresponding author), Dept Immunol, Paris, France.
EM Eleonora.Timperi@curie.fr; Emanuela.Romano@curie.fr
RI Molgora, Martina/G-5591-2018; Timperi, Eleonora/AGU-6201-2022; Colonna,
   Marco/AFW-6458-2022; Vincent-Salomon, Anne/GXV-2625-2022;
   MECHTA-GRIGORIOU, Fatima/C-5253-2017
OI BAULANDE, Sylvain/0000-0003-3104-1684; timperi,
   eleonora/0000-0002-8357-6587; KIEFFER, Yann/0000-0003-2722-3071;
   Gueguen, Paul/0000-0003-2930-6073
FU Agence Nationale de la Recherche ("Investissements d'Avenir" program)
   [ANR-10-EQPX-03, ANR-10-INBS-09-08]; ITMO-Cancer Aviesan (Plan Cancer
   III); SiRIC-Curie program (SiRIC) [INCa-DGOS-4654]; Foundation ARC [AAP
   SIGN'IT 2019]; Fonds Amgen France pour la Science et l'Humain; CIC
   IGR-Curie [1428]; INSERM, Institut Curie, CNRS; NIH [R01 CA262684]; AIRC
   [20934]; Cancer Research Institute-Lloyd J. Old Memorial Fellowship in
   Tumor Immunology;  [ANR-10-IDEX-0001-02 PSL];  [ANR11-LABX-0043]
FX The authors thank all the platforms and services at Curie involved in
   the study: 10X, Cytometry, and Pathology. High-throughput sequencing was
   performed by the ICGex NGS platform of the Institut Curie supported by
   the grants ANR-10-EQPX-03 (Equipex) and ANR-10-INBS-09-08 (France
   G~enomique Consortium) from the Agence Nationale de la Recherche
   ("Investissements d'Avenir" program), by the ITMO-Cancer Aviesan (Plan
   Cancer III), and by the SiRIC-Curie program (SiRIC Grant
   INCa-DGOS-4654). The authors thank Maija Hollm~en for the collaboration
   and for providing us with the antibody (STAB1); Immunologie Clinique and
   Olivier Lantz for their collaboration; Rodrigo Nalio Ramos, Jimena
   Tosello, Mercedes Tkach, Giulia Vanoni, and Arnaud Manon for technical
   advice; Julie Helft and Elodie Segura for the constructive discussions;
   Jules Gilet for bioinformatic analysis; Leclerc Renaud from the
   experimental pathology platform for technical support on Multiplex IHC
   analysis; Maud Kamal, Christophe le Tourneau, Charlotte Martinat, and
   all the colleagues involved in the SCANDARE and STROMA circuits; and all
   the patients and families. This work was supported by the following
   grants to E. Romano: Foundation ARC (grant no. AAP SIGN'IT 2019), Fonds
   Amgen France pour la Science et l'Humain; CIC IGR-Curie 1428;
   ANR-10-IDEX-0001-02 PSL; and ANR11-LABX-0043; S. Amigorena: INSERM,
   Institut Curie, CNRS; M. Colonna: NIH (grant no. R01 CA262684). E.
   Timperi was supported by a postdoctoral fellowship abroad from the AIRC
   (2018/2020-number: 20934). M. Molgora is a recipient of the Cancer
   Research Institute-Lloyd J. Old Memorial Fellowship in Tumor Immunology.
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NR 45
TC 120
Z9 125
U1 12
U2 85
PU AMER ASSOC CANCER RESEARCH
PI PHILADELPHIA
PA 615 CHESTNUT ST, 17TH FLOOR, PHILADELPHIA, PA 19106-4404 USA
SN 0008-5472
EI 1538-7445
J9 CANCER RES
JI Cancer Res.
PD SEP 15
PY 2022
VL 82
IS 18
BP 3291
EP 3306
DI 10.1158/0008-5472.CAN-22-1427
PG 16
WC Oncology
WE Science Citation Index Expanded (SCI-EXPANDED)
SC Oncology
GA 4U8BS
UT WOS:000859013500001
PM 35862581
OA Green Submitted
HC Y
HP N
DA 2025-03-13
ER

PT J
AU Maggiolini, M
   Santolla, MF
   Avino, S
   Aiello, F
   Rosano, C
   Garofalo, A
   Grande, F
AF Maggiolini, Marcello
   Santolla, Maria Francesca
   Avino, Silvia
   Aiello, Francesca
   Rosano, Camillo
   Garofalo, Antonio
   Grande, Fedora
TI Identification of two benzopyrroloxazines acting as selective GPER
   antagonists in breast cancer cells and cancer-associated fibroblasts
SO FUTURE MEDICINAL CHEMISTRY
LA English
DT Article
ID ESTROGEN-RECEPTOR; GENE-EXPRESSION; GPR30; MICROENVIRONMENT; ACTIVATION;
   DISCOVERY; AGONIST; DISEASE; RATS
AB Background: G-protein coupled estrogen receptor (GPER) is involved in numerous intracellular physiological and pathological events including cancer cell migration and proliferation. Its characterization is yet incomplete due to the limited number of specific ligands. Results: Two novel selective GPER antagonists, based on a benzo[b] pyrrolo[1,2-d][1,4]oxazin-4-one structure, have been designed and synthesized. Their binding to the receptor was confirmed by a competition assay, while the antagonist effects were ascertained by their capability to prevent the ligand-stimulated action of GPER. The transcription mediated by the classical estrogen receptor was not influenced, demonstrating selectivity for GPER. Conclusion: These novel compounds may be considered useful leads toward the dissection of the GPER signaling and the development of new pharmacological treatments in breast cancer.
C1 [Maggiolini, Marcello; Santolla, Maria Francesca; Avino, Silvia; Aiello, Francesca; Garofalo, Antonio; Grande, Fedora] Univ Calabria, Dept Pharm Hlth & Nutr Sci, I-87036 Arcavacata Di Rende, Cs, Italy.
   [Rosano, Camillo] Natl Inst Canc Res, IRCCS AOU San Martino IST, UOS Biopolymers & Prote, I-16132 Genoa, Italy.
C3 University of Calabria; University of Genoa; IRCCS AOU San Martino IST
RP Grande, F (corresponding author), Univ Calabria, Dept Pharm Hlth & Nutr Sci, Via P Bucci, I-87036 Arcavacata Di Rende, Cs, Italy.
EM fedora.grande@unical.it
RI Grande, Fedora/AAX-7430-2020; garofalo, antonio/ABA-1466-2020; Rosano,
   Camillo/AAA-9954-2021; Maggiolini, Marcello/Z-4729-2019; Aiello,
   Francesca/A-7546-2012; Santolla, Maria/AAH-5481-2020
OI Grande, Fedora/0000-0002-6154-4330; Santolla, Maria
   Francesca/0000-0002-4838-5953; Rosano, Camillo/0000-0003-2949-9215;
   Maggiolini, Marcello/0000-0002-7485-854X; garofalo,
   antonio/0000-0003-1337-5509; AIELLO, Francesca/0000-0001-6846-5582
FU Associazione Italiana per la Ricerca sul Cancro (AIRC), AIRC project
   Calabria [12849/2012]; Fondazione Cassa di Risparmio di Calabria e
   Lucania CR; 'Compagnia di San Paolo di Torino'
FX This work was supported by Associazione Italiana per la Ricerca sul
   Cancro (AIRC, project n. 12849/2012), AIRC project Calabria 2011
   (www.airc.it/) and Fondazione Cassa di Risparmio di Calabria e Lucania
   CR. The authors thank the 'Compagnia di San Paolo di Torino' for the
   generous support to this research. The authors have no other relevant
   affiliations or financial involvement with any organization or entity
   with a financial interest in or financial conflict with the subject
   matter or materials discussed in the manuscript apart from those
   disclosed.
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NR 33
TC 35
Z9 39
U1 0
U2 16
PU FUTURE SCI LTD
PI LONDON
PA UNITED HOUSE, 2 ALBERT PL, LONDON, N3 1QB, ENGLAND
SN 1756-8919
EI 1756-8927
J9 FUTURE MED CHEM
JI Future Med. Chem.
PY 2015
VL 7
IS 4
BP 437
EP 448
DI 10.4155/FMC.15.3
PG 12
WC Chemistry, Medicinal
WE Science Citation Index Expanded (SCI-EXPANDED)
SC Pharmacology & Pharmacy
GA CT5ZH
UT WOS:000362889300003
PM 25875871
DA 2025-03-13
ER

PT J
AU Qiu, ZW
   Zhong, YT
   Lu, ZM
   Yan, N
   Kong, RJ
   Huang, JQ
   Li, ZF
   Nie, JM
   Li, RQ
   Cheng, H
AF Qiu, Zi-Wen
   Zhong, Ying-Tao
   Lu, Zhen-Ming
   Yan, Ni
   Kong, Ren-Jiang
   Huang, Jia-Qi
   Li, Zhuo-Feng
   Nie, Jun-Mei
   Li, Runqing
   Cheng, Hong
TI Breaking Physical Barrier of Fibrotic Breast Cancer for Photodynamic
   Immunotherapy by Remodeling Tumor Extracellular Matrix and Reprogramming
   Cancer-Associated Fibroblasts
SO ACS NANO
LA English
DT Article
DE fibrotic breast cancer; cancer-associated fibroblasts; tumor
   extracellular matrix; photodynamic therapy; immune checkpoint blockade
ID NANOMEDICINES
AB Cancer-associated fibroblasts (CAFs) assist in breast cancer (BRCA) invasion and immune resistance by overproduction of extracellular matrix (ECM). Herein, we develop FPC@S, a photodynamic immunomodulator that targets the ECM, to improve the photodynamic immunotherapy for fibrotic BRCA. FPC@S combines a tumor ECM-targeting peptide, a photosensitizer (protoporphyrin IX) and an antifibrotic drug (SIS3). After anchoring to the ECM, FPC@S causes ECM remodeling and BRCA cell death by generating reactive oxygen species (ROS) in situ. Interestingly, the ROS-mediated ECM remodeling can normalize the tumor blood vessel to improve hypoxia and in turn facilitate more ROS production. Besides, upon the acidic tumor microenvironment, FPC@S will release SIS3 for reprograming CAFs to reduce their activity but not kill them, thus inhibiting fibrosis while preventing BRCA metastasis. The natural physical barrier formed by the dense ECM is consequently eliminated in fibrotic BRCA, allowing the drugs and immune cells to penetrate deep into tumors and have better efficacy. Furthermore, FPC@S can stimulate the immune system and effectively suppress primary, distant and metastatic tumors by combining with immune checkpoint blockade therapy. This study provides different insights for the development of fibrotic tumor targeted delivery systems and exploration of synergistic immunotherapeutic mechanisms against aggressive BRCA.
C1 [Qiu, Zi-Wen; Zhong, Ying-Tao; Lu, Zhen-Ming; Yan, Ni; Kong, Ren-Jiang; Huang, Jia-Qi; Li, Zhuo-Feng; Nie, Jun-Mei; Cheng, Hong] Southern Med Univ, Sch Biomed Engn, Guangzhou 510515, Peoples R China.
   [Qiu, Zi-Wen; Zhong, Ying-Tao; Lu, Zhen-Ming; Yan, Ni; Kong, Ren-Jiang; Huang, Jia-Qi; Li, Zhuo-Feng; Nie, Jun-Mei; Cheng, Hong] Southern Med Univ, Guangdong Prov Key Lab Construct & Detect Tissue E, Guangzhou 510515, Peoples R China.
   [Li, Runqing] Xi An Jiao Tong Univ, Affiliated Hosp 1, Dept Radiol, Xian 710061, Peoples R China.
C3 Southern Medical University - China; Southern Medical University -
   China; Xi'an Jiaotong University
RP Cheng, H (corresponding author), Southern Med Univ, Sch Biomed Engn, Guangzhou 510515, Peoples R China.; Cheng, H (corresponding author), Southern Med Univ, Guangdong Prov Key Lab Construct & Detect Tissue E, Guangzhou 510515, Peoples R China.
EM chengh@smu.edu.cn
RI 孔, 任江/KHV-5141-2024; Li, Run-Qing/ABH-2730-2021; Huang,
   Jia-Qi/ISV-3970-2023; qiu, zi wen/KHW-8127-2024
OI qiu, zi wen/0009-0002-8105-9233
FU National Natural Science Foundation of China [52073140, 52103183];
   National Natural Science Foundation of China [2022B1515020095];
   Guangdong Basic and Applied Basic Research Foundation
FX This work was supported by the National Natural Science Foundation of
   China (52073140, 52103183), and the Guangdong Basic and Applied Basic
   Research Foundation (2022B1515020095).
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NR 39
TC 13
Z9 14
U1 21
U2 64
PU AMER CHEMICAL SOC
PI WASHINGTON
PA 1155 16TH ST, NW, WASHINGTON, DC 20036 USA
SN 1936-0851
EI 1936-086X
J9 ACS NANO
JI ACS Nano
PD MAR 20
PY 2024
VL 18
IS 13
BP 9713
EP 9735
DI 10.1021/acsnano.4c01499
EA MAR 2024
PG 23
WC Chemistry, Multidisciplinary; Chemistry, Physical; Nanoscience &
   Nanotechnology; Materials Science, Multidisciplinary
WE Science Citation Index Expanded (SCI-EXPANDED)
SC Chemistry; Science & Technology - Other Topics; Materials Science
GA MT6B9
UT WOS:001189143300001
PM 38507590
DA 2025-03-13
ER

PT J
AU Jian, C
   Wu, TT
   Wang, LL
   Gao, C
   Fu, ZW
   Zhang, Q
   Shi, C
AF Jian, Chen
   Wu, Tingting
   Wang, Lulu
   Gao, Chen
   Fu, Zhiwen
   Zhang, Qian
   Shi, Chen
TI Biomimetic Nanoplatform for Dual-Targeted Clearance of Activated and
   Senescent Cancer-Associated Fibroblasts to Improve Radiation Resistance
   in Breast Cancer
SO SMALL
LA English
DT Article
DE biomimetic nanoplatform; cancer-associated fibroblasts; radiation
   resistance; senescent cancer-associated fibroblasts; tumor
   microenvironment
ID STEM-CELLS; IONIZING-RADIATION; ANTITUMOR IMMUNITY; NANOPARTICLES;
   EXPRESSION; THERAPY; RADIOTHERAPY; IRRADIATION; MECHANISMS; COUMARIN
AB Radiation resistance in breast cancer resulting in residual lesions or recurrence is a significant cause to radiotherapy failure. Cancer-associated fibroblasts (CAFs) and radiotherapy-induced senescent CAFs can further lead to radiation resistance and tumor immunosuppressive microenvironment. Here, an engineering cancer-cell-biomimetic nanoplatform is constructed for dual-targeted clearance of CAFs as well as senescent CAFs. The nanoplatform is prepared by 4T1 cell membrane vesicles chimerized with FAP single-chain fragment variable as the biomimetic shell for targeting of CAFs and senescent CAFs, and PLGA nanoparticles (NPs) co-encapsulated with nintedanib and ABT-263 as the core for clearance of CAFs and senescent CAFs, which are noted as FAP-CAR-CM@PLGA-AB NPs. It is evidenced that FAP-CAR-CM@PLGA-AB NPs directly suppressed the tumor-promoting effect of senescent CAFs. It also exhibits prolonged blood circulation and enhanced tumor accumulation, dual-cleared CAFs and senescent CAFs, improved radiation resistance in both acquired and patient-derived radioresistant tumor cells, and effective antitumor effect with the tumor suppression rate of 86.7%. In addition, FAP-CAR-CM@PLGA-AB NPs reverse the tumor immunosuppressive microenvironment and enhance systemic antitumor immunity. The biomimetic system for dual-targeted clearance of CAFs and senescent CAFs provides a potential strategy for enhancing the radio-sensitization of breast cancer.
   FAP-CAR-CM@PLGA-AB NPs consisting of PLGA-AB NPs encapsulated with the anti-senescent drug ABT-263 and the anti-fibrotic drug nintedanib as the core, and 4T1 cell membrane chimeric with FAP single-chain fragment variable as the shell, can accumulate in tumor and dually clear cancer-associated fibroblasts and senescent cancer-associated fibroblasts to remodel the tumor microenvironment and improve radiotherapy resistance.image
C1 [Jian, Chen; Wu, Tingting; Wang, Lulu; Gao, Chen; Fu, Zhiwen; Shi, Chen] Huazhong Univ Sci & Technol, Union Hosp, Tongji Med Coll, Dept Pharm, Wuhan 430022, Peoples R China.
   [Jian, Chen; Wu, Tingting; Wang, Lulu; Gao, Chen; Fu, Zhiwen; Shi, Chen] Hubei Prov Clin Res Ctr Precis Med Crit Illness, Wuhan 430022, Peoples R China.
   [Zhang, Qian] Shanghai Jiao Tong Univ, Sch Elect Informat & Elect Engn, Key Lab Thin Film & Microfabricat Technol, Inst Nano Biomed & Engn,Minist Educ,Dept Instrumen, Shanghai 200240, Peoples R China.
C3 Huazhong University of Science & Technology; Shanghai Jiao Tong
   University
RP Shi, C (corresponding author), Huazhong Univ Sci & Technol, Union Hosp, Tongji Med Coll, Dept Pharm, Wuhan 430022, Peoples R China.; Shi, C (corresponding author), Hubei Prov Clin Res Ctr Precis Med Crit Illness, Wuhan 430022, Peoples R China.
EM shichen@hust.edu.cn
RI wu, tingting/H-8032-2012; Zhang, Qian/AAY-5368-2020; shi,
   chen/KEH-8339-2024
FU National Natural Science Foundation of China; Natural Science Foundation
   of Shanghai [22ZR1467600]; Cancer Center of Union Hospital of HUST; 
   [82073402];  [81901884];  [82272821]
FX This work was supported by the National Natural Science Foundation of
   China (no. 82073402, 81901884, and 82272821) and the Natural Science
   Foundation of Shanghai (no. 22ZR1467600). The authors thank the Medical
   Subcenter of Huazhong University of Science & Technology (HUST)
   Analytical and Testing Center for the TEM test. The authors thank the
   Cancer Center of Union Hospital of HUST, Wuhan, China for providing
   professional radiation technology.
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NR 65
TC 12
Z9 12
U1 28
U2 59
PU WILEY-V C H VERLAG GMBH
PI WEINHEIM
PA POSTFACH 101161, 69451 WEINHEIM, GERMANY
SN 1613-6810
EI 1613-6829
J9 SMALL
JI Small
PD JUN
PY 2024
VL 20
IS 25
DI 10.1002/smll.202309279
EA JAN 2024
PG 22
WC Chemistry, Multidisciplinary; Chemistry, Physical; Nanoscience &
   Nanotechnology; Materials Science, Multidisciplinary; Physics, Applied;
   Physics, Condensed Matter
WE Science Citation Index Expanded (SCI-EXPANDED)
SC Chemistry; Science & Technology - Other Topics; Materials Science;
   Physics
GA A3S0I
UT WOS:001140912200001
PM 38214439
DA 2025-03-13
ER

PT J
AU Reid, SE
   Pantaleo, J
   Bolivar, P
   Bocci, M
   Sjölund, J
   Morsing, M
   Cordero, E
   Larsson, S
   Malmberg, M
   Seashore-Ludlow, B
   Pietras, K
AF Reid, Steven E.
   Pantaleo, Jessica
   Bolivar, Paulina
   Bocci, Matteo
   Sjolund, Jonas
   Morsing, Mikkel
   Cordero, Eugenia
   Larsson, Sara
   Malmberg, Maria
   Seashore-Ludlow, Brinton
   Pietras, Kristian
TI Cancer-associated fibroblasts rewire the estrogen receptor response in
   luminal breast cancer, enabling estrogen independence
SO ONCOGENE
LA English
DT Article
ID COMPREHENSIVE MOLECULAR PORTRAITS; EXPRESSION; GROWTH; CELLS;
   INHIBITION; PROLIFERATION; GENE; TRANSCRIPTOME; CARCINOMA; INVASION
AB Advanced breast cancers represent a major therapeutic challenge due to their refractoriness to treatment. Cancer-associated fibroblasts (CAFs) are the most abundant constituents of the tumor microenvironment and have been linked to most hallmarks of cancer. However, the influence of CAFs on therapeutic outcome remains largely unchartered. Here, we reveal that spatial coincidence of abundant CAF infiltration with malignant cells was associated with reduced estrogen receptor (ER)-alpha expression and activity in luminal breast tumors. Notably, CAFs mediated estrogen-independent tumor growth by selectively regulating ER-alpha signaling. Whereas most prototypical estrogen-responsive genes were suppressed, CAFs maintained gene expression related to therapeutic resistance, basal-like differentiation, and invasion. A functional drug screen in co-cultures identified effector pathways involved in the CAF-induced regulation of ER-alpha signaling. Among these, the Transforming Growth Factor-beta and the Janus kinase signaling cascades were validated as actionable targets to counteract the CAF-induced modulation of ER-alpha activity. Finally, genes that were downregulated in cancer cells by CAFs were predictive of poor response to endocrine treatment. In conclusion, our work reveals that CAFs directly control the luminal breast cancer phenotype by selectively modulating ER-alpha expression and transcriptional function, and further proposes novel targets to disrupt the crosstalk between CAFs and tumor cells to reinstate treatment response to endocrine therapy in patients.
C1 [Reid, Steven E.; Pantaleo, Jessica; Bolivar, Paulina; Bocci, Matteo; Sjolund, Jonas; Morsing, Mikkel; Cordero, Eugenia; Larsson, Sara; Malmberg, Maria; Pietras, Kristian] Lund Univ, Div Translat Canc Res Canc Ctr, Dept Lab Med, Div Translat Canc Res,Canc Ctr, Lund, Sweden.
   [Seashore-Ludlow, Brinton] Dept Oncol Pathol, SciLifeLab, Stockholm, Sweden.
   [Seashore-Ludlow, Brinton] Chem Biol Consortium Sweden CBCS, S-17165 Solna, Sweden.
C3 Lund University; SciLifeLab
RP Pietras, K (corresponding author), Lund Univ, Div Translat Canc Res Canc Ctr, Dept Lab Med, Div Translat Canc Res,Canc Ctr, Lund, Sweden.
EM kristian.pietras@med.lu.se
RI Bocci, Matteo/AAB-5016-2021; Reid, Steven/AAB-4506-2021; Pietras,
   Kristian/ABE-8727-2020; Seashore-Ludlow, Brinton/E-2309-2017
OI Morsing, Mikkel/0000-0001-8322-8796; Larsson, Sara/0000-0002-0002-0779;
   Reid, Steven/0000-0002-6103-3354; Sjolund, Jonas/0000-0002-6992-3415;
   Seashore-Ludlow, Brinton/0000-0001-8658-5967; Bocci,
   Matteo/0000-0002-8774-0006; Pantaleo, Jessica/0000-0002-2012-3310;
   Bolivar Balbas, Paulina/0000-0002-7908-7297
FU Cancerfonden (Swedish Cancer Society); Institute for Molecular Medicine
   Finland
FX We thank the Centre for Translational Genomics, Lund University and
   Clinical Genomics Lund, SciLifeLab for providing sequencing services. We
   thank the Institute for Molecular Medicine Finland (FIMM) Oncology for
   the use of the compound library. We thank Professor Akira Orimo,
   Juntendo University for the kind gift of the CAF2 cell line. We thank
   Professor Ole W Petersen, University of Copenhagen for the kind gift of
   human breast cancer CAFs. We thank Dr Kamila Kaminska, Lund University
   for the kind gift of MCF7 cells. The preparation of the schematic
   illustrations used Servier Medical Art, provided by Servier, licensed
   under a Creative Commons Attribution 3.0 unported license.
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NR 71
TC 5
Z9 5
U1 1
U2 3
PU SPRINGERNATURE
PI LONDON
PA CAMPUS, 4 CRINAN ST, LONDON, N1 9XW, ENGLAND
SN 0950-9232
EI 1476-5594
J9 ONCOGENE
JI Oncogene
PD APR 5
PY 2024
VL 43
IS 15
BP 1113
EP 1126
DI 10.1038/s41388-024-02973-x
EA FEB 2024
PG 14
WC Biochemistry & Molecular Biology; Oncology; Cell Biology; Genetics &
   Heredity
WE Science Citation Index Expanded (SCI-EXPANDED)
SC Biochemistry & Molecular Biology; Oncology; Cell Biology; Genetics &
   Heredity
GA NA9A0
UT WOS:001169651400001
PM 38388711
OA hybrid, Green Published
DA 2025-03-13
ER

PT J
AU Pupo, M
   Vivacqua, A
   Perrotta, I
   Pisano, A
   Aquila, S
   Abonante, S
   Gasperi-Campani, A
   Pezzi, V
   Maggiolini, M
AF Pupo, Marco
   Vivacqua, Adele
   Perrotta, Ida
   Pisano, Assunta
   Aquila, Saveria
   Abonante, Sergio
   Gasperi-Campani, Anna
   Pezzi, Vincenzo
   Maggiolini, Marcello
TI The nuclear localization signal is required for nuclear GPER
   translocation and function in breast Cancer-Associated Fibroblasts
   (CAFs)
SO MOLECULAR AND CELLULAR ENDOCRINOLOGY
LA English
DT Article
DE Breast cancer; Cancer-associated fibroblasts; Estrogen signaling; GPER;
   Nuclear localization signal
ID PROTEIN-COUPLED RECEPTOR-30; GROWTH-FACTOR RECEPTOR; GENE-EXPRESSION
   CHANGES; ESTROGEN-RECEPTOR; G-PROTEIN-COUPLED-RECEPTOR-30 GPR30;
   TUMOR-GROWTH; CELLS; 17-BETA-ESTRADIOL; ACTIVATION; PROLIFERATION
AB Cancer associated fibroblasts (CAFs) actively contribute to the growth and invasion of cancer cells. In recent years, the G protein estrogen receptor (GPER) has been largely involved in the estrogenic signals in diverse types of normal and tumor cells. In CAFs, GPER was localized into the nucleus, however the molecular mechanisms which regulate its nuclear shuttle remain to be clarified. In the present study, we demonstrate that in breast CAFs GPER translocates into the nucleus through an importin-dependent mechanism. Moreover, we show that a nuclear localization signal is involved in the nuclear import of GPER, in the up-regulation of its target genes c-fos and CTGF and in the migration of CAFs induced by estrogens. Our data provide novel insights into the nuclear localization and function of GPER in CAFs toward a better understanding of the estrogen action elicited through these key players of the tumor microenvironment. (C) 2013 Elsevier Ireland Ltd. All rights reserved.
C1 [Pupo, Marco; Vivacqua, Adele; Pisano, Assunta; Aquila, Saveria; Pezzi, Vincenzo; Maggiolini, Marcello] Univ Calabria, Dept Pharm Hlth & Nutr Sci, I-87036 Arcavacata Di Rende, Italy.
   [Perrotta, Ida] Univ Calabria, Dept Ecol, I-87036 Arcavacata Di Rende, Italy.
   [Abonante, Sergio] Reg Hosp, Cosenza, Italy.
   [Gasperi-Campani, Anna] Alma Mater Studiorum Univ Bologna, Sch Med, Dept Expt Diagnost & Specialty Med DIMES, Bologna, Italy.
   [Gasperi-Campani, Anna] Univ Bologna, Interdept Ctr Res Canc Giorgio Prodi, I-40126 Bologna, Italy.
C3 University of Calabria; University of Calabria; University of Bologna;
   University of Bologna
RP Maggiolini, M (corresponding author), Univ Calabria, Dept Pharm Hlth & Nutr Sci, I-87036 Arcavacata Di Rende, Italy.
EM marcellomaggiolini@yahoo.it
RI Pezzi, Vincenzo/AAL-4017-2020; Maggiolini, Marcello/Z-4729-2019;
   vivacqua, adele/I-2771-2015
OI pezzi, Vincenzo/0000-0003-2311-2286; Abonante,
   Sergio/0000-0003-4686-6961; AQUILA, Saveria/0000-0003-4738-6927;
   vivacqua, adele/0000-0001-5333-8396; Perrotta, Ida/0000-0002-9061-9776;
   Maggiolini, Marcello/0000-0002-7485-854X
FU Associazione Italiana per la Ricerca sul Cancro (AIRC) [12849/2012];
   AIRC; Fondazione Cassa di Risparmio di Calabria e Lucania; Roberto
   Pallotti's Legacy for Cancer Research, Cornelia Pallotti's Legacy for
   Cancer Research, RFO University of Bologna
FX This work was supported by Associazione Italiana per la Ricerca sul
   Cancro (AIRC, Project n.12849/2012), AIRC project Calabria 2011 and
   Fondazione Cassa di Risparmio di Calabria e Lucania. AGC was supported
   by Roberto Pallotti's Legacy for Cancer Research, Cornelia Pallotti's
   Legacy for Cancer Research, RFO University of Bologna.
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NR 91
TC 61
Z9 70
U1 0
U2 13
PU ELSEVIER IRELAND LTD
PI CLARE
PA ELSEVIER HOUSE, BROOKVALE PLAZA, EAST PARK SHANNON, CO, CLARE, 00000,
   IRELAND
SN 0303-7207
J9 MOL CELL ENDOCRINOL
JI Mol. Cell. Endocrinol.
PD AUG 25
PY 2013
VL 376
IS 1-2
BP 23
EP 32
DI 10.1016/j.mce.2013.05.023
PG 10
WC Cell Biology; Endocrinology & Metabolism
WE Science Citation Index Expanded (SCI-EXPANDED)
SC Cell Biology; Endocrinology & Metabolism
GA 200TZ
UT WOS:000323095100003
PM 23748028
DA 2025-03-13
ER

PT J
AU Xu, SJ
   Zheng, S
   Ma, NH
   Zhang, HY
   Shi, JB
   Huang, JY
   Luo, NH
   Wang, ML
   Xiong, Y
AF Xu, Shujun
   Zheng, Shuang
   Ma, Ninghui
   Zhang, Hongyan
   Shi, Jingbin
   Huang, Jingyi
   Luo, Ninghchao
   Wang, Menglin
   Xiong, Yang
TI Rhein potentiates doxorubicin in treating triple negative breast cancer
   by inhibiting cancer-associated fibroblasts
SO BIOCHEMICAL PHARMACOLOGY
LA English
DT Article
DE Rhein; Desmoplastic triple -negative breast cancer; Cancer -associated
   fibroblasts; Doxorubicin
ID EXTRACELLULAR-MATRIX; TUMOR; NANOPARTICLES
AB Cancer-associated fibroblasts (CAFs), one of the most abundant stromal cells in the tumor microenvironment, mediate desmoplastic responses. CAFs are major drivers for the failure of triple-negative breast cancer (TNBC) chemotherapy. It is well-documented that many traditional Chinese medicines (TCMs) exhibit potent antifibrotic effects based on their capacity to suppress the production of ECM proteins. Therefore, the combination of TCMs exhausting CAFs with chemotherapy is a potential regimen for treating TNBC. Here, TGF-beta was used to induce the transformation of NIH/3T3 cells into CAFs for screening TCMs to inhibit tumor fibrosis. After screening 11 candidate TCMs for inhibiting CAFs using the TMS method, rhein (Rhe) was found to strongly inhibit the proliferation of CAFs. Therefore, Rhe was chosen as a representative TCM to inhibit CAFs in TNBC. A 4T1Fluc/CAFs tumor sphere resembling the TME in vivo was constructed to explore the feasibility of inhibiting CAFs to sensitize DOX in treating TNBC. It was found that CAFs apparently hindered the penetration of DOX into 4T1Fluc/CAFs tumor spheres and decreased the the sensitivity of 4T1Fluc cells to DOX, while Rhe significantly restored the sensitivity of 4T1Fluc cells to DOX by inhibiting the proliferation of CAFs. Consistent with in vitro results, Rhe reversed the abnormal activation of CAFs and diminished the accumulation of collagen in 4T1Fluc mouse xenograft models. This removal of stromal barrier facilitated the antitumor efficacy of DOX. Altogether, this study demonstrated for the first time that Rhe could inhibit tumor tissue fibrosis and synergize DOX to treat TNBC.
C1 [Xu, Shujun; Ma, Ninghui; Zhang, Hongyan; Shi, Jingbin; Huang, Jingyi; Luo, Ninghchao; Xiong, Yang] Zhejiang Chinese Med Univ, Coll Pharmaceut Sci, Hangzhou 311402, Zhejiang, Peoples R China.
   [Xu, Shujun; Ma, Ninghui; Zhang, Hongyan; Shi, Jingbin; Huang, Jingyi; Luo, Ninghchao; Xiong, Yang] Zhejiang Chinese Med Univ, Acad Chinese Med Sci, Hangzhou, Peoples R China.
   [Zheng, Shuang] Taizhou Tradit Chinese Med Hosp, Taizhou, Peoples R China.
   [Wang, Menglin] Univ N Carolina, Eshelman Sch Pharm, Div Pharmacoengn & Mol Pharmaceut, Chapel Hill, NC USA.
C3 Zhejiang Chinese Medical University; Zhejiang Chinese Medical
   University; University of North Carolina; University of North Carolina
   Chapel Hill
RP Xiong, Y (corresponding author), Zhejiang Chinese Med Univ, Coll Pharmaceut Sci, Hangzhou 311402, Zhejiang, Peoples R China.; Xiong, Y (corresponding author), Zhejiang Chinese Med Univ, Acad Chinese Med Sci, Hangzhou, Peoples R China.
EM xiongyang@zcmu.edu.cn
RI Huang, Jingyi/B-5541-2015; Wang, Menglin/MFK-1979-2025
FU Public Platform of Pharmaceutical Research Center, Academy of Chinese
   Medical Science, Zhejiang Chinese Medical University; National Natural
   Science Foundation of China [82174095]; Natural Science Foundation of
   Zhejiang Province [LZ22H290001]; Zhejiang Province Traditional Chinese
   Medicine Science and Technology Project [2023ZL362]
FX We appreciate great support from the Public Platform of Pharmaceutical
   Research Center, Academy of Chinese Medical Science, Zhejiang Chinese
   Medical University. We gratefully acknowledge the great experimental
   support from the Public Platform of Medical Research Center, Academy of
   Chinese Med- ical Science, Zhejiang Chinese Medical University. This
   work was funded by the National Natural Science Foundation of China
   (82174095) , the Natural Science Foundation of Zhejiang Province
   (LZ22H290001) , and the Zhejiang Province Traditional Chinese Medicine
   Science and Technology Project (2023ZL362) .
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NR 26
TC 4
Z9 4
U1 3
U2 13
PU PERGAMON-ELSEVIER SCIENCE LTD
PI OXFORD
PA THE BOULEVARD, LANGFORD LANE, KIDLINGTON, OXFORD OX5 1GB, ENGLAND
SN 0006-2952
EI 1873-2968
J9 BIOCHEM PHARMACOL
JI Biochem. Pharmacol.
PD MAY
PY 2024
VL 223
AR 116139
DI 10.1016/j.bcp.2024.116139
EA MAR 2024
PG 9
WC Pharmacology & Pharmacy
WE Science Citation Index Expanded (SCI-EXPANDED)
SC Pharmacology & Pharmacy
GA PW9P8
UT WOS:001217239800001
PM 38499109
DA 2025-03-13
ER

PT J
AU Capparelli, C
   Chiavarina, B
   Whitaker-Menezes, D
   Pestell, TG
   Pestell, RG
   Hulit, J
   Andò, S
   Howell, A
   Martinez-Outschoorn, UE
   Sotgia, F
   Lisanti, MP
AF Capparelli, Claudia
   Chiavarina, Barbara
   Whitaker-Menezes, Diana
   Pestell, Timothy G.
   Pestell, Richard G.
   Hulit, James
   Ando, Sebastiano
   Howell, Anthony
   Martinez-Outschoorn, Ubaldo E.
   Sotgia, Federica
   Lisanti, Michael P.
TI CDK inhibitors (p16/p19/p21) induce senescence and autophagy in
   cancer-associated fibroblasts, "fueling" tumor growth via paracrine
   interactions, without an increase in neo-angiogenesis
SO CELL CYCLE
LA English
DT Article
DE aging; CDK inhibitors; cell cycle arrest; senescence; tumor stroma;
   cancer-associated fibroblast; glycolysis; autophagy; mitophagy; cancer
   metabolism; tumor initiation; PD0332991
ID PRIMARY BILIARY-CIRRHOSIS; INDEPENDENT CELL-DEATH; HUMAN BREAST-CANCER;
   OXIDATIVE STRESS; MITOCHONDRIAL METABOLISM; PREMATURE SENESCENCE;
   AEROBIC GLYCOLYSIS; STROMAL CAVEOLIN-1; HYDROGEN-PEROXIDE; KETONE
   PRODUCTION
AB Here, we investigated the compartment-specific role of cell cycle arrest and senescence in breast cancer tumor growth. For this purpose, we generated a number of hTE RT-immortalized senescent fibroblast cell lines overexpressing CDK inhibitors, such as p16(INK4A), p19(ARF) or p21(WAF1/CIP1). Interestingly, all these senescent fibroblast cell lines showed evidence of increased susceptibility toward the induction of autophagy (either at baseline or after starvation), as well as significant mitochondrial dysfunction. Most importantly, these senescent fibroblasts also dramatically promoted tumor growth (up to similar to 2-fold), without any comparable increases in tumor angiogenesis. Conversely, we generated human breast cancer cells (MDA-MB-231 cells) overexpressing CDK inhibitors, namely p16(INK4A) or p21(WAF1/CIP1). Senescent MDA-MB-231 cells also showed increased expression of markers of cell cycle arrest and autophagy, including beta-galactosidase, as predicted. Senescent MDA-MB-231 cells had retarded tumor growth, with up to a near 2-fold reduction in tumor volume. Thus, the effects of CDK inhibitors are compartment-specific and are related to their metabolic effects, which results in the induction of autophagy and mitochondrial dysfunction. Finally, induction of cell cycle arrest with specific inhibitors (PD0332991) or cellular stressors [hydrogen peroxide (H2O2) or starvation] indicated that the onset of autophagy and senescence are inextricably linked biological processes. The compartment-specific induction of senescence (and hence autophagy) may be a new therapeutic target that could be exploited for the successful treatment of human breast cancer patients.
C1 [Capparelli, Claudia; Chiavarina, Barbara; Whitaker-Menezes, Diana; Pestell, Timothy G.; Pestell, Richard G.; Martinez-Outschoorn, Ubaldo E.; Sotgia, Federica; Lisanti, Michael P.] Thomas Jefferson Univ, Jefferson Stem Cell Biol & Regenerat Med Ctr, Kimmel Canc Ctr, Philadelphia, PA 19107 USA.
   [Capparelli, Claudia; Chiavarina, Barbara; Whitaker-Menezes, Diana; Pestell, Timothy G.; Pestell, Richard G.; Martinez-Outschoorn, Ubaldo E.; Sotgia, Federica; Lisanti, Michael P.] Thomas Jefferson Univ, Dept Stem Cell Biol & Regenerat Med Ctr, Kimmel Canc Ctr, Philadelphia, PA 19107 USA.
   [Capparelli, Claudia; Chiavarina, Barbara; Whitaker-Menezes, Diana; Pestell, Timothy G.; Pestell, Richard G.; Martinez-Outschoorn, Ubaldo E.; Sotgia, Federica; Lisanti, Michael P.] Thomas Jefferson Univ, Dept Canc Biol, Kimmel Canc Ctr, Philadelphia, PA 19107 USA.
   [Capparelli, Claudia; Ando, Sebastiano] Univ Calabria, Fac Pharm, I-87036 Cosenza, Italy.
   [Capparelli, Claudia; Ando, Sebastiano] Univ Calabria, Dept Pharmacobiol, I-87036 Cosenza, Italy.
   [Hulit, James; Howell, Anthony; Sotgia, Federica; Lisanti, Michael P.] Univ Manchester, Manchester Breast Ctr, Manchester, Lancs, England.
   [Hulit, James; Howell, Anthony; Sotgia, Federica; Lisanti, Michael P.] Univ Manchester, Breakthrough Breast Canc Res Unit, Paterson Inst Canc Res, Sch Canc Enabling Sci & Technol,Manchester Acad H, Manchester, Lancs, England.
   [Pestell, Richard G.; Martinez-Outschoorn, Ubaldo E.; Lisanti, Michael P.] Thomas Jefferson Univ, Dept Med Oncol, Kimmel Canc Ctr, Philadelphia, PA 19107 USA.
C3 Thomas Jefferson University; Thomas Jefferson University; Thomas
   Jefferson University; University of Calabria; University of Calabria;
   University of Manchester; University of Manchester; Paterson Institute
   for Cancer Research; Thomas Jefferson University
RP Sotgia, F (corresponding author), Thomas Jefferson Univ, Jefferson Stem Cell Biol & Regenerat Med Ctr, Kimmel Canc Ctr, Philadelphia, PA 19107 USA.
EM fsotgia@gmail.com; michaelp.lisanti@gmail.com
RI Martinet, Wim/I-7375-2015; Lisanti, Michael/C-6866-2013; Pestell,
   Richard/JQW-3484-2023
OI Howell, Anthony/0000-0002-6233-719X; Sotgia,
   Federica/0000-0003-2826-4529; Lisanti, Michael/0000-0003-2034-1382;
   Martinez-Outschoorn, Ubaldo/0000-0003-1483-4551
FU Breast Cancer Alliance (BCA); American Cancer Society (ACS); Margaret Q.
   Landenberger Research Foundation; NIH/NCI [R01-CA-080250, R01-CA-098779,
   R01-CA-120876, R01-AR-055660, R01-CA-70896, R01-CA-75503, R01-CA-86072,
   R01-CA-107382]; Susan G. Komen Breast Cancer Foundation; Dr. Ralph and
   Marian C. Falk Medical Research Trust; NIH/NCI Cancer Center Core grant
   [P30-CA-56036]; Pennsylvania Department of Health; Breakthrough Breast
   Cancer in the UK; European Research Council
FX F.S. and her laboratory were supported by grants from the Breast Cancer
   Alliance (BCA) and the American Cancer Society (ACS). U. E. M. was
   supported by a Young Investigator Award from the Margaret Q.
   Landenberger Research Foundation. M. P. L. was supported by grants from
   the NIH/NCI (R01-CA-080250; R01-CA-098779; R01-CA-120876; R01-AR-055660)
   and the Susan G. Komen Breast Cancer Foundation. R. G. P. was supported
   by grants from the NIH/NCI (R01-CA-70896, R01-CA-75503, R01-CA-86072 and
   R01-CA-107382) and the Dr. Ralph and Marian C. Falk Medical Research
   Trust. The Kimmel Cancer Center was supported by the NIH/NCI Cancer
   Center Core grant P30-CA-56036 (to R. G. P.). Funds were also
   contributed by the Margaret Q. Landenberger Research Foundation (to M.
   P. L. and U.E.M.O.). This project is funded, in part, under a grant with
   the Pennsylvania Department of Health (to M. P. L. and F. S.). The
   department specifically disclaims responsibility for any analyses,
   interpretations or conclusions. This work was also supported, in part,
   by a centre grant in Manchester from Breakthrough Breast Cancer in the
   UK (to A. H.) and an Advanced ERC Grant from the European Research
   Council.
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NR 70
TC 173
Z9 199
U1 0
U2 21
PU LANDES BIOSCIENCE
PI AUSTIN
PA 1806 RIO GRANDE ST, AUSTIN, TX 78702 USA
SN 1538-4101
J9 CELL CYCLE
JI Cell Cycle
PD OCT 1
PY 2012
VL 11
IS 19
BP 3599
EP 3610
DI 10.4161/cc.21884
PG 12
WC Cell Biology
WE Science Citation Index Expanded (SCI-EXPANDED)
SC Cell Biology
GA 016JE
UT WOS:000309513300019
PM 22935696
OA Green Published
DA 2025-03-13
ER

PT J
AU Zeng, H
   Hou, YX
   Zhou, XY
   Lang, L
   Luo, HJ
   Sun, Y
   Wan, XY
   Yuan, TX
   Wang, R
   Liu, YC
   Tang, R
   Cheng, SJ
   Xu, M
   Liu, MR
AF Zeng, Huan
   Hou, Yixuan
   Zhou, Xinyue
   Lang, Lei
   Luo, Haojun
   Sun, Yan
   Wan, Xueying
   Yuan, Taixian
   Wang, Rui
   Liu, Yongcan
   Tang, Rui
   Cheng, Shaojie
   Xu, Ming
   Liu, Manran
TI Cancer-associated fibroblasts facilitate premetastatic niche formation
   through lncRNA SNHG5-mediated angiogenesis and vascular permeability in
   breast cancer
SO THERANOSTICS
LA English
DT Article
DE Cancer-associated fibroblasts; premetastatic niche; angiogenesis;
   vascular permeability; lncSNHG5
ID METASTASIS; ACTIVATION; CONTRIBUTE; TUMORS; CELLS
AB Background: Metastasis is the leading cause of death in patients with breast cancer (BC). Primary tumors create a premetastatic niche (PMN) in secondary organs for subsequent metastases. Cancer -associated fibroblasts (CAFs) are a predominant stromal component in the tumor microenvironment and serve as a major contributor to tumor metastasis. However, the function and mechanism of primary CAFs in the premetastatic niche of secondary organs remain unclear in BC.Methods: We investigated the expression profiles of lncRNAs in pairs of CAFs and NFs derived from breast tumor tissues using lncRNA microarray. The expression levels of lncSNHG5, ZNF281, IGF2BP2, CCL2 and CCL5 were assessed by qRT-PCR; the protein levels of related genes (e.g., ZNF281, IGF2BP2, CCL2, and CCL5) were analyzed using western blotting and/or ELISA in primary and immortalized CAFs and clinical samples. Tubule formation and three-dimensional sprouting assays and tissue fluorescence staining were conducted to investigate angiogenesis. In vitro permeability assays, trans-endothelial invasion assays, in vivo permeability assays and tissue fluorescence staining were conducted to examine vascular permeability. The regulatory mechanism of lncSNHG5 was investigated by RNA sequencing, fluorescent in situ hybridization, cellular fractionation assay, mass spectrometry, RNA pull-down, RNA immunoprecipitation, gene-specific m6A assay, chromatin immunoprecipitation, dual luciferase reporter assay and actinomycin D treatment in CAFs and NFs. Results: LncSNHG5 was highly expressed in breast CAFs and played an essential role in premetastatic niche formation by promoting angiogenesis and vascular leakiness through regulation of ZNF281 in CAFs. lncSNHG5 enhanced ZNF281 mRNA stability by binding with the m6A reader IGF2BP2. Enhanced ZNF281 transcriptionally regulated CCL2 and CCL5 expression to activate P38 MAPK signaling in endothelial cells. High CCL2 and CCL5 expression was associated with tumor metastasis and poor prognosis in BC patients. The inhibitors RS102895, marasviroc and cenicriviroc inhibited angiogenesis and vascular permeability in the PMN by blocking the binding of CCL2/CCR2 and CCL5/CCR5. The lncSNHG5-ZNF281-CCL2/CCL5 signaling axis plays an essential role in inducing premetastatic niche formation to promote BC metastasis. Conclusions: Our work demonstrates that lncSNHG5 and its downstream signaling ZNF281-CCL2/CCL5 in CAFs play a crucial role in premetastatic niche formation in breast cancer and may serve as potential targets for the diagnosis and treatment of BC metastasis.
C1 [Zeng, Huan; Zhou, Xinyue; Lang, Lei; Wan, Xueying; Yuan, Taixian; Wang, Rui; Liu, Yongcan; Tang, Rui; Cheng, Shaojie; Xu, Ming; Liu, Manran] Chongqing Med Univ, Key Lab Lab Med Diagnost, Chinese Minist Educ, Chongqing 400016, Peoples R China.
   [Hou, Yixuan] Chongqing Med Univ, Expt Teaching & Lab Management Ctr, Chongqing 400016, Peoples R China.
   [Luo, Haojun] Chongqing Med Univ, Affiliated Hosp 2, Dept Breast & Thyroid Surg, Chongqing 400010, Peoples R China.
   [Sun, Yan] Chongqing Med Univ, Basic Med Sch, Dept Cell Biol & Med Genet, 1 Yi Xue Yuan Rd, Chongqing 400016, Peoples R China.
   [Liu, Manran] Chongqing Med Univ, Key Lab Lab Med Diagnost, Chinese Minist Educ, 1 Yi Xue Yuan Rd, Chongqing 400016, Peoples R China.
C3 Chongqing Medical University; Chongqing Medical University; Chongqing
   Medical University; Chongqing Medical University; Chongqing Medical
   University
RP Liu, MR (corresponding author), Chongqing Med Univ, Key Lab Lab Med Diagnost, Chinese Minist Educ, 1 Yi Xue Yuan Rd, Chongqing 400016, Peoples R China.
EM manranliu@cqmu.edu.cn
RI tangrui, 芮/GQP-0655-2022; zhou, xinyue/JOJ-6874-2023; lang,
   lei/CAA-5992-2022
OI li, lu/0009-0009-8381-3093; lang, lei/0000-0002-1839-0014
FU National Natural Science Foundation of China [NSFC 81773078, NSFC
   81560430]; National Key Projects of the Ministry of Science and
   Technology of China [MOST 2018YFE0113700]; Chongqing Graduate Research
   and Innovation Project (2020) [CYB20161]; NSFC [81472476, 81874199]
FX This work was supported in part by the National Natural Science
   Foundation of China (NSFC 81773078, and NSFC 81560430) for Yixuan Hou;
   partly by the National Key Projects of the Ministry of Science and
   Technology of China (MOST 2018YFE0113700), NSFC 81472476, and NSFC
   81874199 for Manran Liu; and partly supported by the Chongqing Graduate
   Research and Innovation Project (2020) (CYB20161) for Huan Zeng.
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NR 52
TC 55
Z9 61
U1 4
U2 28
PU IVYSPRING INT PUBL
PI LAKE HAVEN
PA PO BOX 4546, LAKE HAVEN, NSW 2263, AUSTRALIA
SN 1838-7640
J9 THERANOSTICS
JI Theranostics
PY 2022
VL 12
IS 17
BP 7351
EP 7370
DI 10.7150/thno.74753
PG 20
WC Medicine, Research & Experimental
WE Science Citation Index Expanded (SCI-EXPANDED)
SC Research & Experimental Medicine
GA 5V6YV
UT WOS:000877374600010
PM 36438499
OA Green Published, gold
DA 2025-03-13
ER

PT J
AU Al-Kharashi, LA
   Bakheet, T
   AlHarbi, WA
   Al-Moghrabi, N
   Aboussekhra, A
AF Al-Kharashi, Layla A.
   Bakheet, Tala
   AlHarbi, Wejdan A.
   Al-Moghrabi, Nisreen
   Aboussekhra, Abdelilah
TI Eugenol modulates genomic methylation and inactivates breast
   cancer-associated fibroblasts through E2F1-dependent downregulation of
   DNMT1/DNMT3A
SO MOLECULAR CARCINOGENESIS
LA English
DT Article
DE breast cancer; cancer-associated fibroblasts; DNMT1; eugenol;
   methylation
ID TRANSCRIPTION; INHIBITION
AB Active cancer-associated fibroblasts (CAFs) are major components of the tumor microenvironment, which promote carcinogenesis and modulate response to therapy. Therefore, targeting these cells or reducing their paracrine pro-carcinogenic effects could be of great therapeutic value. To this end, we sought to investigate the effect of eugenol, a natural phenolic molecule, on active breast CAFs. We have shown that decitabine (5-Aza-2 '-deoxycytidine, DAC) and eugenol inhibit the expression of the DNA methyltransferase genes DNMT1 and DNMT3A at both the protein and mRNA levels in breast CAF cells. While the effect of eugenol was persistent, DAC had only a transient inhibitory effect on the mRNA level of both DNMT genes. Furthermore, eugenol and DAC suppressed the invasive/migratory and proliferative potential of CAF cells as well as their paracrine pro-carcinogenic effects both in vitro and in humanized orthotopic tumor xenografts. Interestingly, these inhibitory effects of decitabine and eugenol were mediated through E2F1 downregulation. Indeed, ectopic expression of E2F1 upregulated both genes and attenuated the effects of eugenol. Additionally, we provide clear evidence that eugenol, like DAC, strongly modulates the methylation pattern in active CAF cells, through methylating several oncogenes and demethylating various important tumor suppressor genes, which affected their mRNA expression levels. Importantly, the E2F1 promoter was also hypermethylated and the gene downregulated in response to eugenol. Together, these findings show that the active features of breast CAF cells can be normalized through eugenol-dependent targeting of DNMT1/DNMT3A and the consequent modulation in gene methylation.
C1 [Al-Kharashi, Layla A.; AlHarbi, Wejdan A.; Al-Moghrabi, Nisreen; Aboussekhra, Abdelilah] King Faisal Specialist Hosp & Res Ctr, Dept Mol Oncol, MBC 03,POB 3354, Riyadh 11211, Saudi Arabia.
   [Al-Kharashi, Layla A.] King Saud Univ, Fac Pharm, Dept Pharmacol & Toxicol, Riyadh, Saudi Arabia.
   [Bakheet, Tala] King Faisal Specialist Hosp & Res Ctr, Res Ctr, Dept Mol BioMed, Riyadh, Saudi Arabia.
C3 King Faisal Specialist Hospital & Research Center; King Saud University;
   King Faisal Specialist Hospital & Research Center
RP Aboussekhra, A (corresponding author), King Faisal Specialist Hosp & Res Ctr, Dept Mol Oncol, MBC 03,POB 3354, Riyadh 11211, Saudi Arabia.
EM aboussekhra@kfshrc.edu.sa
RI Aboussekhra, Abdelilah/JCD-8138-2023; Alkharashi, Layla/F-2598-2018
FU Research Center Administration; RAC [2160005]; King Faisal Specialist
   Hospital & Research Center.
FX The authors are thankful to the Comparative Medicine staff for their
   help with animal experiments. The authors also appreciate the continuous
   support of the Research Center Administration. This study was performed
   under RAC#2160005, and was supported in totality by the King Faisal
   Specialist Hospital & Research Center.
CR Al-Ansari MM, 2014, PLOS ONE, V9, DOI 10.1371/journal.pone.0090907
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NR 26
TC 20
Z9 20
U1 0
U2 7
PU WILEY
PI HOBOKEN
PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA
SN 0899-1987
EI 1098-2744
J9 MOL CARCINOGEN
JI Mol. Carcinog.
PD NOV
PY 2021
VL 60
IS 11
BP 784
EP 795
DI 10.1002/mc.23344
EA SEP 2021
PG 12
WC Biochemistry & Molecular Biology; Oncology
WE Science Citation Index Expanded (SCI-EXPANDED)
SC Biochemistry & Molecular Biology; Oncology
GA WG7PG
UT WOS:000693305500001
PM 34473867
DA 2025-03-13
ER

PT J
AU Migneco, G
   Whitaker-Menezes, D
   Chiavarina, B
   Castello-Cros, R
   Pavlides, S
   Pestell, RG
   Fatatis, A
   Flomenberg, N
   Tsirigos, A
   Howell, A
   Martinez-Outschoorn, UE
   Sotgia, F
   Lisanti, MP
AF Migneco, Gemma
   Whitaker-Menezes, Diana
   Chiavarina, Barbara
   Castello-Cros, Remedios
   Pavlides, Stephanos
   Pestell, Richard G.
   Fatatis, Alessandro
   Flomenberg, Neal
   Tsirigos, Aristotelis
   Howell, Anthony
   Martinez-Outschoorn, Ubaldo E.
   Sotgia, Federica
   Lisanti, Michael P.
TI Glycolytic cancer associated fibroblasts promote breast cancer tumor
   growth, without a measurable increase in angiogenesis Evidence for
   stromal-epithelial metabolic coupling
SO CELL CYCLE
LA English
DT Article
DE caveolin-1; tumor stroma; glycolytic fibroblasts; cancer associated
   fibroblasts; aerobic glycolysis; hexokinase; enolase; pyruvate kinase;
   lactate dehydrogenase; the Warburg effect; H-Ras (G12V)
ID PROSTATE-CANCER; EXPRESSION; CAVEOLIN-1; DISEASE; ABSENCE; SYSTEM; CELLS
AB Previously, we proposed a new model for understanding the Warburg effect in tumorigenesis and metastasis. In this model, the stromal fibroblasts would undergo aerobic glycolysis (a.k.a., the Warburg effect)-producing and secreting increased pyruvate/lactate that could then be used by adjacent epithelial cancer cells as "fuel" for the mitochondrial TCA cycle, oxidative phosphorylation, and ATP production. to test this model more directly, here we used a matched set of metabolically well-characterized immortalized fibroblasts that differ in a single gene. CL3 fibroblasts show a shift towards oxidative metabolism, and have an increased mitochondrial mass. In contrast, CL4 fibroblasts show a shift towards aerobic glycolysis, and have a reduced mitochondrial mass. We validated these differences in CL3 and CL4 fibroblasts by performing an unbiased proteomics analysis, showing the functional upregulation of 4 glycolytic enzymes, namely ENO1, ALDOA, LDHA and TPI1, in CL4 fibroblasts. Many of the proteins that were upregulated in CL4 fibroblasts, as seen by unbiased proteomics, were also transcriptionally upregulated in the stroma of human breast cancers, especially in the patients that were prone to metastasis. Importantly, when CL4 fibroblasts were co-injected with human breast cancer cells (MDA-MB-231) in a xenograft model, tumor growth was dramatically enhanced. CL4 fibroblasts induced a >4-fold increase in tumor mass, and a near 8-fold increase in tumor volume, without any measurable increases in tumor angiogenesis. In parallel, CL3 and CL4 fibroblasts both failed to form tumors when they were injected alone, without epithelial cancer cells. Mechanistically, under co-culture conditions, CL4 glycolytic fibroblasts increased mitochondrial activity in adjacent breast cancer cells (relative to CL3 cells), consistent with the "Reverse Warburg effect". Notably, Western blot analysis of CL4 fibroblasts revealed a significant reduction in caveolin-1 (Cav-1) protein levels. In human breast cancer patients, a loss of stromal Cav-1 is associated with an increased risk of early tumor recurrence, metastasis, tamoxifen-resistance, and poor clinical outcome. thus, loss of stromal Cav-1 may be an effective marker for predicting the "Reverse Warburg effect" in the stroma of human breast cancer patients. As such, CL4 fibroblasts are a new attractive model for mimicking the "glycolytic phenotype" of cancer-associated fibroblasts. Nutrients derived from glycolytic cancer associated fibroblasts could provide an escape mechanism to confer drug-resistance during anti-angiogenic therapy, by effectively reducing the dependence of cancer cells on a vascular blood supply.
C1 [Migneco, Gemma; Whitaker-Menezes, Diana; Chiavarina, Barbara; Castello-Cros, Remedios; Pavlides, Stephanos; Pestell, Richard G.; Martinez-Outschoorn, Ubaldo E.; Sotgia, Federica; Lisanti, Michael P.] Thomas Jefferson Univ, Dept Stem Cell Biol & Regenerat Med, Philadelphia, PA 19107 USA.
   [Migneco, Gemma; Whitaker-Menezes, Diana; Chiavarina, Barbara; Castello-Cros, Remedios; Pavlides, Stephanos; Pestell, Richard G.; Martinez-Outschoorn, Ubaldo E.; Sotgia, Federica; Lisanti, Michael P.] Thomas Jefferson Univ, Dept Canc Biol, Philadelphia, PA 19107 USA.
   [Migneco, Gemma; Whitaker-Menezes, Diana; Chiavarina, Barbara; Castello-Cros, Remedios; Pavlides, Stephanos; Pestell, Richard G.; Martinez-Outschoorn, Ubaldo E.; Sotgia, Federica; Lisanti, Michael P.] Thomas Jefferson Univ, Jefferson Stem Cell Biol & Regenerat Med Ctr, Philadelphia, PA 19107 USA.
   Thomas Jefferson Univ, Dept Pathol Anat & Cell Biol, Philadelphia, PA 19107 USA.
   [Flomenberg, Neal; Martinez-Outschoorn, Ubaldo E.; Lisanti, Michael P.] Thomas Jefferson Univ, Dept Med Oncol, Kimmel Canc Ctr, Philadelphia, PA 19107 USA.
   [Fatatis, Alessandro] Drexel Univ, Coll Med, Dept Pharmacol & Physiol, Philadelphia, PA 19104 USA.
   [Fatatis, Alessandro] Drexel Univ, Coll Med, Dept Pathol & Lab Med, Philadelphia, PA 19104 USA.
   [Tsirigos, Aristotelis] IBM Corp, Thomas J Watson Res Ctr, Computat Genom Grp, Yorktown Hts, NY 10598 USA.
   [Howell, Anthony; Sotgia, Federica; Lisanti, Michael P.] Univ Manchester, Manchester Breast Ctr, Manchester M13 9PL, Lancs, England.
   [Howell, Anthony; Sotgia, Federica; Lisanti, Michael P.] Univ Manchester, Breakthrough Breast Canc Res Unit, Paterson Inst Canc Res, Sch Canc Enabling Sci & Technol,Manchester Acad H, Manchester M13 9PL, Lancs, England.
C3 Thomas Jefferson University; Thomas Jefferson University; Thomas
   Jefferson University; Thomas Jefferson University; Thomas Jefferson
   University; Drexel University; Drexel University; International Business
   Machines (IBM); IBM USA; University of Manchester; University of
   Manchester; Paterson Institute for Cancer Research
RP Sotgia, F (corresponding author), Thomas Jefferson Univ, Dept Stem Cell Biol & Regenerat Med, Philadelphia, PA 19107 USA.
EM federica.sotgia@jefferson.edu; michael.lisanti@kimmelcancercenter.org
RI Pavlides, Stephanos/F-9673-2011; Lisanti, Michael/C-6866-2013; Pestell,
   Richard/JQW-3484-2023; Martinet, Wim/I-7375-2015
OI Martinez-Outschoorn, Ubaldo/0000-0003-1483-4551; Tsirigos,
   Aristotelis/0000-0002-7512-8477; Sotgia, Federica/0000-0003-2826-4529;
   Howell, Anthony/0000-0002-6233-719X
FU NIH/NCI [R01-CA-080250, R01-CA-098779, R01-CA-120876, R01-AR-055660,
   R01-CA-70896, R01-CA-75503, R01-CA-86072, R01-CA-107382]; Susan G. Komen
   Breast Cancer Foundation; W.W. Smith Charitable Trust; Breast Cancer
   Alliance (BCA); American Cancer Society (ACS); Dr. Ralph and Marian C.
   Falk Medical Research Trust; NIH/NCI Cancer Center Core [P30-CA-56036];
   Margaret Q. Landenberger Research Foundation; Pennsylvania Department of
   Health; Breakthrough Breast Cancer in the U.K.; European Research
   Council
FX M. P. L. and his laboratory were supported by grants from the NIH/NCI
   (R01-CA-080250; R01-CA-098779; R01-CA-120876; R01-AR-055660), and the
   Susan G. Komen Breast Cancer Foundation. F. S. was supported by grants
   from the W.W. Smith Charitable Trust, the Breast Cancer Alliance (BCA),
   and a Research Scholar Grant from the American Cancer Society (ACS). R.
   G. P. was supported by grants from the NIH/NCI (R01-CA-70896,
   R01-CA-75503, R01-CA-86072 and R01-CA-107382) and the Dr. Ralph and
   Marian C. Falk Medical Research Trust. The Kimmel Cancer Center was
   supported by the NIH/NCI Cancer Center Core grant P30-CA-56036 (to R. G.
   P.). Funds were also contributed by the Margaret Q. Landenberger
   Research Foundation (to M. P. L.). This project is funded, in part,
   under a grant with the Pennsylvania Department of Health (to M. P. L.).
   The Department specifically disclaims responsibility for any analyses,
   interpretations or conclusions. This work was also supported, in part,
   by a Centre grant in Manchester from Breakthrough Breast Cancer in the
   U.K. (to A. H.) and an Advanced ERC Grant from the European Research
   Council.
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NR 20
TC 120
Z9 140
U1 1
U2 23
PU TAYLOR & FRANCIS INC
PI PHILADELPHIA
PA 530 WALNUT STREET, STE 850, PHILADELPHIA, PA 19106 USA
SN 1538-4101
EI 1551-4005
J9 CELL CYCLE
JI Cell Cycle
PD JUN 15
PY 2010
VL 9
IS 12
BP 2412
EP 2422
DI 10.4161/cc.9.12.11989
PG 11
WC Cell Biology
WE Science Citation Index Expanded (SCI-EXPANDED)
SC Cell Biology
GA 615QC
UT WOS:000279149000030
PM 20562527
DA 2025-03-13
ER

PT J
AU Boyle, ST
   Poltavets, V
   Kular, J
   Pyne, NT
   Sandow, JJ
   Lewis, AC
   Murphy, KJ
   Kolesnikoff, N
   Moretti, PAB
   Tea, MN
   Tergaonkar, V
   Timpson, P
   Pitson, SM
   Webb, AI
   Whitfield, RJ
   Lopez, AF
   Kochetkova, M
   Samuel, MS
AF Boyle, Sarah Theresa
   Poltavets, Valentina
   Kular, Jasreen
   Pyne, Natasha Theresa
   Sandow, Jarrod John
   Lewis, Alexander Charles
   Murphy, Kendelle Joan
   Kolesnikoff, Natasha
   Moretti, Paul Andre Bartholomew
   Tea, Melinda Nay
   Tergaonkar, Vinay
   Timpson, Paul
   Pitson, Stuart Maxwell
   Webb, Andrew Ian
   Whitfield, Robert John
   Lopez, Angel Francisco
   Kochetkova, Marina
   Samuel, Michael Susithiran
TI ROCK-mediated selective activation of PERK signalling causes fibroblast
   reprogramming and tumour progression through a CRELD2-dependent
   mechanism
SO NATURE CELL BIOLOGY
LA English
DT Article
ID RHO-ASSOCIATED KINASE; CARCINOMA-ASSOCIATED FIBROBLASTS;
   CANCER-ASSOCIATED FIBROBLASTS; UNFOLDED PROTEIN RESPONSE; TISSUE
   STIFFNESS; HUMAN BREAST; ER STRESS; EXPRESSION; MYOSIN; INHIBITION
AB Boyle et al. show that ROCK upregulates PERK signalling in epithelia of breast cancer, thereby enhancing recruitment and function of cancer-associated fibroblasts through CRELD2 to promote tumourigenesis.
   It is well accepted that cancers co-opt the microenvironment for their growth. However, the molecular mechanisms that underlie cancer-microenvironment interactions are still poorly defined. Here, we show that Rho-associated kinase (ROCK) in the mammary tumour epithelium selectively actuates protein-kinase-R-like endoplasmic reticulum kinase (PERK), causing the recruitment and persistent education of tumour-promoting cancer-associated fibroblasts (CAFs), which are part of the cancer microenvironment. An analysis of tumours from patients and mice reveals that cysteine-rich with EGF-like domains 2 (CRELD2) is the paracrine factor that underlies PERK-mediated CAF education downstream of ROCK. We find that CRELD2 is regulated by PERK-regulated ATF4, and depleting CRELD2 suppressed tumour progression, demonstrating that the paracrine ROCK-PERK-ATF4-CRELD2 axis promotes the progression of breast cancer, with implications for cancer therapy.
C1 [Boyle, Sarah Theresa; Poltavets, Valentina; Kular, Jasreen; Pyne, Natasha Theresa; Lewis, Alexander Charles; Kolesnikoff, Natasha; Moretti, Paul Andre Bartholomew; Tea, Melinda Nay; Tergaonkar, Vinay; Pitson, Stuart Maxwell; Lopez, Angel Francisco; Kochetkova, Marina; Samuel, Michael Susithiran] SA Pathol, Ctr Canc Biol, Adelaide, SA, Australia.
   [Boyle, Sarah Theresa; Poltavets, Valentina; Kular, Jasreen; Pyne, Natasha Theresa; Lewis, Alexander Charles; Kolesnikoff, Natasha; Moretti, Paul Andre Bartholomew; Tea, Melinda Nay; Pitson, Stuart Maxwell; Lopez, Angel Francisco; Kochetkova, Marina; Samuel, Michael Susithiran] Univ South Australia, Adelaide, SA, Australia.
   [Sandow, Jarrod John; Webb, Andrew Ian] Walter & Eliza Hall Inst Med Res, Div Syst Biol & Personalised Med, Parkville, Vic, Australia.
   [Sandow, Jarrod John] Univ Melbourne, Dept Med Biol, Parkville, Vic, Australia.
   [Murphy, Kendelle Joan] Univ NSW, St Vincents Clin Sch, Garvan Inst Med Res, Sydney, NSW, Australia.
   [Murphy, Kendelle Joan; Timpson, Paul] Univ NSW, St Vincents Clin Sch, Kinghorn Canc Ctr, Canc Div, Sydney, NSW, Australia.
   [Tergaonkar, Vinay; Timpson, Paul] ASTAR, Inst Mol & Cell Biol, Singapore, Singapore.
   [Tergaonkar, Vinay] Natl Univ Singapore, Yong Loo Lin Sch Med, Dept Pathol, Singapore, Singapore.
   [Pitson, Stuart Maxwell; Samuel, Michael Susithiran] Univ Adelaide, Fac Hlth & Med Sci, Adelaide Med Sch, Adelaide, SA, Australia.
   [Whitfield, Robert John] Royal Adelaide Hosp, Breast Endocrine & Surg Oncol Unit, Adelaide, SA, Australia.
   [Lewis, Alexander Charles] Peter MacCallum Canc Ctr, Translat Haematol Program, Melbourne, Vic, Australia.
C3 SA Pathology; Centre for Cancer Biology; University of South Australia;
   Walter & Eliza Hall Institute; University of Melbourne; Garvan Institute
   of Medical Research; University of New South Wales Sydney; The Kinghorn
   Cancer Centre; University of New South Wales Sydney; Agency for Science
   Technology & Research (A*STAR); A*STAR - Institute of Molecular & Cell
   Biology (IMCB); National University of Singapore; University of
   Adelaide; Royal Adelaide Hospital; Peter Maccallum Cancer Center
RP Kochetkova, M; Samuel, MS (corresponding author), SA Pathol, Ctr Canc Biol, Adelaide, SA, Australia.; Kochetkova, M; Samuel, MS (corresponding author), Univ South Australia, Adelaide, SA, Australia.; Samuel, MS (corresponding author), Univ Adelaide, Fac Hlth & Med Sci, Adelaide Med Sch, Adelaide, SA, Australia.
EM Marina.Kochetkova@unisa.edu.au; Michael.Samuel@unisa.edu.au
RI Timpson, Paul/A-9429-2016; Kochetkova, Marina/ABE-9538-2021; Lopez,
   Angel/E-2260-2011; Pitson, Stuart/B-9342-2009; Samuel,
   Michael/D-2706-2011; Boyle, Sarah/B-3048-2019
OI Prizzi, Natasha/0000-0003-4314-4779; Pitson, Stuart/0000-0002-9527-2740;
   Poltavets, Valentina/0000-0003-1976-7765; Webb,
   Andrew/0000-0001-5061-6995; Lopez, Angel F/0000-0001-7430-0135; Kular,
   Jasreen/0000-0002-9123-7411; Samuel, Michael/0000-0001-7880-6379;
   Kochetkova, Marina/0000-0002-0599-7378; Boyle,
   Sarah/0000-0001-6143-9285; Timpson, Paul/0000-0002-5514-7080; Tea,
   Melinda/0000-0001-7045-1198; Murphy, Kendelle/0000-0002-3234-3812
FU NHMRC; ARC; Cancer Council of South Australia; Cancer Council of New
   South Wales; RAH Research Fund; Fay Fuller Foundation; RAH Research
   Committee Early Career Fellowship; Australian Cancer Research Foundation
   (Cancer Discovery Accelerator)
FX We thank J. Visvader for mouse mammary cancer tissue; P. Thomas for
   providing CRISPR vector pDG461; and M. White for assistance in designing
   CRISPR guides. The PyMT mammary cancer cell line was provided by K.
   Blyth through SEARCHBreast (https://searchbreast.org/).This research was
   supported by the NHMRC (to M.S.S., P.T., S.M.P., A.F.L. and M.K.), ARC
   (to M.S.S. and P.T.), the Cancer Councils of South Australia (M.S.S.)
   and New South Wales (P.T.), the RAH Research Fund (M.S.S.) and the Fay
   Fuller Foundation (S.M.P). S.T.B. was supported by a RAH Research
   Committee Early Career Fellowship. We thank donors to the Health
   Services Charitable Gifts Board of SA and the Australian Cancer Research
   Foundation (Cancer Discovery Accelerator) for funding the imaging
   equipment used.
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NR 70
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Z9 53
U1 3
U2 29
PU NATURE PORTFOLIO
PI BERLIN
PA HEIDELBERGER PLATZ 3, BERLIN, 14197, GERMANY
SN 1465-7392
EI 1476-4679
J9 NAT CELL BIOL
JI Nat. Cell Biol.
PD JUL
PY 2020
VL 22
IS 7
BP 882
EP +
DI 10.1038/s41556-020-0523-y
EA MAY 2020
PG 32
WC Cell Biology
WE Science Citation Index Expanded (SCI-EXPANDED)
SC Cell Biology
GA MH4LS
UT WOS:000535642600002
PM 32451439
DA 2025-03-13
ER

PT J
AU Zhang, XN
   Liang, S
   Wang, EZ
   Tao, N
AF Zhang, Xiangnan
   Liang, Shuo
   Wang, Enze
   Tao, Ning
TI Fibroblasts and mouse breast cancer cells can form cellular aggregates
   in improved soft agar culture medium
SO MOLECULAR AND CELLULAR BIOCHEMISTRY
LA English
DT Article
DE Cancer-associated fibroblast; Breast cancer cell; Soft agar culture;
   Cellular aggregate
ID TUMOR; EXOSOMES; GROWTH
AB We aimed to build cellular aggregates of TS/A and normal fibroblasts (LX-2) or CAFs (ME-iLX-2), verifying the value of this model in the screening of anticancer drugs and demonstrating the effect of CD44 on aggregate formation. We improved soft agar culture medium to coculture CAFs (NFs) and TS/A and compared the amount and area of cellular aggregates. Eugenol was added to this model to test its value. The transcription of human CD44 was analyzed through RT-qPCR. Cellular aggregates were formed, and both the amount and area of aggregates in the TS/A-ME-iLX-2 coculture group were higher than those in other groups. The eugenol inhibited the formation of TS/A-fibroblasts aggregates. Human CD44 was highly transcripted in TS/A-ME-iLX-2 aggregates. Cocultured cellular aggregates of fibroblasts and TS/A were successfully formed in the improved soft agar culture medium, and the promotion effect of CAFs on cancer cells was further confirmed. The eugenol test showed its value in the screening of anticancer drugs. The RT-qPCR results demonstrated the important effect of CD44 on aggregate formation.
C1 [Zhang, Xiangnan] Beijing Niulanshan First Secondary Sch, Beijing, Peoples R China.
   [Liang, Shuo] Beijing Dayu Sch, Beijing, Peoples R China.
   [Wang, Enze] Beijing 4 High Sch, Beijing, Peoples R China.
   [Tao, Ning] Chinese Acad Sci, Inst Biophys, Key Lab Prot & Peptide Pharmaceut, 15 Datun Rd, Beijing, Peoples R China.
C3 Chinese Academy of Sciences; Institute of Biophysics, CAS
RP Tao, N (corresponding author), Chinese Acad Sci, Inst Biophys, Key Lab Prot & Peptide Pharmaceut, 15 Datun Rd, Beijing, Peoples R China.
EM tao@ibp.ac.cn
RI Tao, Ning/AAK-7068-2021; Wang, Enze/AAG-8233-2021
OI Wang, Enze/0009-0005-4785-5115; Zhang, Xiangnan/0000-0003-4433-3686
FU Science & Technology Training Program for Adolescents in Beijing
FX We are grateful to The Science & Technology Training Program for
   Adolescents in Beijing for its financial support.
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TC 0
Z9 0
U1 1
U2 12
PU SPRINGER
PI DORDRECHT
PA VAN GODEWIJCKSTRAAT 30, 3311 GZ DORDRECHT, NETHERLANDS
SN 0300-8177
EI 1573-4919
J9 MOL CELL BIOCHEM
JI Mol. Cell. Biochem.
PD JUL
PY 2023
VL 478
IS 7
BP 1457
EP 1464
DI 10.1007/s11010-022-04603-0
EA NOV 2022
PG 8
WC Cell Biology
WE Science Citation Index Expanded (SCI-EXPANDED)
SC Cell Biology
GA H3CM5
UT WOS:000881660300001
PM 36357641
DA 2025-03-13
ER

PT J
AU Tang, X
   Hou, Y
   Yang, G
   Wang, X
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   Du, YE
   Yang, L
   Yu, T
   Zhang, H
   Zhou, M
   Wen, S
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   Liu, M
AF Tang, X.
   Hou, Y.
   Yang, G.
   Wang, X.
   Tang, S.
   Du, Y-E
   Yang, L.
   Yu, T.
   Zhang, H.
   Zhou, M.
   Wen, S.
   Xu, L.
   Liu, M.
TI Stromal miR-200s contribute to breast cancer cell invasion through CAF
   activation and ECM remodeling
SO CELL DEATH AND DIFFERENTIATION
LA English
DT Article
ID MESENCHYMAL TRANSITION; EXTRACELLULAR-MATRIX; NORMAL FIBROBLASTS; LYSYL
   OXIDASE; EXPRESSION; TUMOR; MIGRATION; MICROENVIRONMENT;
   DIFFERENTIATION; MAINTENANCE
AB The activation of cancer-associated fibroblasts (CAFs) is a key event in tumor progression, and alternative extracellular matrix (ECM) proteins derived from CAFs induce ECM remodeling and cancer cell invasion. Here we found that miR-200 s, which are generally downregulated in activated CAFs in breast cancer tissues and in normal fibroblasts (NFs) activated by breast cancer cells, are direct mediators of NF reprogramming into CAFs and of ECM remodeling. NFs with downregulated miR-200 s displayed the traits of activated CAFs, including accelerated migration and invasion. Ectopic expression of miR-200 s in CAFs at least partially restored the phenotypes of NFs. CAF activation may be governed by the targets of miR-200 s, Fli-1 and TCF12, which are responsible for cell development and differentiation; Fli-1 and TCF12 were obviously elevated in CAFs. Furthermore, miR-200 s and their targets influenced collagen contraction by CAFs. The upregulation of fibronectin and lysyl oxidase directly by miR-200 or indirectly through Fli-1 or TCF12 contributed to ECM remodeling, triggering the invasion and metastasis of breast cancer cells both in vitro and vivo. Thus, these data provide important and novel insights into breast CAF activation and ECM remodeling, which trigger tumor cell invasion.
C1 [Tang, X.; Tang, S.; Du, Y-E; Yang, L.; Zhang, H.; Zhou, M.; Wen, S.; Xu, L.; Liu, M.] Chongqing Med Univ, Chinese Minist Educ, Key Lab Lab Med Diagnost, Chongqing 400016, Peoples R China.
   [Hou, Y.] Chongqing Med Univ, Expt Teaching Ctr Basic Med Sci, Chongqing 400016, Peoples R China.
   [Yang, G.; Yu, T.] Chongqing Med Univ, Affiliated Hosp 1, Dept Endocrine & Breast Surg, Chongqing 400016, Peoples R China.
   [Wang, X.] Chongqing Med Univ, Affiliated Hosp 2, Dept Orthopaed, Chongqing 400010, Peoples R China.
C3 Chongqing Medical University; Chongqing Medical University; Chongqing
   Medical University; Chongqing Medical University
RP Liu, M (corresponding author), Chongqing Med Univ, Chinese Minist Educ, Key Lab Lab Med Diagnost, 1 Yi Xue Yuan Rd, Chongqing 400016, Peoples R China.
EM mliu-hncq@hotmail.com
FU National Natural Science Foundation of China [NSFC 81402180, NSFC
   81472476, NSFC 81072147]; Ministry of Education, China [20125503110001];
   Scientific Research Foundation for the Returned Overseas Chinese
   Scholars, Ministry of Education, China [[2011] 508]
FX This work was supported in part by the National Natural Science
   Foundation of China (NSFC 81402180, NSFC 81472476 and NSFC 81072147),
   the Doctoral Fund of the Ministry of Education, China (20125503110001)
   and the Scientific Research Foundation for the Returned Overseas Chinese
   Scholars, Ministry of Education, China ([2011] 508).
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NR 48
TC 150
Z9 167
U1 2
U2 35
PU NATURE PUBLISHING GROUP
PI LONDON
PA MACMILLAN BUILDING, 4 CRINAN ST, LONDON N1 9XW, ENGLAND
SN 1350-9047
EI 1476-5403
J9 CELL DEATH DIFFER
JI Cell Death Differ.
PD JAN
PY 2016
VL 23
IS 1
BP 132
EP 145
DI 10.1038/cdd.2015.78
PG 14
WC Biochemistry & Molecular Biology; Cell Biology
WE Science Citation Index Expanded (SCI-EXPANDED)
SC Biochemistry & Molecular Biology; Cell Biology
GA DA8NM
UT WOS:000368062000005
PM 26068592
OA hybrid, Green Published
DA 2025-03-13
ER

PT J
AU Samoudi, A
   Abolhasani-Zadeh, F
   Afgar, A
   Jalilian, E
   Zeinalynezhad, H
   Langroudi, L
AF Samoudi, Arash
   Abolhasani-Zadeh, Firoozeh
   Afgar, Ali
   Jalilian, Elnaz
   Zeinalynezhad, Hamid
   Langroudi, Ladan
TI Treatment of cancer-associated fibroblast-like cells with celecoxib
   enhances the anti-cancer T helper 1/Treg responses in breast cancer
SO NAUNYN-SCHMIEDEBERGS ARCHIVES OF PHARMACOLOGY
LA English
DT Article; Early Access
DE Tumor microenvironment; Cancer-associated fibroblasts; Cycloxygenase-2;
   Celecoxib; Immunotherapy
ID TUMOR-ASSOCIATED MACROPHAGES; PROSTAGLANDIN E-2; DENDRITIC CELLS;
   EXPRESSION; COX-2; CYCLOOXYGENASE-2; INHIBITOR; PGE(2); PROLIFERATION;
   INFLAMMATION
AB Tumor inflammation, as one of the hallmarks of cancer, has been the target for anti-cancer treatments. Celecoxib is a selective inhibitor of the enzyme cycloxygenase-2 (COX-2) and inhibits the production of PGE2, which is an important mediator of tumor inflammation produced by cancer cells and cells of the tumor microenvironment. In this study, we aimed at inhibiting COX-2 using celecoxib, expressed in cancer-associated fibroblast (CAF)-like cells isolated from breast cancer and evaluated the alterations in their cytokine profile and gene expression. CAF-like cells were isolated by explant culture from 13 breast cancer tissues. Simultaneously, peripheral blood mononuclear cells (PBMCs) were isolated from patients' blood. CAF-like cells were treated with 10 mu M of celecoxib and expression of genes COX-2, smooth muscle actin-alpha (alpha-SMA), and production of prostaglandin E2 (PGE2), Interleukin 10 (IL10), and transforming growth factor beta1 (TGF-beta 1) was evaluated. Next, PBMCs were co-cultured with celecoxib-treated CAF-like cells and the expression of genes T-bet, Foxp3, GATA-3; production of cytokines IFN-gamma, IL-10, IL-4, TGF-beta 1, and the mediator PGE2 were assessed by real-time-PCR and ELISA, respectively. Isolated CAF-like cells showed expression of fibroblast activation protein (FAP). Treatment with celecoxib was able to efficiently reduce the production of PGE2 and the expression of alpha-SMA in isolated CAF-like cells. Furthermore, PBMCs in co-culture with these cells showed enhanced Th1 phenotype including T-bet and IFN gamma expression and decreased the phenotypical markers of regulatory T cells such as FoxP3 and IL-10 and TGF-beta 1 production. Our study shows the important role of COX-2 in CAFs by promoting immune suppression. Our results suggested that high expression of COX-2 in CAFs may serve as a new therapeutic, targeting CAFs in enhancing immune responses in breast cancer treatment.
C1 [Samoudi, Arash; Jalilian, Elnaz; Langroudi, Ladan] Kerman Univ Med Sci, Sch Med, Dept Med Immunol, Pajoohesh Sq, Kerman 7616914111, Iran.
   [Abolhasani-Zadeh, Firoozeh; Zeinalynezhad, Hamid] Kerman Univ Med Sci, Sch Med, Dept Surg, Kerman, Iran.
   [Afgar, Ali] Kerman Univ Med Sci, Res Ctr Hydatid Dis Iran, Kerman, Iran.
C3 Kerman University of Medical Sciences; Kerman University of Medical
   Sciences; Kerman University of Medical Sciences
RP Langroudi, L (corresponding author), Kerman Univ Med Sci, Sch Med, Dept Med Immunol, Pajoohesh Sq, Kerman 7616914111, Iran.
EM l.langroudi@kmu.ac.ir
RI Afgar, Ali/C-4702-2019
FU Kerman univ [IR.KMU.REC.1398.257]
FX Kerman univ, IR.KMU.REC.1398.257
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NR 68
TC 0
Z9 0
U1 5
U2 5
PU SPRINGER
PI NEW YORK
PA ONE NEW YORK PLAZA, SUITE 4600, NEW YORK, NY, UNITED STATES
SN 0028-1298
EI 1432-1912
J9 N-S ARCH PHARMACOL
JI Naunyn-Schmiedebergs Arch. Pharmacol.
PD 2024 DEC 9
PY 2024
DI 10.1007/s00210-024-03641-3
EA DEC 2024
PG 14
WC Pharmacology & Pharmacy
WE Science Citation Index Expanded (SCI-EXPANDED)
SC Pharmacology & Pharmacy
GA O7D2Y
UT WOS:001372682300001
PM 39652176
DA 2025-03-13
ER

PT J
AU Al-Ansari, MM
   Hendrayani, SF
   Shehata, AI
   Aboussekhra, A
AF Al-Ansari, M. M.
   Hendrayani, S. F.
   Shehata, A. I.
   Aboussekhra, A.
TI p16<SUP>INK4A</SUP> Represses the paracrine tumor-promoting effects of
   breast stromal fibroblasts
SO ONCOGENE
LA English
DT Article
DE AUF1; breast cancer; cell nonautonomous tumor suppression; p16(INK4A);
   stromal fibroblasts
ID GENE-EXPRESSION; MOLECULAR CHARACTERIZATION; CANCER; SUPPRESSOR;
   MICROENVIRONMENT; CARCINOMAS; P21(WAF1/CIP1); INHIBITION; INDUCTION;
   INVASION
AB Cancer-associated fibroblasts (CAFs), the most abundant and probably the most active cellular component of breast cancer-associated stroma, promote carcinogenesis through paracrine effects; however, the molecular basis remains elusive. We have shown here that p16(INK4A) expression is reduced in 83% CAFs as compared with their normal adjacent counterparts cancer-free tissues isolated from the same patients. This decrease is mainly due to AUF1-dependent higher turnover of the CDKN2A mRNA in CAFs. Importantly, p16(INK4A) downregulation using specific siRNA activated breast fibroblasts and increased the expression/secretion levels of stromal cell-derived factor 1 (SDF-1) and matrix metalloproteinase (MMP)-2. Consequently, media conditioned with these cells stimulated the proliferation of epithelial cells. Furthermore, the migration/invasion of breast cancer cells was also enhanced in an SDF-1-dependent manner. This effect was mediated through inducing an epithelial-mesenchymal transition state. By contrast, increase in p16(INK4A) level through ectopic expression or AUF1 downregulation, reduced the secreted levels of SDF-1 and MMP-2 and suppressed the pro-carcinogenic effects of CAFs. In addition, p16(INK4A)-defective fibroblasts accelerated breast tumor xenograft formation and growth rate in mice. Importantly, tumors formed in the presence of p16(INK4A)-defective fibroblasts exhibited higher levels of active Akt, Cox-2, MMP-2 and MMP-9, showing their greater aggressiveness as compared with xenografts formed in the presence of p16(INK4A)-proficient fibroblasts. These results provide the first indication that p16(INK4A) downregulation in breast stromal fibroblasts is an important step toward their activation.
C1 [Al-Ansari, M. M.; Hendrayani, S. F.; Aboussekhra, A.] Dept Mol Oncol, Riyadh, Saudi Arabia.
   [Shehata, A. I.] King Saud Univ, Dept Microbiol, Riyadh, Saudi Arabia.
C3 King Saud University
RP Aboussekhra, A (corresponding author), King Faisal Specialist Hosp & Res Ctr, DMO, MBC 03-66,POB 3354, Riyadh 11211, Saudi Arabia.
EM aboussekhra@kfshrc.edu.sa
RI Aboussekhra, Abdelilah/JCD-8138-2023; Al-Ansari, Mysoon/K-1915-2013
OI Al-Ansari, Mysoon/0000-0002-2501-691X
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NR 41
TC 64
Z9 70
U1 0
U2 9
PU SPRINGERNATURE
PI LONDON
PA CAMPUS, 4 CRINAN ST, LONDON, N1 9XW, ENGLAND
SN 0950-9232
EI 1476-5594
J9 ONCOGENE
JI Oncogene
PD MAY
PY 2013
VL 32
IS 18
BP 2356
EP 2364
DI 10.1038/onc.2012.270
PG 9
WC Biochemistry & Molecular Biology; Oncology; Cell Biology; Genetics &
   Heredity
WE Science Citation Index Expanded (SCI-EXPANDED)
SC Biochemistry & Molecular Biology; Oncology; Cell Biology; Genetics &
   Heredity
GA 140VF
UT WOS:000318683600012
PM 22751126
OA Green Published, hybrid
DA 2025-03-13
ER

PT J
AU Taralli, S
   Lorusso, M
   Perrone, E
   Perotti, G
   Zagaria, L
   Calcagni, ML
AF Taralli, Silvia
   Lorusso, Margherita
   Perrone, Elisabetta
   Perotti, Germano
   Zagaria, Luca
   Calcagni, Maria Lucia
TI PET/CT with Fibroblast Activation Protein Inhibitors in Breast Cancer:
   Diagnostic and Theranostic Application-A Literature Review
SO CANCERS
LA English
DT Review
DE PET; CT; 68Ga-FAPI; FAPI; breast cancer; theranostics
ID PATIENT; METASTASIS
AB Simple Summary The fibroblast activation protein (FAP) is highly expressed on cancer-associated fibroblasts in many tumors. Radiolabeled FAP inhibitors (FAPIs) have been recently developed as new promising radiotracers in an oncological setting, both as diagnostic imaging by Positron Emission Tomography/Computed Tomography (PET/CT) and as new anti-cancer treatment, in a theranostic perspective. This narrative review aimed to summarize the current evidence on the role of FAPI radiotracers in the diagnostic and therapeutic management of patients with breast cancer (BC). Despite some clinical and methodological heterogeneity among the evaluated studies, Ga-68-FAPI PET/CT emerges as a valuable diagnostic tool in BC patients, demonstrating a general high tumor uptake across all histological and molecular BC subtypes, along with technical advantages and an overall better performance than the standard-of-care F-18-FDG. Moreover, although with still limited clinical evidence, treatment with radiolabeled FAPIs seems a promising approach in BC patients, increasing the possibility of more personalized treatments. Growing studies have recently reported on the promising application of radiolabeled-fibroblast activation protein inhibitors (FAPIs) as diagnostic and therapeutic agents in various oncological populations. To exclusively evaluate the current evidence on the diagnostic and therapeutic role of FAPI radiotracers in patients with breast cancer (BC), a narrative review of the available literature was performed. A search algorithm from PubMed/MEDLINE, based on the combination of "PET" OR "positron emission tomography" and "FAPI" and "cancer", with a last update in February 2022, was applied. From 233 identified articles, 33 studies conducted in BC patients and with available data on PET imaging or radiolabeled-FAPI therapy were finally considered, for a total of 191 patients. Despite some clinical and methodological heterogeneity among the reviewed articles, Ga-68-FAPI PET/CT emerges as a valuable diagnostic tool in BC patients both at staging and restaging, also demonstrating several technical advantages and an overall better performance than F-18-FDG, especially in histotypes with well-known low F-18-FDG avidity. Moreover, although with still limited clinical evidence in BC, radiolabeled FAPIs emerge as promising therapeutic agents in a theranostic perspective, increasing the possibility of more personalized treatments. From these results, future research directions on FAPI radiotracers application in BC patients are suggested.
C1 [Taralli, Silvia; Lorusso, Margherita; Perrone, Elisabetta; Perotti, Germano; Zagaria, Luca; Calcagni, Maria Lucia] Fdn Policlin Univ A Gemelli IRCCS, Dipartimento Diagnost Immagini Radioterapia Oncolo, Nucl Med Unit, I-00168 Rome, Italy.
   [Perrone, Elisabetta; Calcagni, Maria Lucia] Univ Cattolica Sacro Cuore, Dipartimento Univ Sci Radiolog Ematolog, I-00168 Rome, Italy.
C3 Catholic University of the Sacred Heart; IRCCS Policlinico Gemelli;
   Catholic University of the Sacred Heart; IRCCS Policlinico Gemelli
RP Perrone, E (corresponding author), Fdn Policlin Univ A Gemelli IRCCS, Dipartimento Diagnost Immagini Radioterapia Oncolo, Nucl Med Unit, I-00168 Rome, Italy.; Perrone, E (corresponding author), Univ Cattolica Sacro Cuore, Dipartimento Univ Sci Radiolog Ematolog, I-00168 Rome, Italy.
EM bets.perrone@gmail.com
RI Lorusso, Margherita/AAC-7723-2022; Calcagni, Maria Lucia/AAC-7214-2022;
   Taralli, Silvia/AAD-1534-2022
OI PEROTTI, Germano/0000-0002-2675-8384; Perrone,
   Elisabetta/0009-0002-8404-8206
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NR 56
TC 13
Z9 14
U1 0
U2 16
PU MDPI
PI BASEL
PA ST ALBAN-ANLAGE 66, CH-4052 BASEL, SWITZERLAND
EI 2072-6694
J9 CANCERS
JI Cancers
PD FEB
PY 2023
VL 15
IS 3
AR 908
DI 10.3390/cancers15030908
PG 18
WC Oncology
WE Science Citation Index Expanded (SCI-EXPANDED)
SC Oncology
GA 8T4QV
UT WOS:000929249500001
PM 36765866
OA Green Published, gold
DA 2025-03-13
ER

PT J
AU Giorello, MB
   Borzone, FR
   Labovsky, V
   Piccioni, FV
   Chasseing, NA
AF Belen Giorello, Maria
   Raul Borzone, Francisco
   Labovsky, Vivian
   Valeria Piccioni, Flavia
   Alejandra Chasseing, Norma
TI Cancer-Associated Fibroblasts in the Breast Tumor Microenvironment
SO JOURNAL OF MAMMARY GLAND BIOLOGY AND NEOPLASIA
LA English
DT Article
DE Breast cancer; Cancer associated fibroblasts; Pro-tumoral activity;
   Immunosuppression activity; Biomarkers of CAFs
ID MESENCHYMAL STEM-CELLS; SMOOTH MUSCLE ACTIN; BONE-MARROW;
   PROGNOSTIC-SIGNIFICANCE; EPITHELIAL-CELLS; GENE-EXPRESSION; STROMAL
   CELLS; TGF-BETA; TRANSFORMING GROWTH-FACTOR-BETA-1; MATRIX
   METALLOPROTEINASES
AB Years of investigation have shed light on a theory in which breast tumor epithelial cells are under the effect of the stromal microenvironment. This review aims to discuss recent findings concerning the phenotypic and functional characteristics of cancer associated fibroblasts (CAFs) and their involvement in tumor evolution, as well as their potential implications for anti-cancer therapy. In this manuscript, we reviewed that CAFs play a fundamental role in initiation, growth, invasion, and metastasis of breast cancer, and also serve as biomarkers in the clinical diagnosis, therapy, and prognosis of this disease.
C1 [Belen Giorello, Maria; Raul Borzone, Francisco; Labovsky, Vivian; Valeria Piccioni, Flavia; Alejandra Chasseing, Norma] Inst Biol & Med Expt, Lab Inmunohematol IBYME, Consejo Nacl Invest Cient & Tecn CONICET, Vuelta Obligado 2490,CP 1428 Ciudad Autonoma Buen, Buenos Aires, DF, Argentina.
   [Valeria Piccioni, Flavia] Inst Biol & Med Expt, Lab Oncol Mol & Nuevos Blancos Terapeut IBYME, Consejo Nacl Invest Cient & Tecn CONICET, Vuelta Obligado 2490,CP 1428 Ciudad Autonoma Buen, Buenos Aires, DF, Argentina.
C3 Consejo Nacional de Investigaciones Cientificas y Tecnicas (CONICET);
   Institute of Biology & Experimental Medicine; Consejo Nacional de
   Investigaciones Cientificas y Tecnicas (CONICET); Institute of Biology &
   Experimental Medicine
RP Giorello, MB; Chasseing, NA (corresponding author), Inst Biol & Med Expt, Lab Inmunohematol IBYME, Consejo Nacl Invest Cient & Tecn CONICET, Vuelta Obligado 2490,CP 1428 Ciudad Autonoma Buen, Buenos Aires, DF, Argentina.
EM mbgiorello@gmail.com; achasseing@ibyme.conicet.gov.ar
OI Chasseing, Norma Alejandra/0000-0001-5486-2245; Giorello, Maria
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NR 213
TC 35
Z9 37
U1 1
U2 22
PU SPRINGER/PLENUM PUBLISHERS
PI NEW YORK
PA 233 SPRING ST, NEW YORK, NY 10013 USA
SN 1083-3021
EI 1573-7039
J9 J MAMMARY GLAND BIOL
JI J. Mammary Gland Biol. Neoplasia
PD JUN
PY 2021
VL 26
IS 2
BP 135
EP 155
DI 10.1007/s10911-020-09475-y
EA JAN 2021
PG 21
WC Oncology; Endocrinology & Metabolism; Physiology
WE Science Citation Index Expanded (SCI-EXPANDED)
SC Oncology; Endocrinology & Metabolism; Physiology
GA SZ9DD
UT WOS:000604826200001
PM 33398516
DA 2025-03-13
ER

PT J
AU Ma, B
   Li, FF
   Ma, BL
AF Ma, Bin
   Li, Fangfang
   Ma, Binlin
TI Down-regulation of COL1A1 inhibits tumor-associated fibroblast
   activation and mediates matrix remodeling in the tumor microenvironment
   of breast cancer
SO OPEN LIFE SCIENCES
LA English
DT Article
DE fibroblasts; tumor microenvironment; matrix remodeling; collagen type I
   A1; CAV-1
ID EXOSOMES; METASTASIS; BIOMARKERS
AB We investigated the effects of collagen type I alpha 1 (COL1A1) on tumor-associated fibroblast activation and matrix remodeling in the tumor microenvironment of breast cancer. Cells were divided into the blank control, negative control, and siRNA-COL1A1 groups, or HKF control, HKF + exosomes (EXO), HKF + siRNA negative control-EXO, and HKF + siRNA-COL1A1-EXO co-culture groups. Western blot and quantitative real-time PCR detected gene expressions. COL I, COL III, and TGF-beta 1 were detected by enzyme-linked immunosorbent assay. We found that compared with blank and negative control groups, COL1A1 expression and the secretion of exosomes by breast cancer cells were inhibited in the siRNA-COL1A1 group. Compared with the HKF control group, the COL I, COL III, TGF-beta 1, alpha-SMA, and fibroblast activation protein (FAP) were increased, while the E-cadherin and CAV-1 were decreased in the HKF + EXO, HKF + siRNA negative control-EXO, and HKF + siRNA-COL1A1-EXO co-culture groups. Compared with HKF + EXO and HKF + siRNA negative control-EXO co-culture groups, the COL I, COL III, TGF-beta 1, alpha-SMA, and FAP were decreased, and the E-cadherin and CAV-1 were increased in the HKF + siRNA-COL1A1-EXO co-culture group. Collectively, COL1A1 down-regulation may inhibit exosome secretion possibly via inhibiting COL I and upregulating CAV-1, thereby inhibiting tumor-associated fibroblast activation and matrix remodeling in the tumor microenvironment.
C1 [Ma, Bin; Li, Fangfang; Ma, Binlin] Xinjiang Med Univ, Affiliated Canc Hosp, Dept Breast & Thyroid Surg, 789 Suzhou East St, Urumqi 830011, Xinjiang, Peoples R China.
   [Ma, Bin] Sichuan Univ, West China Hosp 4, West China Sch Publ Hlth, Dept Thyriod & Breast Surg, Chengdu 610041, Peoples R China.
C3 Xinjiang Medical University; Sichuan University
RP Ma, BL (corresponding author), Xinjiang Med Univ, Affiliated Canc Hosp, Dept Breast & Thyroid Surg, 789 Suzhou East St, Urumqi 830011, Xinjiang, Peoples R China.
EM 55898790@qq.com
FU Natural Science Foundation of Xinjiang Uygur Autonomous Region
   [2020D01C203]
FX This work was supported by the Natural Science Foundation of Xinjiang
   Uygur Autonomous Region (No. 2020D01C203).
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TC 4
Z9 4
U1 4
U2 6
PU DE GRUYTER POLAND SP Z O O
PI WARSAW
PA BOGUMILA ZUGA 32A STR, 01-811 WARSAW, MAZOVIA, POLAND
SN 2391-5412
J9 OPEN LIFE SCI
JI Open Life Sci.
PD NOV 30
PY 2023
VL 18
IS 1
AR 20220776
DI 10.1515/biol-2022-0776
PG 10
WC Biology
WE Science Citation Index Expanded (SCI-EXPANDED)
SC Life Sciences & Biomedicine - Other Topics
GA Z3QA5
UT WOS:001111240200001
PM 38045487
OA gold
DA 2025-03-13
ER

PT J
AU Sharma, M
   Turaga, RC
   Yuan, Y
   Satyanarayana, G
   Mishra, F
   Bian, Z
   Liu, W
   Sun, L
   Yang, J
   Liu, ZR
AF Sharma, Malvika
   Turaga, Ravi Chakra
   Yuan, Yi
   Satyanarayana, Ganesh
   Mishra, Falguni
   Bian, Zhen
   Liu, Wei
   Sun, Li
   Yang, Jenny
   Liu, Zhi-Ren
TI Simultaneously targeting cancer-associated fibroblasts and angiogenic
   vessel as a treatment for TNBC
SO JOURNAL OF EXPERIMENTAL MEDICINE
LA English
DT Article
ID NEGATIVE BREAST-CANCER; TUMOR-STROMA RATIO; LYSYL OXIDASE;
   GROWTH-FACTOR; INTEGRIN ALPHA(V)BETA(3); EXPRESSION; METASTASIS;
   CHEMORESISTANCE; MYOFIBROBLASTS; NORMALIZATION
AB Fibrotic tumor stroma plays an important role in facilitating triple-negative breast cancer (TNBC) progression and chemotherapeutic resistance. We previously reported a rationally designed protein (ProAgio) that targets integrin alpha(v)beta(3) at a novel site. ProAgio induces apoptosis via the integrin. Cancer-associated fibroblasts (CAFs) and angiogenic endothelial cells (aECs) in TNBC tumor express high levels of integrin alpha(v)beta(3). ProAgio effectively induces apoptosis in CAFs and aECs. The depletion of CAFs by ProAgio reduces intratumoral collagen and decreases growth factors released from CAFs in the tumor, resulting in decreased cancer cell proliferation and apoptotic resistance. ProAgio also eliminates leaky tumor angiogenic vessels, which consequently reduces tumor hypoxia and improves drug delivery. The depletion of CAFs and reduction in hypoxia by ProAgio decreases lysyl oxidase (LOX) secretion, which may play a role in the reduction of metastasis. ProAgio stand-alone or in combination with a chemotherapeutic agent provides survival benefit in TNBC murine models, highlighting the therapeutic potential of ProAgio as a treatment strategy.
C1 [Sharma, Malvika; Turaga, Ravi Chakra; Yuan, Yi; Satyanarayana, Ganesh; Mishra, Falguni; Bian, Zhen; Liu, Wei; Liu, Zhi-Ren] Georgia State Univ, Dept Biol, Atlanta, GA 30302 USA.
   [Liu, Wei] Harbin Med Univ Canc Hosp, Harbin, Peoples R China.
   [Sun, Li] Amoytop Biotech Inc, Xiamen, Peoples R China.
   [Yang, Jenny] Georgia State Univ, Dept Chem, Atlanta, GA 30303 USA.
C3 University System of Georgia; Georgia State University; Harbin Medical
   University; University System of Georgia; Georgia State University
RP Liu, ZR (corresponding author), Georgia State Univ, Dept Biol, Atlanta, GA 30302 USA.
EM zliu8@gsu.edu
RI Satyanarayana, Ganesh/HLG-8727-2023; Yang, Jenny/KCJ-6006-2024; Sharma,
   Malvika/KZU-2234-2024; TURAGA, RAVI/B-5559-2009; Yuan, Yi/KGL-5178-2024
OI Sharma, Malvika/0000-0002-2695-1635; YUAN, YI/0000-0003-1821-2178;
   Mishra, Falguni/0000-0003-0092-5559; Turaga, Ravi
   Chakra/0000-0001-9075-7645; Satyanarayana, Ganesh/0000-0002-1136-1990;
   Liu, Zhi-Ren/0000-0002-2460-1631
FU National Institutes of Health [CA175112, CA118113, CA178730, CA217482];
   Georgia Cancer Coalition; Molecular Basis of Disease fellowship, Georgia
   State University
FX This work is supported in part by research grants from the National
   Institutes of Health (CA175112, CA118113, CA178730, CA217482) and
   Georgia Cancer Coalition to Z.-R. Liu. R.C. Turaga and M. Sharma are
   supported by a Molecular Basis of Disease fellowship, Georgia State
   University.
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NR 66
TC 33
Z9 35
U1 3
U2 27
PU ROCKEFELLER UNIV PRESS
PI NEW YORK
PA 950 THIRD AVE, 2ND FLR, NEW YORK, NY 10022 USA
SN 0022-1007
EI 1540-9538
J9 J EXP MED
JI J. Exp. Med.
PD APR 5
PY 2021
VL 218
IS 4
AR e20200712
DI 10.1084/jem.20200712
PG 27
WC Immunology; Medicine, Research & Experimental
WE Science Citation Index Expanded (SCI-EXPANDED)
SC Immunology; Research & Experimental Medicine
GA QY5BW
UT WOS:000630055800001
PM 33561195
OA Green Published, hybrid
DA 2025-03-13
ER

PT J
AU Wang, YC
   Lv, WC
   Yi, Y
   Zhang, Q
   Zhang, J
   Wu, YP
AF Wang, Yichen
   Lv, Wenchang
   Yi, Yi
   Zhang, Qi
   Zhang, Jun
   Wu, Yiping
TI A novel signature based on cancer-associated fibroblast genes to predict
   prognosis, immune feature, and therapeutic response in breast cancer
SO AGING-US
LA English
DT Article
DE breast cancer; cancer -associated fibroblasts; prognosis signature;
   therapeutic targets; immune infiltration
ID CAVEOLIN-1 EXPRESSION; MICROENVIRONMENT; METASTASIS
AB Breast cancer (BC) ranks first in the incidence of tumors in women and remains the most prevalent malignancy in women worldwide. Cancer-associated fibroblasts (CAFs) in the tumor microenvironment (TME) profoundly influence the progression, recurrence, and therapeutic resistance in BC. Here, we intended to establish a risk signature based on screened CAF-associated genes in BC (BCCGs) for patient stratification. Initially, BCCGs were screened by a combination of several CAF gene sets. The identified BCGGs were found to differ significantly in the overall survival (OS) of BC patients. Accordingly, we constructed a prognostic prediction signature of 5 BCCGs, which were independent prognostic factors associated with BC based on univariate and multivariate Cox regression. The risk model divided patients into low-and high-risk groups, accompanied by different OS, clinical features, and immune infiltration characteristics. Receiver operating characteristic (ROC) curves and a nomogram further validated the predictive performance of the prognostic model. Notably, 21 anticancer agents targeting these BCCGs possessed better sensitivity in BC patients. Meanwhile, the elevated expression of the majority of immune checkpoint genes suggested that the high-risk group may benefit more from immune checkpoint inhibitors (ICIs) therapy. Taken together, our well-established model is a robust instrument to precisely and comprehensively predict the prognosis, immune features, and drug sensitivity in BC patients, for combating BC.
C1 [Wang, Yichen; Lv, Wenchang; Yi, Yi; Zhang, Qi; Wu, Yiping] Huazhong Univ Sci & Technol, Tongji Hosp, Tongji Med Coll, Dept Plast Surg, Wuhan 430030, Hubei, Peoples R China.
   [Zhang, Jun] Shenzhen Qianhai Shekou Free Trade Zone Hosp, Dept Thyroid & Breast Surg, Shenzhen 518067, Guangdong, Peoples R China.
C3 Huazhong University of Science & Technology; Shenzhen Qianhai Shekou
   Free Trade Zone Hospital
RP Zhang, Q; Wu, YP (corresponding author), Huazhong Univ Sci & Technol, Tongji Hosp, Tongji Med Coll, Dept Plast Surg, Wuhan 430030, Hubei, Peoples R China.; Zhang, J (corresponding author), Shenzhen Qianhai Shekou Free Trade Zone Hosp, Dept Thyroid & Breast Surg, Shenzhen 518067, Guangdong, Peoples R China.
EM zhangqi06172@foxmail.com; zhangjun_tjh@126.com; tongjiplastic@163.com
RI Wu, Yiping/JJF-6185-2023
FU China GuangHua Science and Technology Foundation [2019JZXM001]; Wuhan
   Science and Technology Bureau [2020020601012241]
FX Funding This article acknowledges contributions from the China GuangHua
   Science and Technology Foundation (No. 2019JZXM001) and Wuhan Science
   and Technology Bureau (No. 2020020601012241) .
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NR 37
TC 3
Z9 3
U1 0
U2 3
PU IMPACT JOURNALS LLC
PI ORCHARD PARK
PA 6666 E QUAKER ST, STE 1, ORCHARD PARK, NY 14127 USA
SN 1945-4589
J9 AGING-US
JI Aging-US
PD MAY 15
PY 2023
VL 15
IS 9
BP 3480
EP 3497
PG 18
WC Cell Biology; Geriatrics & Gerontology
WE Science Citation Index Expanded (SCI-EXPANDED)
SC Cell Biology; Geriatrics & Gerontology
GA H5TN7
UT WOS:000996587500018
PM 37142271
OA Green Published, gold
DA 2025-03-13
ER

PT J
AU Al-Rakan, MA
   Colak, D
   Hendrayani, SF
   Al-Bakheet, A
   Al-Mohanna, FH
   Kaya, N
   Al-Malik, O
   Aboussekhra, A
AF Al-Rakan, Maha A.
   Colak, Dilek
   Hendrayani, Siti-Faujiah
   Al-Bakheet, Albandary
   Al-Mohanna, Falah H.
   Kaya, Namik
   Al-Malik, Osama
   Aboussekhra, Abdelilah
TI Breast stromal fibroblasts from histologically normal surgical margins
   are pro-carcinogenic
SO JOURNAL OF PATHOLOGY
LA English
DT Article
DE breast cancer; stromal fibroblasts; gene expression;
   epithelial-to-mesenchymal transition
ID CANCER-ASSOCIATED FIBROBLASTS; GENE-EXPRESSION; TUMOR; STRESS;
   PROGRESSION; CARCINOMAS; RECURRENCE; INVASION
AB There is evidence that normal breast stromal fibroblasts (NBFs) suppress tumour growth, while cancer-associated fibroblasts (CAFs) promote tumourigenesis through functional interactions with tumour cells. Little is known about the biology and the carcinogenic potential of stromal fibroblasts present in histologically normal surgical margins (TCFs). Therefore, we first undertook gene expression analysis on five CAF/TCF pairs from breast cancer patients and three NBF samples (derived from mammoplasties). This comparative analysis revealed variation in gene expression between these three categories of cells, with a TCF-specific gene expression profile. This variability was higher in TCFs than in their paired CAFs and also NBFs. Cytokine arrays show that TCFs have a specific secretory cytokine profile. In addition, stromal fibroblasts from surgical margins expressed high levels of -SMA and SDF-1 and exhibited higher migratory/invasiveness abilities. Indirect co-culture showed that TCF cells enhance the proliferation of non-cancerous mammary epithelial cells and the epithelial-to-mesenchymal transition of breast cancer cells. Moreover, TCF and CAF cells increased the level of PCNA, MMP-2 and the phosphorylated/activated form of Akt in normal breast luminal fibroblasts in a paracrine manner. Furthermore, TCFs were able to promote the formation and growth of humanized orthotopic breast tumours in nude mice. Interestingly, these TCF phenotypes and the extent of their effects were intermediate between those of NBFs and CAFs. Together, these results indicate that stromal fibroblasts located in non-cancerous tissues exhibit a tumour-promoting phenotype, indicating that their presence post-surgery may play important roles in cancer recurrence. (c) 2013 The Authors. Journal of Pathology published by John Wiley & Sons Ltd on behalf of Pathological Society of Great Britain and Ireland.
C1 [Al-Rakan, Maha A.; Hendrayani, Siti-Faujiah; Aboussekhra, Abdelilah] King Faisal Specialist Hosp & Res Ctr, DMO, Riyadh 11211, Saudi Arabia.
   [Colak, Dilek] King Faisal Specialist Hosp & Res Ctr, Dept Biostat Epidemiol & Sci Comp, Riyadh 11211, Saudi Arabia.
   [Al-Bakheet, Albandary; Kaya, Namik] King Faisal Specialist Hosp & Res Ctr, Dept Genet, Riyadh 11211, Saudi Arabia.
   [Al-Mohanna, Falah H.] King Faisal Specialist Hosp & Res Ctr, Dept Comparat Med, Riyadh 11211, Saudi Arabia.
   [Al-Malik, Osama] King Faisal Specialist Hosp & Res Ctr, Dept Surg, Riyadh 11211, Saudi Arabia.
C3 King Faisal Specialist Hospital & Research Center; King Faisal
   Specialist Hospital & Research Center; King Faisal Specialist Hospital &
   Research Center; King Faisal Specialist Hospital & Research Center; King
   Faisal Specialist Hospital & Research Center
RP Aboussekhra, A (corresponding author), King Faisal Specialist Hosp & Res Ctr, DMO, MBC 03,POB 3354, Riyadh 11211, Saudi Arabia.
EM aboussekhra@kfshrc.edu.sa
RI Kaya, Namik/GQA-7857-2022; Colak, Dilek/IQT-4246-2023; Almohanna,
   Falah/IYJ-6603-2023; Albakheet, Albandary/LVS-0715-2024; Aboussekhra,
   Abdelilah/JCD-8138-2023
OI Almohanna, Falah/0000-0002-2426-0945; Colak, Dilek/0000-0001-6485-8768
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NR 34
TC 28
Z9 30
U1 1
U2 8
PU WILEY
PI HOBOKEN
PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA
SN 0022-3417
EI 1096-9896
J9 J PATHOL
JI J. Pathol.
PD DEC
PY 2013
VL 231
IS 4
BP 457
EP 465
DI 10.1002/path.4256
PG 9
WC Oncology; Pathology
WE Science Citation Index Expanded (SCI-EXPANDED)
SC Oncology; Pathology
GA 251VR
UT WOS:000326960100008
PM 24009142
OA Green Published
DA 2025-03-13
ER

PT J
AU Ota, D
   Kanayama, M
   Matsui, Y
   Ito, K
   Maeda, N
   Kutomi, G
   Hirata, K
   Torigoe, T
   Sato, N
   Takaoka, A
   Chambers, AF
   Morimoto, J
   Uede, T
AF Ota, Daichi
   Kanayama, Masashi
   Matsui, Yutaka
   Ito, Koyu
   Maeda, Naoyoshi
   Kutomi, Goro
   Hirata, Koichi
   Torigoe, Toshihiko
   Sato, Noriyuki
   Takaoka, Akinori
   Chambers, Ann F.
   Morimoto, Junko
   Uede, Toshimitsu
TI Tumor-α9β1 integrin-mediated signaling induces breast cancer growth and
   lymphatic metastasis via the recruitment of cancer-associated
   fibroblasts
SO JOURNAL OF MOLECULAR MEDICINE-JMM
LA English
DT Article
DE Osteopontin; alpha 9 beta 1 integrin; Tumor microenvironment;
   Cancer-associated fibroblasts; Breast cancer
ID PROMOTE TUMOR-GROWTH; STROMAL FIBROBLASTS; TENASCIN-C; OSTEOPONTIN;
   ALPHA(9)BETA(1); MODEL; INTEGRIN-ALPHA-9-BETA-1; MICROENVIRONMENT;
   EXPRESSION; REGULATOR
AB Tumor-derived matricellular proteins such as osteopontin (OPN) and tenascin-C (TN-C) have been implicated in tumor growth and metastasis. However, the molecular basis of how these proteins contribute to tumor progression remains to be elucidated. Importantly, these matricellular proteins are known to interact with alpha 9 beta 1 integrin. Therefore, we hypothesized that tumor-derived alpha 9 beta 1 integrin may contribute to tumor progression. To clarify the roles of alpha 9 beta 1 integrin in tumor growth and lymphatic metastasis, we used an inhibitory anti-human alpha 9 beta 1 integrin antibody (anti-h alpha 9 beta 1 antibody) and a alpha 9 beta 1 integrin-positive human breast cancer cell line, MDA-MB-231 luc-D3H2LN (D3H2LN), in vitro functional assays, and an in vivo orthotopic xenotransplantation model. In this study, we demonstrated that tumor, but not host alpha 9 beta 1 integrin, contributes to tumor growth, lymphatic metastasis, recruitment of cancer-associated fibroblasts (CAFs), and host-derived OPN production. We also found that CAFs contributed to tumor growth, lymphatic metastasis, and host-derived OPN levels. Consistent with those findings, tumor volume was well-correlated with numbers of CAFs and levels of host-derived OPN. Furthermore, it was shown that the inoculation of D3H2LN cells into mammary fat pads with mouse embryonic fibroblasts (MEFs), obtained from wild type, but not OPN knock-out mice, resulted in enhancement of tumor growth, thus indicating that CAF-derived OPN enhanced tumor growth. These results suggested that tumor alpha 9 beta 1-mediated signaling plays a pivotal role in generating unique primary tumor tissue microenvironments, which favor lymphatic metastasis and tumor growth.
C1 [Ota, Daichi; Matsui, Yutaka; Ito, Koyu; Uede, Toshimitsu] Hokkaido Univ, Inst Med Genet, Dept Matrix Med, Kita Ku, Sapporo, Hokkaido 0600815, Japan.
   [Kanayama, Masashi; Maeda, Naoyoshi] Hokkaido Univ, Inst Med Genet, Div Mol Immunol, Kita Ku, Sapporo, Hokkaido 0600815, Japan.
   [Kutomi, Goro; Hirata, Koichi] Sapporo Med Univ, Sapporo Med Univ Hosp, Dept Surg 1, Chuo Ku, Sapporo, Hokkaido 0608543, Japan.
   [Torigoe, Toshihiko; Sato, Noriyuki] Sapporo Med Univ, Dept Pathol 1, Sch Med, Sapporo, Hokkaido 0608556, Japan.
   [Takaoka, Akinori] Hokkaido Univ, Inst Med Genet, Div Signaling Canc & Immunol, Kita Ku, Sapporo, Hokkaido 0600815, Japan.
   [Chambers, Ann F.] Univ Western Ontario, London Reg Canc Program, Dept Oncol, London, ON N6A 4L6, Canada.
   [Chambers, Ann F.] Univ Western Ontario, London Reg Canc Program, Dept Pathol, London, ON N6A 4L6, Canada.
   [Chambers, Ann F.] Univ Western Ontario, London Reg Canc Program, Dept Med Biophys, London, ON N6A 4L6, Canada.
   [Morimoto, Junko] Univ Tokushima, Inst Enzyme Res, Tokushima 7708503, Japan.
C3 Hokkaido University; Hokkaido University; Sapporo Medical University;
   Sapporo Medical University; Hokkaido University; Western University
   (University of Western Ontario); University Western Ontario Hospital;
   Western University (University of Western Ontario); University Western
   Ontario Hospital; Western University (University of Western Ontario);
   University Western Ontario Hospital; Tokushima University
RP Ota, D (corresponding author), Hokkaido Univ, Inst Med Genet, Dept Matrix Med, Kita Ku, Kita 15,Nishi 7, Sapporo, Hokkaido 0600815, Japan.
EM dai-o@igm.hokudai.ac.jp; uedetoshimitsu@icloud.com
RI uede, toshimitsu/A-4273-2012; Morimoto, Junko/MAH-1954-2025; Ito,
   Koyu/CAH-5669-2022; Chambers, Ann/L-6285-2015
OI Ito, Koyu/0000-0001-7944-9692; Kanayama, Masashi/0000-0001-8366-5275;
   Chambers, Ann/0000-0002-9509-5123
FU Ministry of Education, Culture, Science, Sports, and Technology of Japan
   [21390113]; Grants-in-Aid for Scientific Research [21390113] Funding
   Source: KAKEN
FX We thank Chiemi Kimura and Orie Yamamori (Hokkaido University) for
   excellent technical assistance, and Tetsuro Nakamura (Gene Techono
   Science Corporation, Sapporo, Japan) for valuable suggestion about the
   use of anti-h alpha 9 beta 1 antibody and for valuable discussions
   during course of experiments. This study was supported by grant-in-aids
   from the Ministry of Education, Culture, Science, Sports, and Technology
   of Japan (21390113(B)) to Toshimitsu Uede.
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NR 33
TC 20
Z9 22
U1 0
U2 9
PU SPRINGER
PI NEW YORK
PA 233 SPRING ST, NEW YORK, NY 10013 USA
SN 0946-2716
EI 1432-1440
J9 J MOL MED
JI J. Mol. Med.
PD DEC
PY 2014
VL 92
IS 12
BP 1271
EP 1281
DI 10.1007/s00109-014-1183-9
PG 11
WC Genetics & Heredity; Medicine, Research & Experimental
WE Science Citation Index Expanded (SCI-EXPANDED)
SC Genetics & Heredity; Research & Experimental Medicine
GA AU5KF
UT WOS:000345644900006
PM 25099519
DA 2025-03-13
ER

PT J
AU Geng, SZ
   Xiang, TT
   Zhang, YY
   Guo, PK
   Zhang, HL
   Zhang, ZZ
   Gu, MC
   Zhang, KX
   Song, HW
   Shi, JJ
   Liu, JJ
AF Geng, Shizhen
   Xiang, Tingting
   Zhang, Yunya
   Guo, Pengke
   Zhang, Hongling
   Zhang, Zhenzhong
   Gu, Mengchao
   Zhang, Kaixiang
   Song, Haiwei
   Shi, Jinjin
   Liu, Junjie
TI Safe engineering of cancer-associated fibroblasts enhances checkpoint
   blockade immunotherapy
SO JOURNAL OF CONTROLLED RELEASE
LA English
DT Article
DE Cancer-associated fibroblasts; Photoactivatable gene-expression; Immune
   checkpoint blockade therapy; Thermochromic nanoparticles; Antigen
   presentation
ID TUMOR; ACTIVATION; RECEPTOR; THERAPY; CELLS
AB Abundant cancer-associated fibroblasts (CAFs) in highly fibrotic breast cancer constitute an immunosuppressive barrier for T cell activity and are closely related to the failure of immune checkpoint blockade therapy (ICB). Inspired by the similar antigen-processing capacity of CAFs to professional antigen-presenting cells (APCs), a "turning foes to friends" strategy is proposed by in situ engineering immune-suppressed CAFs into immune-activated APCs for improving response rates of ICB. To achieve safe and specific CAFs engineering in vivo, a thermochromic spatiotemporal photo-controlled gene expression nanosystem was developed by self-assembly of molten eutectic mixture, chitosan and fusion plasmid. After photoactivatable gene expression, CAFs could be engineered as APCs via co-stimulatory molecule (CD86) expression, which effectively induced activation and proliferation of antigen-specific CD8 + T cells. Meanwhile, engineered CAFs could also secrete PD-L1 trap protein in situ for ICB, avoiding potential autoimmune-like disorders caused by "off-target" effects of clinically applied PD-L1 antibody. The study demonstrated that the designed nanosystem could efficiently engineer CAFs, signif-icantly enhance the percentages of CD8+ T cells (4-folds), result in about 85% tumor inhibition rate and 83.3% survival rate at 60 days in highly fibrotic breast cancer, further inducing long-term immune memory effects and effectively inhibiting lung metastasis.
C1 [Geng, Shizhen; Xiang, Tingting; Zhang, Yunya; Guo, Pengke; Zhang, Hongling; Zhang, Zhenzhong; Gu, Mengchao; Zhang, Kaixiang; Song, Haiwei; Shi, Jinjin; Liu, Junjie] Zhengzhou Univ, Sch Pharmaceut Sci, Zhengzhou 450001, Peoples R China.
   [Zhang, Hongling; Zhang, Zhenzhong; Zhang, Kaixiang; Shi, Jinjin; Liu, Junjie] Key Lab Targeting Therapy & Diag Crit Dis, Zhengzhou, Henan, Peoples R China.
   [Zhang, Hongling; Zhang, Zhenzhong; Zhang, Kaixiang; Shi, Jinjin; Liu, Junjie] Minist Educ, Key Lab Adv Drug Preparat Technol, Zhengzhou 450001, Peoples R China.
   [Zhang, Zhenzhong] State Key Lab Esophageal Canc Prevent & Treatment, Zhengzhou 450001, Peoples R China.
   [Song, Haiwei] ASTAR, Inst Mol & Cell Biol, Singapore 138673, Singapore.
C3 Zhengzhou University; Agency for Science Technology & Research (A*STAR);
   A*STAR - Institute of Molecular & Cell Biology (IMCB)
RP Song, HW; Shi, JJ; Liu, JJ (corresponding author), Zhengzhou Univ, Sch Pharmaceut Sci, Zhengzhou 450001, Peoples R China.
EM haiwei@imcb.a-star.edu.sg; shijinyxy@zzu.edu.cn; liujunjie@zzu.edu.cn
RI Zhang, Kaixiang/M-7659-2016
FU National Natural Science Foundation of China [82172762, 31900991,
   21904119, 82073395]; Science and Technology Innovation Talents Support
   Project of Henan Province [23HASTIT041]; Henan Provincial Science and
   Technology Research and Development Plan Joint Fund [222301420050];
   Postdoctoral Science Foundation of China [2020TQ0288, 2021M690140];
   Postdoctoral Innovative Talent Support Program of Henan Province
   [ZYYCYU202012179]
FX Acknowledgements This work was supported by the National Natural Science
   Foundation of China [Nos. 82172762, 31900991, 21904119, 82073395] ;
   Science and Technology Innovation Talents Support Project of Henan
   Province (no. 23HASTIT041) , and Henan Provincial Science and Technology
   Research and Development Plan Joint Fund (no. 222301420050) ;
   Postdoctoral Science Foundation of China [Nos. 2020TQ0288, 2021M690140]
   ; Postdoctoral Innovative Talent Support Program of Henan Province [No.
   ZYYCYU202012179] . Authors thank Modern Analysis and Computing Center of
   Zhengzhou University for technical assistance. All animal handling
   procedures were performed in accor-dance with the guidelines of the
   Regional Ethics Committee for Animal Experiments and the Care
   Regulations approved by the Institutional Animal Care and Use Committee
   of Zhengzhou University.
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NR 37
TC 11
Z9 11
U1 9
U2 48
PU ELSEVIER
PI AMSTERDAM
PA RADARWEG 29, 1043 NX AMSTERDAM, NETHERLANDS
SN 0168-3659
EI 1873-4995
J9 J CONTROL RELEASE
JI J. Control. Release
PD APR
PY 2023
VL 356
BP 272
EP 287
DI 10.1016/j.jconrel.2023.02.041
EA MAR 2023
PG 16
WC Chemistry, Multidisciplinary; Pharmacology & Pharmacy
WE Science Citation Index Expanded (SCI-EXPANDED)
SC Chemistry; Pharmacology & Pharmacy
GA 0A2TA
UT WOS:000951679000001
PM 36870541
DA 2025-03-13
ER

PT J
AU Chen, Z
   Yan, X
   Li, K
   Ling, Y
   Kang, H
AF Chen, Z.
   Yan, X.
   Li, K.
   Ling, Y.
   Kang, H.
TI Stromal fibroblast-derived MFAP5 promotes the invasion and migration of
   breast cancer cells via Notch1/slug signaling
SO CLINICAL & TRANSLATIONAL ONCOLOGY
LA English
DT Article
DE Cancer-associated fibroblasts; Breast cancer; MFAP5; Invasion;
   Metastasis
ID EPITHELIAL-MESENCHYMAL TRANSITION; EXTRACELLULAR-MATRIX; IDENTIFICATION;
   INTERACTS; NOTCH; EMT
AB Background The tumor microenvironment (TME) regulates tumor progression, and cancer-associated fibroblasts (CAFs) are the primary stromal components of the TME, with the potential to drive tumor metastasis via the secretion of paracrine factors, but the specific mechanisms driving this process have not been defined. Methods Proteins secreted from CAFs and normal fibroblasts (NFs) were analyzed via proteomic analysis (fold change > 2, p < 0.05) to identify tumor-promoting proteins secreted by CAFs. Results Proteomic analysis revealed that microfibrillar-associated protein 5 (MFAP5) is preferentially expressed and secreted by CAFs relative to NFs, which was confirmed by Western blotting and RT-qPCR. Transwell and wound healing assays confirmed that MFAP5 is secreted by CAFs, and drives the invasion and migration of MCF7 breast cancer cells. We further found that in MCF7 cells MFAP5 promoted epithelial-mesenchymal transition, activating Notch1 signaling and consequently upregulating NICD1 and slug. When Notch1 was knocked down in MCF7 cells, the ability of MFAP5 to promote invasion and migration decreased. Conclusion CAFs promote cancer cells invasion and migration via MFAP5 secretion and activation of the Notch1/slug signaling. These data highlight this pathway as a therapeutic target to disrupt tumor progression through the interference of CAF-tumor crosstalk.
C1 [Chen, Z.; Li, K.; Ling, Y.; Kang, H.] Capital Med Univ, Xuanwu Hosp, Dept Gen Surg, Beijing, Peoples R China.
   [Yan, X.] Capital Med Univ, Sch Basic Med Sci, Beijing, Peoples R China.
C3 Capital Medical University; Capital Medical University
RP Kang, H (corresponding author), Capital Med Univ, Xuanwu Hosp, Dept Gen Surg, Beijing, Peoples R China.
EM surgeonchen2017@163.com; xdyan1309@163.com; henryling602@163.com;
   drkanghua@163.com
RI Yan, Xiaodong/GYU-7450-2022
OI Kang, Hua/0000-0002-1230-7961
FU National Natural Science Foundation of China [81172517]; Beijing Breast
   Prevention Institute of Breast Cancer Prevention and Treatment Research
   Fund; Beijing Municipal Health System Academic Leaders of High-Level
   Health Personnel Program [2011-2-28]
FX This work was supported by the National Natural Science Foundation of
   China (No. 81172517) and Beijing Breast Prevention Institute of Breast
   Cancer Prevention and Treatment Research Fund and the Beijing Municipal
   Health System Academic Leaders of High-Level Health Personnel Program
   (No. 2011-2-28).
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NR 32
TC 18
Z9 20
U1 1
U2 11
PU SPRINGER INT PUBL AG
PI CHAM
PA GEWERBESTRASSE 11, CHAM, CH-6330, SWITZERLAND
SN 1699-048X
EI 1699-3055
J9 CLIN TRANSL ONCOL
JI Clin. Transl. Oncol.
PD APR
PY 2020
VL 22
IS 4
BP 522
EP 531
DI 10.1007/s12094-019-02156-1
PG 10
WC Oncology
WE Science Citation Index Expanded (SCI-EXPANDED)
SC Oncology
GA KW0FO
UT WOS:000520849200009
PM 31190277
DA 2025-03-13
ER

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AU Tang, SC
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   Chen, Kai
   Guo, Rong
TI Metabolic Heterogeneity and Potential Immunotherapeutic Responses
   Revealed by Single-Cell Transcriptomics of Breast Cancer
SO APOPTOSIS
LA English
DT Article
DE Metabolic heterogeneity; Chemotherapy; Immunotherapeutic response;
   Single-cell RNA sequencing; Breast cancer
ID TUMOR HETEROGENEITY
AB BackgroundBreast cancer (BC) exhibits remarkable heterogeneity. However, the transcriptomic heterogeneity of BC at the single-cell level has not been fully elucidated.MethodsWe acquired BC samples from 14 patients. Single-cell RNA sequencing (scRNA-seq), bioinformatic analyses, along with immunohistochemistry (IHC) and immunofluorescence (IF) assays were carried out.ResultsAccording to the scRNA-seq results, 10 different cell types were identified. We found that Cancer-Associated Fibroblasts (CAFs) exhibited distinct biological functions and may promote resistance to therapy. Metabolic analysis of tumor cells revealed heterogeneity in glycolysis, gluconeogenesis, and fatty acid synthetase reprogramming, which led to chemotherapy resistance. Furthermore, patients with multiple metastases and progression were predicted to benefit from immunotherapy based on a heterogeneity analysis of T cells and tumor cells.ConclusionsOur findings provide a comprehensive understanding of the heterogeneity of BC, provide comprehensive insight into the correlation between cancer metabolism and chemotherapy resistance, and enable the prediction of immunotherapy responses based on T-cell heterogeneity.
C1 [Tang, Shicong; Wang, Qing; Song, Ying; Liu, Rui; Tan, Xin; Li, Huimeng; Lv, Yafeng; Yang, Fuying; Zhao, Jiawen; Li, Sijia; Bi, Pingping; Yang, Jiali; Zheng, Kai; Guo, Rong] Kunming Med Univ, Canc Hosp Yunnan Prov, Affiliated Hosp 3, Dept Breast Surg, Kunming 650118, Yunnan, Peoples R China.
   [Sun, Ke; Zhu, Zhengna; Chen, Kai] Kunming Univ Sci & Technol, Inst Primate Translat Med, State Key Lab Primate Biomed Res, Kunming 650500, Yunnan, Peoples R China.
   [Sun, Ke; Chen, Kai] Yunnan Key Lab Primate Biomed Res, Kunming 650500, Yunnan, Peoples R China.
   [Chen, Dong; Chuan, Zhirui; Luo, Xiaomao] Kunming Med Univ, Caner Hosp Yunnan Prov, Affiliated Hosp 3, Dept Ultrasound, Kunming 650118, Yunnan, Peoples R China.
   [Hu, Zaoxiu; Liu, Ying] Kunming Med Univ, Caner Hosp Yunnan Prov, Affiliated Hosp 3, Dept Pathol, Kunming 650118, Yunnan, Peoples R China.
   [Li, Zhenhui; Ke, Tengfei] Kunming Med Univ, Caner Hosp Yunnan Prov, Affiliated Hosp 3, Dept Radiol, Kunming 650118, Yunnan, Peoples R China.
   [Jiang, Dewei] Chinese Acad Sci & Yunnan Prov, Kunming Inst Zool, Key Lab Anim Models & Human Dis Mech, Kunming, Yunnan, Peoples R China.
   [Jiang, Dewei] Univ Chinese Acad Sci, Kunming Coll Life Sci, Kunming, Yunnan, Peoples R China.
   [Yang, Rirong] Guangxi Med Univ, Ctr Genom & Personalized Med, Guangxi Collaborat Innovat Ctr Genom & Personalize, Guangxi key Lab Genom & Personalized Med, Nanning 530021, Guangxi, Peoples R China.
   [Yang, Rirong] Guangxi Med Univ, Sch Basic Med Sci, Dept Immunol, Nanning 530021, Guangxi, Peoples R China.
C3 Kunming Medical University; Kunming University of Science & Technology;
   Kunming Medical University; Kunming Medical University; Kunming Medical
   University; Chinese Academy of Sciences; Kunming Institute of Zoology,
   CAS; Chinese Academy of Sciences; University of Chinese Academy of
   Sciences, CAS; Guangxi Medical University; Guangxi Medical University
RP Tang, SC; Guo, R (corresponding author), Kunming Med Univ, Canc Hosp Yunnan Prov, Affiliated Hosp 3, Dept Breast Surg, Kunming 650118, Yunnan, Peoples R China.; Chen, K (corresponding author), Kunming Univ Sci & Technol, Inst Primate Translat Med, State Key Lab Primate Biomed Res, Kunming 650500, Yunnan, Peoples R China.; Chen, K (corresponding author), Yunnan Key Lab Primate Biomed Res, Kunming 650500, Yunnan, Peoples R China.; Yang, RR (corresponding author), Guangxi Med Univ, Ctr Genom & Personalized Med, Guangxi Collaborat Innovat Ctr Genom & Personalize, Guangxi key Lab Genom & Personalized Med, Nanning 530021, Guangxi, Peoples R China.; Yang, RR (corresponding author), Guangxi Med Univ, Sch Basic Med Sci, Dept Immunol, Nanning 530021, Guangxi, Peoples R China.
EM tang_shicong@126.com; 520yrr@163.com; kchbio@yahoo.com;
   guorong2320@126.com
RI zheng, kai/LDF-6248-2024; chen, dong/IRZ-3816-2023; yang,
   Jiali/AAH-3959-2020; Jiang, Dewei/AEQ-0323-2022; Zhang,
   Qingzhu/S-7221-2019
FU National Natural Science Foundation of China
FX We thank the breast cancer patients from Yunnan Cancer Hospital who
   participated in this study and acknowledge the contributions to this
   study of the entire research team.
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NR 58
TC 4
Z9 4
U1 7
U2 20
PU SPRINGER
PI DORDRECHT
PA VAN GODEWIJCKSTRAAT 30, 3311 GZ DORDRECHT, NETHERLANDS
SN 1360-8185
EI 1573-675X
J9 APOPTOSIS
JI Apoptosis
PD OCT
PY 2024
VL 29
IS 9-10
BP 1466
EP 1482
DI 10.1007/s10495-024-01952-7
EA APR 2024
PG 17
WC Biochemistry & Molecular Biology; Cell Biology
WE Science Citation Index Expanded (SCI-EXPANDED)
SC Biochemistry & Molecular Biology; Cell Biology
GA G8A9U
UT WOS:001197320200001
PM 38578322
DA 2025-03-13
ER

PT J
AU Yu, T
   Yang, G
   Hou, Y
   Tang, X
   Wu, C
   Wu, XA
   Guo, L
   Zhu, Q
   Luo, H
   Du, YE
   Wen, S
   Xu, L
   Yin, J
   Tu, G
   Liu, M
AF Yu, T.
   Yang, G.
   Hou, Y.
   Tang, X.
   Wu, C.
   Wu, X-A
   Guo, L.
   Zhu, Q.
   Luo, H.
   Du, Y-E
   Wen, S.
   Xu, L.
   Yin, J.
   Tu, G.
   Liu, M.
TI Cytoplasmic GPER translocation in cancer-associated fibroblasts mediates
   cAMP/PKA/CREB/glycolytic axis to confer tumor cells with multidrug
   resistance
SO ONCOGENE
LA English
DT Article
ID BREAST-CANCER; ESTROGEN-RECEPTOR; NUCLEAR EXPORT; PROGNOSTIC VALUE; FDG
   UPTAKE; GPR30; EXPRESSION; MICROENVIRONMENT; PHOSPHORYLATION; ACTIVATION
AB Multiple drug resistance is a challenging issue in the clinic. There is growing evidence that the G-protein-coupled estrogen receptor (GPER) is a novel mediator in the development of multidrug resistance in both estrogen receptor (ER)-positive and -negative breast cancers, and that cancer-associated fibroblasts (CAFs) in the tumor microenvironment may be a new agent that promotes drug resistance in tumor cells. However, the role of cytoplasmic GPER of CAFs on tumor therapy remains unclear. Here we first show that the breast tumor cell-activated PI3K/AKT (phosphoinositide 3-kinase/AKT) signaling pathway induces the cytoplasmic GPER translocation of CAFs in a CRM1-dependent pattern, and leads to the activation of a novel estrogen/GPER/cAMP/PKA/CREB signaling axis that triggers the aerobic glycolysis switch in CAFs. The glycolytic CAFs feed the extra pyruvate and lactate to tumor cells for augmentation of mitochondrial activity, and this energy metabolically coupled in a 'host-parasite relationship' between catabolic CAFs and anabolic cancer cells confers the tumor cells with multiple drug resistance to several conventional clinical treatments including endocrine therapy (tamoxifen), Her-2-targeted therapy (herceptin) and chemotherapy (epirubicin). Moreover, the clinical data from F-18-fluorodeoxyglucose positron emission tomography/computed tomography further present a strong association between the GPER/cAMP/PKA/CREB pathway of stromal fibroblasts with tumor metabolic activity and clinical treatment, suggesting that targeting cytoplasmic GPER in CAFs may rescue the drug sensitivity in patients with breast cancer. Thus, our data define novel insights into the stromal GPER-mediated multiple drug resistance from the point of reprogramming of tumor energy metabolism and provide the rationale for CAFs as a promising target for clinical therapy.
C1 [Yu, T.; Yang, G.; Wu, C.; Wu, X-A; Guo, L.; Zhu, Q.; Tu, G.] Chongqing Med Univ, Dept Endocrine & Breast Surg, Affiliated Hosp 1, 1 You Yi Rd, Chongqing 400016, Peoples R China.
   [Yu, T.; Hou, Y.; Tang, X.; Du, Y-E; Wen, S.; Xu, L.; Yin, J.; Liu, M.] Chongqing Med Univ, Key Lab Lab Med Diagnost, Chinese Minist Educ, 1 You Yi Rd, Chongqing 400016, Peoples R China.
   [Yu, T.] Jiangxi Canc Hosp, Dept Breast Surg, Nanchang, Jiangxi, Peoples R China.
   [Luo, H.] Chongqing Med Univ, Dept Breast & Thyroid Surg, Affiliated Hosp 2, Chongqing, Peoples R China.
C3 Chongqing Medical University; Chongqing Medical University; Chongqing
   Medical University
RP Tu, G (corresponding author), Chongqing Med Univ, Dept Endocrine & Breast Surg, Affiliated Hosp 1, 1 You Yi Rd, Chongqing 400016, Peoples R China.; Liu, M (corresponding author), Chongqing Med Univ, Key Lab Lab Med Diagnost, Chinese Minist Educ, 1 You Yi Rd, Chongqing 400016, Peoples R China.
EM tugang68@126.com; mliu-hncq@hotmail.com
OI li, lu/0009-0009-8381-3093
FU National Natural Science Foundation of China [NSFC 81372398, NSFC
   81472676, NSFC 31171336]
FX This work was supported by National Natural Science Foundation of China
   (NSFC 81372398) (to GT) and by National Natural Science Foundation of
   China (NSFC 81472676, NSFC 31171336) (to ML).
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TC 117
Z9 130
U1 0
U2 36
PU SPRINGERNATURE
PI LONDON
PA CAMPUS, 4 CRINAN ST, LONDON, N1 9XW, ENGLAND
SN 0950-9232
EI 1476-5594
J9 ONCOGENE
JI Oncogene
PD APR 13
PY 2017
VL 36
IS 15
BP 2131
EP 2145
DI 10.1038/onc.2016.370
PG 15
WC Biochemistry & Molecular Biology; Oncology; Cell Biology; Genetics &
   Heredity
WE Science Citation Index Expanded (SCI-EXPANDED)
SC Biochemistry & Molecular Biology; Oncology; Cell Biology; Genetics &
   Heredity
GA ES8DK
UT WOS:000399782500009
PM 27721408
DA 2025-03-13
ER

PT J
AU Muralidharan, H
   Hansen, T
   Steinle, A
   Schumacher, D
   Stickeler, E
   Maurer, J
AF Muralidharan, Harshini
   Hansen, Thomas
   Steinle, Anja
   Schumacher, David
   Stickeler, Elmar
   Maurer, Jochen
TI Breast Cancer Stem Cells Upregulate IRF6 in Stromal Fibroblasts to
   Induce Stromagenesis
SO CELLS
LA English
DT Article
DE IRF6; triple-negative BCSC; BCSC niche; BCSC-fibroblast interaction;
   CAF; fibrosis; tumor stroma; stromagenesis
ID INVASIVE DUCTAL CARCINOMAS; DIFFERENTIATION; MICROENVIRONMENT;
   METASTASIS; ACTIVATION; PHENOTYPE; PROGRAM; MATRIX; SKIN
AB The microenvironment of a cancer stem cell (CSC) niche is often found in coexistence with cancer-associated fibroblasts (CAFs). Here, we show the first in-depth analysis of the interaction between primary triple-negative breast cancer stem cells (BCSCs) with fibroblasts. Using 2D co-culture models with specific seeding ratios, we identified stromal fibroblast aggregation at the BCSC cluster periphery, and, on closer observation, the aggregated fibroblasts was found to encircle BCSC clusters in nematic organization. In addition, collagen type I and fibronectin accumulation were also found at the BCSC-stromal periphery. MACE-Seq analysis of BCSC-encapsulating fibroblasts displayed the transformation of stromal fibroblasts to CAFs and the upregulation of fibrosis regulating genes of which the Interferon Regulatory Factor 6 (IRF6) gene was identified. Loss of function experiments with the IRF6 gene decreased fibroblast encapsulation around BCSC clusters in 2D co-cultures. In BCSC xenografts, fibroblast IRF6 expression led to an increase in the stromal area and fibroblast density in tumors, in addition to a reduction in necrotic growth. Based on our findings, we propose that fibroblast IRF6 function is an important factor in the development of the stromal microenvironment and in sustaining the BCSC tumor niche.
C1 [Muralidharan, Harshini; Hansen, Thomas; Steinle, Anja; Stickeler, Elmar; Maurer, Jochen] Univ Hosp Aachen UKA, Dept Obstet & Gynecol, D-52074 Aachen, Germany.
   [Schumacher, David] Rhein Westfal TH Aachen, Univ Hosp, Dept Anesthesiol, D-52074 Aachen, Germany.
   [Schumacher, David] Rhein Westfal TH Aachen, Dept Nephrol & Clin Immunol, D-52074 Aachen, Germany.
   [Stickeler, Elmar; Maurer, Jochen] Ctr Integrated Oncol CIO, Venusberg Campus 1, D-53127 Bonn, Germany.
C3 RWTH Aachen University; RWTH Aachen University Hospital; RWTH Aachen
   University; RWTH Aachen University Hospital; RWTH Aachen University;
   University of Bonn
RP Maurer, J (corresponding author), Univ Hosp Aachen UKA, Dept Obstet & Gynecol, D-52074 Aachen, Germany.; Maurer, J (corresponding author), Ctr Integrated Oncol CIO, Venusberg Campus 1, D-53127 Bonn, Germany.
EM jmaurer@ukaachen.de
RI Maurer, Jochen/G-4832-2018; Schumacher, David/AAD-2810-2019
OI Schumacher, David/0000-0002-2308-6543; Maurer,
   Jochen/0000-0003-3962-3128
FU State of Baden-Wurttemberg [MIVT-1]
FX This research was funded by the State of Baden-Wurttemberg, grant ID:
   MIVT-1: MEMONO-Metabolisches Monitoring in einem Organ-on-chip-System.
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WC Cell Biology
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SC Cell Biology
GA F6Y7S
UT WOS:001311259000001
PM 39273037
OA gold
DA 2025-03-13
ER

PT J
AU Primac, I
   Maquoi, E
   Blacher, S
   Heljasvaara, R
   Van Deun, J
   Smeland, HYH
   Canale, A
   Louis, T
   Stuhr, L
   Sounni, NE
   Cataldo, D
   Pihlajaniemi, T
   Pequeux, C
   De Wever, O
   Gullberg, D
   Noel, A
AF Primac, Irina
   Maquoi, Erik
   Blacher, Silvia
   Heljasvaara, Ritva
   Van Deun, Jan
   Smeland, Hilde Y. H.
   Canale, Annalisa
   Louis, Thomas
   Stuhr, Linda
   Sounni, Nor Eddine
   Cataldo, Didier
   Pihlajaniemi, Taina
   Pequeux, Christel
   De Wever, Olivier
   Gullberg, Donald
   Noel, Agnes
TI Stromal integrin α11 regulates PDGFRβ signaling and promotes breast
   cancer progression
SO JOURNAL OF CLINICAL INVESTIGATION
LA English
DT Article
ID CARCINOMA-ASSOCIATED FIBROBLASTS; TENASCIN-C; PROGNOSTIC-SIGNIFICANCE;
   IN-SITU; EXPRESSION; GROWTH; RECEPTORS; CELLS; METASTASIS; TISSUE
AB Cancer-associated fibroblasts (CAFs) are key actors in modulating the progression of many solid tumors, such as breast cancer (BC). Herein, we identify an integrin alpha 11/PDGFR beta-positive CAF subset displaying tumor-promoting features in BC. In the preclinical MMTV-PyMT mouse model, integrin alpha 11 deficiency led to a drastic reduction of tumor progression and metastasis. A clear association between integrin alpha 11 and PDGFR beta was found at both transcriptional and histological levels in BC specimens. High stromal integrin alpha 11/PDGFR beta expression was associated with high grades and poorer clinical outcome in human BC patients. Functional assays using 5 CAF subpopulations (1 murine, 4 human) revealed that integrin alpha 11 promotes CAF invasion and CAF-induced tumor cell invasion upon PDGF-BB stimulation. Mechanistically, the proinvasive activity of integrin alpha 11 relies on its ability to interact with PDGFR beta in a ligand-dependent manner and to promote its downstream JNK activation, leading to the production of tenascin C, a proinvasive matricellular protein. Pharmacological inhibition of PDGFR beta and JNK impaired tumor cell invasion induced by integrin alpha 11 CAFs. Collectively, our study uncovers an integrin alpha 11 subset of protumoral CAFs that exploits the PDGFR beta/JNK signaling axis to promote tumor invasiveness in BC.
C1 [Primac, Irina; Maquoi, Erik; Blacher, Silvia; Canale, Annalisa; Louis, Thomas; Sounni, Nor Eddine; Cataldo, Didier; Pequeux, Christel; Noel, Agnes] Univ Liege, GIGA Canc, Lab Tumor & Dev Biol, Liege, Belgium.
   [Heljasvaara, Ritva; Pihlajaniemi, Taina] Univ Oulu, Oulu Ctr Cell Extracellular Matrix Res, Oulu, Finland.
   [Heljasvaara, Ritva; Pihlajaniemi, Taina] Univ Oulu, Bioctr Oulu, Fac Biochem & Mol Med, Oulu, Finland.
   [Heljasvaara, Ritva; Smeland, Hilde Y. H.; Stuhr, Linda; Gullberg, Donald] Univ Bergen, Norwegian Ctr Excellence, Dept Biomed, Bergen, Norway.
   [Heljasvaara, Ritva; Smeland, Hilde Y. H.; Stuhr, Linda; Gullberg, Donald] Univ Bergen, Norwegian Ctr Excellence, Ctr Canc Biomarkers CCBIO, Bergen, Norway.
   [Van Deun, Jan; De Wever, Olivier] Univ Ghent, Dept Human Struct & Repair, Lab Expt Canc Res, Ghent, Belgium.
C3 University of Liege; University of Oulu; University of Oulu; University
   of Bergen; University of Bergen; Ghent University
RP Noel, A (corresponding author), GIGA Canc, Lab Biol Tumeurs & Dev, Ave Hippocrate 13,Tour Pathol B23 4, B-4000 Liege, Belgium.
EM agnes.noel@uliege.be
RI Gullberg, Donald/H-2495-2016; Cataldo, Didier/GPG-3453-2022; Van Deun,
   Jan/AAT-9016-2020; Sounni, Nor Eddine/AAY-8766-2021; de wever,
   olivier/J-3094-2013; primac, irina/J-8857-2013; Van Deun,
   Jan/A-3747-2016
OI Sounni, Nor Eddine/0000-0001-9962-9236; de wever,
   olivier/0000-0002-5453-760X; primac, irina/0000-0001-7989-5027; Canale,
   Annalisa/0000-0002-8277-5998; LOUIS, Thomas/0009-0005-9160-6378; Noel,
   Agnes/0000-0002-7670-6179; Pihlajaniemi, Taina/0000-0002-1664-9045; Van
   Deun, Jan/0000-0003-1707-6266
FU European Union [316610]; Fonds de la Recherche Scientifique (FRS-FNRS,
   Belgium); Fondation contre le Cancer (Foundation of Public Interest,
   Belgium); Fonds Speciaux de la Recherche (University of Liege);
   Fondation Hospital-Universitaire Leon Fredericq (University of Liege);
   Research Council of Norway through its Centres of Excellence [223250];
   Academy of Finland Research Council for Health [308867]; Sigrid Juselius
   Foundation; FNRS-Televie fellowships; FNRS (Belgium); IUAP Bels-po;
   Academy of Finland (AKA) [308867] Funding Source: Academy of Finland
   (AKA)
FX We thank all laboratory members for useful technical advice, and all
   members of Marie Curie CAFFEIN Innovative Training Network (ITN) for
   valuable scientific discussions. We thank GIGA Imaging and Animal
   Facility platforms of ULiege for technical support and mouse housing. We
   thank the Biobank of ULiege for providing BC samples. This project was
   part of the CAFFEIN FP7 ITN consortium and received funding from the
   People Program (Marie Curie Actions) of the European Union's Seventh
   Framework Program FP7/2007-2013/under Research Executive Agency grant
   agreement 316610. The opinions presented in this article reflect only
   the authors' views, and the European Union is not liable for any use
   that may be made of the information contained herein. This work was
   supported by grants from the Fonds de la Recherche Scientifique
   (FRS-FNRS, Belgium), the Fondation contre le Cancer (Foundation of
   Public Interest, Belgium), the Fonds Speciaux de la Recherche
   (University of Liege), the Fondation Hospital-Universitaire Leon
   Fredericq (University of Liege), the Research Council of Norway through
   its Centres of Excellence funding scheme (project 223250), the Academy
   of Finland Research Council for Health (grant 308867), and the Sigrid
   Juselius Foundation, IUAP Bels-po. AC and TL are supported by
   FNRS-Televie fellowships. EM is a Research Associate from FNRS
   (Belgium).
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Z9 118
U1 3
U2 25
PU AMER SOC CLINICAL INVESTIGATION INC
PI ANN ARBOR
PA 2015 MANCHESTER RD, ANN ARBOR, MI 48104 USA
SN 0021-9738
EI 1558-8238
J9 J CLIN INVEST
JI J. Clin. Invest.
PD NOV 1
PY 2019
VL 129
IS 11
BP 4509
EP 4528
DI 10.1172/JCI125890
PG 20
WC Medicine, Research & Experimental
WE Science Citation Index Expanded (SCI-EXPANDED)
SC Research & Experimental Medicine
GA JJ2EM
UT WOS:000493974100017
PM 31287804
OA Bronze, Green Submitted, Green Accepted, Green Published
DA 2025-03-13
ER

EF