Cited by 757Peptidase Inhibition and AnalysisImmune cells in cancerTGF-β signaling in diseases

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FAP Promotes Immunosuppression by Cancer-Associated Fibroblasts in the Tumor Microenvironment via STAT3–CCL2 Signaling

Yang, Xuguang, Lin, Yuli, Shi, Yinghong, Li, Bingji, Liu, Weiren, Yin, Wei, Dang, Yongjun, Chu, Yiwei, Fan, Jia, He, Rui·2016·Cancer Research

DOI 10.1158/0008-5472.can-15-2973

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Abstract

Cancer-associated fibroblasts (CAF) are components of the tumor microenvironment whose contributions to malignant progression are not fully understood. Here, we show that the fibroblast activation protein (FAP) triggers induction of a CAF subset with an inflammatory phenotype directed by STAT3 activation and inflammation-associated expression signature marked by CCL2 upregulation. Enforcing FAP expression in normal fibroblasts was sufficient to endow them with an inflammatory phenotype similar to FAP(+)CAFs. We identified FAP as a persistent activator of fibroblastic STAT3 through a uPAR-dependent FAK-Src-JAK2 signaling pathway. In a murine liver tumor model, we found that FAP(+)CAFs were a major source of CCL2 and that fibroblastic STAT3-CCL2 signaling in this setting promoted tumor growth by enhancing recruitment of myeloid-derived suppressor cells (MDSC). The CCL2 receptor CCR2 was expressed on circulating MDSCs in tumor-bearing subjects and FAP(+)CAF-mediated tumor promotion and MDSC recruitment was abrogated in Ccr2-deficient mice. Clinically, we observed a positive correlation between stromal expression of FAP, p-STAT3, and CCL2 in human intrahepatic cholangiocarcinoma, a highly aggressive liver cancer with dense desmoplastic stroma, where elevated levels of stromal FAP predicted a poor survival outcome. Taken together, our results showed how FAP-STAT3-CCL2 signaling in CAFs was sufficient to program an inflammatory component of the tumor microenvironment, which may hav…

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Authors: Yang, X., Lin, Y., Shi, Y., Li, B., Liu, W., Yin, W., Dang, Y., Chu, Y., Fan, J., & He, R.
Affiliations: Shanghai Medical College of Fudan University (CN)
ORCID: Yang, Xuguang
Lin, Yuli
Li, Bingji
Liu, Weiren
Yin, Wei
Dang, Yongjun
Chu, Yiwei
Fan, Jia
He, Rui
Venue: Cancer Research
Publisher: American Association for Cancer Research (AACR)
Published: 2016-07-14
Volume: 76
Issue: 14
Pages: 4124-4135
ISSN: 0008-5472 (ISSN-L)
1538-7445
DOI: 10.1158/0008-5472.can-15-2973
OpenAlex: W2400022769
Cited by: 748
References: 44
Citations by year: 2026: 66 · 2025: 101 · 2024: 107 · 2023: 115 · 2022: 91 · 2021: 95 · 2020: 67 · 2019: 47 · 2018: 31 · 2017: 25 · 2016: 3
FWCI: 19.03
Type: journal article
Language: en
Open access: closed
Locations: Cancer Research (publishedVersion)
PubMed (publishedVersion)
Funders: NSFC (813220437, 81471555, 81272389)
National Key Sci-Tech Project (2012ZX10002011-002)
Topics: Life Sciences › Biochemistry, Genetics and Molecular Biology › Biochemistry › Peptidase Inhibition and Analysis
Life Sciences › Immunology and Microbiology › Immunology › Immune cells in cancer
Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › TGF-β signaling in diseases
Keywords: fibroblast activation protein, cancer-associated fibroblasts, tumor microenvironment, STAT3 signaling, MCP-1, CCR2, myeloid-derived suppressor cells, uPAR, desmoplasia, intrahepatic cholangiocarcinoma, liver cancer, immunosuppression, tumor stroma
MeSH terms: Cancer-Associated Fibroblasts, Fibroblast Activation Protein Alpha, Animals, Cell Movement, Female, Immune Tolerance, Membrane Proteins, Mice, Inbred C57BL, Endopeptidases, Serine Endopeptidases, Signal Transduction, Gelatinases, Chemokine CCL2, STAT3 Transcription Factor, Mice, Focal Adhesion Protein-Tyrosine Kinases, Janus Kinase 2, Receptors, Urokinase Plasminogen Activator, Tumor Microenvironment

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FAP Promotes Immunosuppression by Cancer-Associated Fibroblasts in the Tumor Microenvironment via STAT3–CCL2 Signaling

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