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

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 +2 more·2016·Cancer Research

Published version of a preprint

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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Crossref · 10.1158/0008-5472.can-15-2973

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  • CAFs secrete growth factors, proinflammatory cytokines, and chemokines, particularly TGF-β, IL-6, and CCL2, which recruit immunosuppressive cells into the tumor stroma and lead to immune escape.

    “In addition, CAFs secrete substantial amounts of growth factors, proinflammatory cytokines, and chemokines, particularly TGF-β, IL-6, and CC-chemokine ligand 2, which recruit immunosuppressive cells into the tumor stroma and lead to immune escape 20-22.”

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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)
Venue
Cancer Research
Published
2016-07-14
Volume
76
Issue
14
Pages
4124-4135
ISSN
  • 0008-5472 (ISSN-L)
  • 1538-7445
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
  • Health Sciences › Medicine › Oncology › 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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