FGF ‐1/‐3/ FGFR 4 signaling in cancer‐associated fibroblasts promotes tumor progression in colon cancer through Erk and MMP ‐7
Open accessAbstract
Cancer‐associated fibroblasts ( CAF s), as the activated fibroblasts in the tumor stroma, are important modifiers of tumour progression. In the present study, we observed that azoxymethane and dextran sodium sulfate treatments induced increasingly severe colorectal mucosal inflammation and the intratumoural accumulation of CAF s. Fibroblast growth factor ( FGF )‐1 and FGF ‐3 were detected in infiltrating cells, and FGFR 4, the specific receptor for FGF ‐1 and FGF ‐3, was detected in colon cancer tissues. The phosphorylation of FGFR 4 enhanced the production of metalloproteinase ( MMP )‐7 and mitogen‐activated protein kinase kinase (Mek)/extracellular signal‐regulated kinase (Erk), which was accompanied by excessive vessel generation and cell proliferation. Moreover, we separated CAF s, pericarcinoma fibroblasts ( PF s), and normal fibroblasts ( NF s) from human colon tissue specimens to characterize the function of CAF s. We observed that CAF s secrete more FGF ‐1/‐3 than NF s and PF s and promote cancer cell growth and angiogenesis through the activation of FGFR 4, which is followed by the activation of Mek/Erk and the modulation of MMP ‐7 expression. The administration of FGF ‐1/‐3‐neutralizing antibodies or the treatment of cells with FGFR 4 si RNA or the FGFR 4 inhibitor PD 173074 markedly suppressed colon cancer cell proliferation and neovascularization. These observations suggest a crucial role for CAF s and FGF signaling in the initiation and progression of colorectal cancer. The inhibition of the FGF signaling pathway may be a useful strategy for the treatment of colon cancer.
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Many receptor tyrosine kinase inhibitors have activity on FGF and PDGF receptors that can drive fibroblast function.
“Many of the expanding range of receptor tyrosine kinase inhibitors have some activity on FGF and PDGF receptors that can drive fibroblast function148,149.”
From A framework for advancing our understanding of cancer-associated fibroblasts (2020) · cites this paper as [149]
The Results section reports that one FGFR-selective inhibitor, PD173074, inhibits FGF-induced FGFR4 signaling in the cancer-associated fibroblast pathway. The paper identifies PDGFRβ as a fibroblast marker, but does not show that PDGF-receptor signaling drives fibroblast function or that many tyrosine kinase inhibitors act on FGF and PDGF receptors. No page numbers are available in our copy. (LLM, conf=0.82)
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A framework for advancing our understanding of cancer-associated fibroblasts
Sahai, E., Astsaturov, I., Cukierman, E., DeNardo, D. G., Egeblad, M., Evans, R. M., Fearon, D., Greten, F. R., Hingorani, S. R., Hunter, T., et al. (2020) · Nature Reviews Cancer · doi:10.1038/s41568-019-0238-1 · Cited by 3,863 · see citing works
Deng, L., Jiang, N., Zeng, J., Wang, Y., & Cui, H. (2021) · Frontiers in Cell and Developmental Biology · doi:10.3389/fcell.2021.733270 · Cited by 51 · see citing works
Fotsitzoudis, C., Koulouridi, A., Messaritakis, I., Konstantinidis, T., Gouvas, N., Tsiaoussis, J., & Souglakos, J. (2022) · Cancers · doi:10.3390/cancers14184394 · Cited by 46 · see citing works
- Authors
- Bai, Y., Shang, K., Chen, H., Ding, F., Wang, Z., Liang, C., Xu, Y., Sun, M., & LI, Y.
- Affiliations
- Shanghai Medical College of Fudan University (CN)
- Fudan University (CN)
- Department of Pathology Fudan University Shanghai Cancer Center Shanghai China
- Corresponding author
- LI, Ying‐Yi
- Venue
- Cancer Science
- Publisher
- Wiley
- Published
- 2015-09-04
- Volume
- 106
- Issue
- 10
- Pages
- 1278-1287
- ISSN
- 1347-9032 (ISSN-L)
- 1349-7006
- PMC
- PMC4637995
- OpenAlex
- W1907149477
- Cited by
- 109
- References
- 3
- Citations by year
- 2026: 6 · 2025: 6 · 2024: 11 · 2023: 12 · 2022: 20 · 2021: 15 · 2020: 11 · 2019: 12 · 2018: 6 · 2017: 7 · 2016: 3
- FWCI
- 2.32
- Type
- journal article
- Language
- en
- Open access
- gold
- doi.org
- Licence
- Locations
- Cancer Science (publishedVersion, cc-by-nc-nd)
- Europe PMC (PubMed Central) (publishedVersion, cc-by-nc-nd)
- PubMed Central (publishedVersion, cc-by-nc-nd)
- PubMed (publishedVersion)
- Funders
- National Science Foundation of China (81272727, 82472223)
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Fibroblast Growth Factor Research
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › TGF-β signaling in diseases
- Health Sciences › Medicine › Oncology › Cancer Cells and Metastasis
- Keywords
- cancer-associated fibroblasts, FGF1, colon cancer, tumor progression, MMP-7, angiogenesis, colorectal inflammation, azoxymethane/dextran sulfate sodium, PD173074, tumor stroma
- MeSH terms
- Animals, Azoxymethane, Colitis, Ulcerative, Colonic Neoplasms, Disease Models, Animal, Fibroblasts, Humans, Phosphorylation, Pyrimidines, Fibroblast Growth Factor 1, Dextran Sulfate, Receptors, Fibroblast Growth Factor, Disease Progression, HT29 Cells, Matrix Metalloproteinase 7, Receptor Protein-Tyrosine Kinases, MAP Kinase Signaling System, RNA Interference, RNA, Small Interfering, HCT116 Cells, Cell Line, Tumor, Extracellular Signal-Regulated MAP Kinases, Mice, Receptor, Fibroblast Growth Factor, Type 4, Fibroblast Growth Factor 3, Human Umbilical Vein Endothelial Cells
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