Open AccessFGF ‐1/‐3/ FGFR 4 signaling in cancer‐associated fibroblasts promotes tumor progression in colon cancer through Erk and MMP ‐7
Author(s) -
Bai YuPan,
Shang Kun,
Chen Huan,
Ding Fei,
Wang Zhen,
Liang Chen,
Xu Ye,
Sun MengHong,
LI YingYi
Publication year - 2015
Publication title -
cancer science
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 2.035
H-Index - 141
eISSN - 1349-7006
pISSN - 1347-9032
DOI - 10.1111/cas.12745
Subject(s) - fibroblast growth factor , matrix metalloproteinase , colorectal cancer , fibroblast growth factor receptor , mapk/erk pathway , cancer , cancer research , cancer associated fibroblasts , tumor progression , medicine , signal transduction , biology , cancer cell , microbiology and biotechnology , receptor
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.