title: FGF-1/-3/FGFR4 signaling in cancer-associated fibroblasts promotes tumor progression in colon cancer through Erk and MMP-7.
abstract: Cancer-associated fibroblasts (CAFs), 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 CAFs. Fibroblast growth factor (FGF)-1 and FGF-3 were detected in infiltrating cells, and FGFR4, the specific receptor for FGF-1 and FGF-3, was detected in colon cancer tissues. The phosphorylation of FGFR4 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 CAFs, pericarcinoma fibroblasts (PFs), and normal fibroblasts (NFs) from human colon tissue specimens to characterize the function of CAFs. We observed that CAFs secrete more FGF-1/-3 than NFs and PFs and promote cancer cell growth and angiogenesis through the activation of FGFR4, 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 FGFR4 siRNA or the FGFR4 inhibitor PD173074 markedly suppressed colon cancer cell proliferation and neovascularization. These observations suggest a crucial role for CAFs 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.
authors.affiliation: Cancer Research Institute, Fudan University Shanghai Cancer Center, Shanghai, China.|Department of Oncology, Shanghai Medical College, Fudan University, Shanghai, China.
authors.forename: Yu-Pan
authors.initials: YP
authors.lastname: Bai
authors.affiliation: Cancer Research Institute, Fudan University Shanghai Cancer Center, Shanghai, China.|Department of Oncology, Shanghai Medical College, Fudan University, Shanghai, China.|Department of Nuclear Medicine, Xuanwu Hospital, Capital Medical University, Beijing, China.
authors.forename: Kun
authors.initials: K
authors.lastname: Shang
authors.affiliation: Department of Pathology, Fudan University Shanghai Cancer Center, Shanghai, China.
authors.forename: Huan
authors.initials: H
authors.lastname: Chen
authors.affiliation: Department of Pathology, Fudan University Shanghai Cancer Center, Shanghai, China.
authors.forename: Fei
authors.initials: F
authors.lastname: Ding
authors.affiliation: Cancer Research Institute, Fudan University Shanghai Cancer Center, Shanghai, China.|Department of Oncology, Shanghai Medical College, Fudan University, Shanghai, China.
authors.forename: Zhen
authors.initials: Z
authors.lastname: Wang
authors.affiliation: Cancer Research Institute, Fudan University Shanghai Cancer Center, Shanghai, China.|Department of Oncology, Shanghai Medical College, Fudan University, Shanghai, China.
authors.forename: Chen
authors.initials: C
authors.lastname: Liang
authors.affiliation: Department of Oncology, Shanghai Medical College, Fudan University, Shanghai, China.|Department of Colorectal Surgery, Fudan University Shanghai Cancer Center, Shanghai, China.
authors.forename: Ye
authors.initials: Y
authors.lastname: Xu
authors.affiliation: Department of Pathology, Fudan University Shanghai Cancer Center, Shanghai, China.
authors.forename: Meng-Hong
authors.initials: MH
authors.lastname: Sun
authors.affiliation: Cancer Research Institute, Fudan University Shanghai Cancer Center, Shanghai, China.|Department of Oncology, Shanghai Medical College, Fudan University, Shanghai, China.
authors.forename: Ying-Yi
authors.initials: YY
authors.lastname: Li
mesh_terms: D000818:Animals; D001397:Azoxymethane; D045744:Cell Line, Tumor; D003093:Colitis, Ulcerative / Q000378:metabolism / Q000473:pathology*; D003110:Colonic Neoplasms / Q000235:genetics / Q000473:pathology*; D016264:Dextran Sulfate; D004195:Disease Models, Animal; D018450:Disease Progression; D048049:Extracellular Signal-Regulated MAP Kinases / Q000378:metabolism*; D016220:Fibroblast Growth Factor 1 / Q000378:metabolism*; D051518:Fibroblast Growth Factor 3 / Q000378:metabolism* / Q000494:pharmacology; D005347:Fibroblasts / Q000378:metabolism; D045325:HCT116 Cells; D019073:HT29 Cells; D061307:Human Umbilical Vein Endothelial Cells; D006801:Humans; D020935:MAP Kinase Signaling System / Q000235:genetics; D020783:Matrix Metalloproteinase 7 / Q000378:metabolism*; D051379:Mice; D010766:Phosphorylation; D011743:Pyrimidines / Q000494:pharmacology; D034622:RNA Interference; D034741:RNA, Small Interfering; D020794:Receptor Protein-Tyrosine Kinases / Q000037:antagonists & inhibitors; D051499:Receptor, Fibroblast Growth Factor, Type 4 / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*; D017468:Receptors, Fibroblast Growth Factor / Q000037:antagonists & inhibitors
chemical_list: C496444:FGF3 protein, human; D051518:Fibroblast Growth Factor 3; C115711:PD 173074; D011743:Pyrimidines; D034741:RNA, Small Interfering; D017468:Receptors, Fibroblast Growth Factor; D016220:Fibroblast Growth Factor 1; D016264:Dextran Sulfate; C496371:FGFR4 protein, human; D020794:Receptor Protein-Tyrosine Kinases; D051499:Receptor, Fibroblast Growth Factor, Type 4; D048049:Extracellular Signal-Regulated MAP Kinases; C060932:MMP7 protein, human; D020783:Matrix Metalloproteinase 7; D001397:Azoxymethane
keywords: Cancer-associated fibroblasts; colon cancer; extracellular signal-regulated kinase; fibroblast growth factor; metalloproteinase-7