Abstract
Although fibroblast growth factor 19 (FGF19) can promote liver carcinogenesis in mice its involvement in human cancer is not well characterized. Here we report that FGF19 and its cognate receptor FGF receptor 4 (FGFR4) are coexpressed in primary human liver, lung and colon tumors and in a subset of human colon cancer cell lines. To test the importance of FGF19 for tumor growth, we developed an anti-FGF19 monoclonal antibody that selectively blocks the interaction of FGF19 with FGFR4. This antibody abolished FGF19-mediated activity in vitro and inhibited growth of colon tumor xenografts in vivo and effectively prevented hepatocellular carcinomas in FGF19 transgenic mice. The efficacy of the antibody in these models was linked to inhibition of FGF19-dependent activation of FGFR4, FRS2, ERK and beta-catenin. These findings suggest that the inactivation of FGF19 could be beneficial for the treatment of colon cancer, liver cancer and other malignancies involving interaction of FGF19 and FGFR4.
MeSH terms
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Animals
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Antibodies, Blocking / therapeutic use*
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Antibodies, Monoclonal / therapeutic use
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Antineoplastic Agents / pharmacology*
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Carcinoma, Hepatocellular / drug therapy*
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Carcinoma, Hepatocellular / genetics
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Carcinoma, Hepatocellular / immunology
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Carcinoma, Squamous Cell / drug therapy
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Carcinoma, Squamous Cell / immunology
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Carcinoma, Squamous Cell / metabolism
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Colonic Neoplasms / drug therapy*
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Colonic Neoplasms / genetics
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Colonic Neoplasms / immunology
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Fibroblast Growth Factors / antagonists & inhibitors*
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Fibroblast Growth Factors / biosynthesis
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Fibroblast Growth Factors / genetics
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Fibroblast Growth Factors / immunology
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Gene Targeting / methods*
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HCT116 Cells
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HT29 Cells
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Humans
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Liver Neoplasms, Experimental / drug therapy*
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Liver Neoplasms, Experimental / immunology
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Lung Neoplasms / drug therapy
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Lung Neoplasms / genetics
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Lung Neoplasms / immunology
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Mice
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Mice, Inbred BALB C
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Mice, Nude
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Mice, Transgenic
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Neoplasm Transplantation
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Receptor, Fibroblast Growth Factor, Type 4 / biosynthesis
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Receptor, Fibroblast Growth Factor, Type 4 / genetics
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Receptor, Fibroblast Growth Factor, Type 4 / metabolism
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Transplantation, Heterologous
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Xenograft Model Antitumor Assays / methods*
Substances
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Antibodies, Blocking
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Antibodies, Monoclonal
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Antineoplastic Agents
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FGF19 protein, human
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Fibroblast Growth Factors
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FGFR4 protein, human
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Receptor, Fibroblast Growth Factor, Type 4