Targeting FGF19 inhibits tumor growth in colon cancer xenograft and FGF19 transgenic hepatocellular carcinoma models

被引：215

作者：

Desnoyers, Lr ^{[1
]}

Pai, R. ^{[2
]}

Ferrando, Re ^{[2
]}

Hotzel, K. ^{[2
]}

Le, T. ^{[3
]}

Ross, J. ^{[3
]}

Carano, R. ^{[3
]}

D'Souza, A. ^{[1
]}

Qing, J. ^{[1
]}

Mohtashemi, I. ^{[4
]}

Ashkenazi, A. ^{[1
]}

French, Dm ^{[2
]}

机构：

[1] Genentech Inc, Dept Mol Oncol, San Francisco, CA 94080 USA

[2] Genentech Inc, Dept Pathol, San Francisco, CA 94080 USA

[3] Genentech Inc, Dept Biomed Imaging, San Francisco, CA 94080 USA

[4] Genentech Inc, Dept Protein Chem, San Francisco, CA 94080 USA

来源：

ONCOGENE | 2008年 / 27卷 / 01期

关键词：

fibroblast growth factor; hepatocellular carcinoma; FGF19; colon adenocarcinoma; FGFR4; beta-catenin;

D O I：

10.1038/sj.onc.1210623

中图分类号：

Q5 [生物化学]; Q7 [分子生物学];

学科分类号：

071010 ; 081704 ;

摘要：

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.

引用

页码：85 / 97

页数：13

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