Targeting FGF19 inhibits tumor growth in colon cancer xenograft and FGF19 transgenic hepatocellular carcinoma models
Targeting FGF19 inhibits tumor growth in colon cancer xenograft and FGF19 transgenic hepatocellular carcinoma models
复制标题
DOI：
10.1038/sj.onc.1210623
复制
发表时间：
2008-01-03
期刊：
影响因子：
8
通讯作者：
French, Dm
中科院分区：
文献类型：
--
作者：
Desnoyers, Lr;Pai, R.;French, Dm
虽然成纤维细胞生长因子19(FGF19)可以促进小鼠肝癌的发生，但它与人类癌症的关系尚不清楚。在这里，我们报道了FGF19及其同源受体FGFR4(FGFR4)在原发的人肝、肺和结肠肿瘤以及人结肠癌细胞亚群中共表达。为了测试FGF19对肿瘤生长的重要性，我们开发了一种抗FGF19的单抗，它可以选择性地阻断FGF19与FGFR4的相互作用。该抗体在体外阻断了FGF19介导的活性，在体内抑制了结肠癌移植瘤的生长，并有效地预防了FGF19转基因小鼠的肝细胞癌。在这些模型中，抗体的有效性与抑制FGF19依赖的FGFR4、FRS2、ERK和β-连环蛋白的激活有关。这些发现表明，FGF19的失活可能有利于结肠癌、肝癌和其他涉及FGF19和FGFR4相互作用的恶性肿瘤的治疗。
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.