Authors' Affiliation: NGM Biopharmaceuticals, Inc., South San Francisco, California.
Authors' Affiliation: NGM Biopharmaceuticals, Inc., South San Francisco, California
Cancer Res. 2014 Jun 15;74(12):3306-16. doi: 10.1158/0008-5472.CAN-14-0208. Epub 2014 Apr 11.
Hepatocellular carcinoma (HCC), one of the leading causes of cancer-related death, develops from premalignant lesions in chronically damaged livers. Although it is well established that FGF19 acts through the receptor complex FGFR4-β-Klotho (KLB) to regulate bile acid metabolism, FGF19 is also implicated in the development of HCC. In humans, FGF19 is amplified in HCC and its expression is induced in the liver under cholestatic and cirrhotic conditions. In mice, ectopic overexpression of FGF19 drives HCC development in a process that requires FGFR4. In this study, we describe an engineered FGF19 (M70) that fully retains bile acid regulatory activity but does not promote HCC formation, demonstrating that regulating bile acid metabolism is distinct and separable from tumor-promoting activity. Mechanistically, we show that FGF19 stimulates tumor progression by activating the STAT3 pathway, an activity eliminated by M70. Furthermore, M70 inhibits FGF19-dependent tumor growth in a rodent model. Our results suggest that selectively targeting the FGF19-FGFR4 pathway may offer a tractable approach to improve the treatment of chronic liver disease and cancer.
肝细胞癌（HCC）是癌症相关死亡的主要原因之一，它由慢性受损肝脏中的癌前病变发展而来。虽然已经确定 FGF19 通过 FGFR4-β-Klotho（KLB）受体复合物发挥作用来调节胆汁酸代谢，但 FGF19 也与 HCC 的发展有关。在人类中，FGF19 在 HCC 中扩增，并且在胆汁淤积和肝硬化条件下在肝脏中诱导其表达。在小鼠中，FGF19 的异位过表达在需要 FGFR4 的情况下驱动 HCC 的发展。在这项研究中，我们描述了一种工程化的 FGF19（M70），它完全保留了胆汁酸调节活性，但不促进 HCC 形成，证明调节胆汁酸代谢与促进肿瘤形成的活性是不同的和可分离的。从机制上讲，我们表明 FGF19 通过激活 STAT3 途径刺激肿瘤进展，而 M70 消除了这种活性。此外，M70 在啮齿动物模型中抑制 FGF19 依赖性肿瘤生长。我们的结果表明，选择性靶向 FGF19-FGFR4 途径可能为改善慢性肝病和癌症的治疗提供一种可行的方法。
