PLoS ONE：靶向FGFR4能够抑制肝细胞癌

近日，来自美国基因泰克公司的研究人员表示，靶向FGFR4能够抑制肝细胞癌。

成纤维细胞生长因子(FGF)是由垂体和下丘脑分泌的多肽，能促进成纤维细胞有丝分裂、中胚层细胞的生长，还可刺激血管形成，在创伤愈合及肢体再生中发挥重要作用。

FGF受体(FGFR)信号系统对正常的发育及生理过程具有至关重要的作用。业已证明，FGF-FGFR信号失调与肿瘤发生及演化息息相关。在老鼠体内，FGFR4–FGF19信号轴已经被发现与肝细胞癌(HCCs)紧密相关，可能在人类也是如此。

在这项研究里，他们发现FGFR4被需要于肝癌的发生。FGF19转基因小鼠的后代能够发展为HCCs，然而，与FGFR4敲除的老鼠所繁殖的后代不会发展为肝癌。

为了进一步研究FGFR4对肝细胞癌的重要性，他们发展了一个抗FGFR4的单克隆抗体(LD1)。LD1能够抑制FGF1和FGF19结合到FGFR4；还能抑制FGFR4介导的信号、集落形成以及体外增生；也能抑制肿瘤以癌症潜伏期模式生长。

结果发现，对比于正常组织，在包括肝癌的几种类型的癌症，FGFR4表达被明显提高。

Benjamin C. Lin表示，该研究阐明了肝细胞癌的发展及演化中FGFR4的调节作用，而FGFR4很有可能成为一个重要的癌症治疗靶点。（生物谷Deepblue）

doi: 10.1371/journal.pone.0036713
PMC:
PMID:

Targeting FGFR4 Inhibits Hepatocellular Carcinoma in Preclinical Mouse Models

Dorothy M. French, Benjamin C. Lin*, Manping Wang, Camellia Adams, Theresa Shek, Kathy Htzel, Brad Bolon, Ronald Ferrando, Craig Blackmore, Kurt Schroeder, Luis A. Rodriguez, Maria Hristopoulos, Rayna Venook, Avi Ashkenazi, Luc R. Desnoyers.

The fibroblast growth factor (FGF)-FGF receptor (FGFR) signaling system plays critical roles in a variety of normal developmental and physiological processes.It is also well documented that dysregulation of FGF-FGFR signaling may have important roles in tumor development and progression. The FGFR4–FGF19 signaling axis has been implicated in the development of hepatocellular carcinomas (HCCs) in mice, and potentially in humans.In this study, we demonstrate that FGFR4 is required for hepatocarcinogenesis; the progeny of FGF19 transgenic mice, which have previously been shown to develop HCCs, bred with FGFR4 knockout mice fail to develop liver tumors.To further test the importance of FGFR4 in HCC, we developed a blocking anti-FGFR4 monoclonal antibody (LD1). LD1 inhibited: 1) FGF1 and FGF19 binding to FGFR4, 2) FGFR4–mediated signaling, colony formation, and proliferation in vitro, and 3) tumor growth in a preclinical model of liver cancer in vivo.Finally, we show that FGFR4 expression is elevated in several types of cancer, including liver cancer, as compared to normal tissues.These findings suggest a modulatory role for FGFR4 in the development and progression of hepatocellular carcinoma and that FGFR4 may be an important and novel therapeutic target in treating this disease.