近日，來自美國基因泰克公司的研究人員表示,，靶向FGFR4能夠抑制肝細(xì)胞癌,。
成纖維細(xì)胞生長因子(FGF)是由垂體和下丘腦分泌的多肽,，能促進(jìn)成纖維細(xì)胞有絲分裂、中胚層細(xì)胞的生長,，還可刺激血管形成,，在創(chuàng)傷愈合及肢體再生中發(fā)揮重要作用。
FGF受體(FGFR)信號系統(tǒng)對正常的發(fā)育及生理過程具有至關(guān)重要的作用,。業(yè)已證明,，F(xiàn)GF-FGFR信號失調(diào)與腫瘤發(fā)生及演化息息相關(guān)。在老鼠體內(nèi),，F(xiàn)GFR4–FGF19信號軸已經(jīng)被發(fā)現(xiàn)與肝細(xì)胞癌(HCCs)緊密相關(guān),，可能在人類也是如此。
在這項(xiàng)研究里,，他們發(fā)現(xiàn)FGFR4被需要于肝癌的發(fā)生,。FGF19轉(zhuǎn)基因小鼠的后代能夠發(fā)展為HCCs，然而,，與FGFR4敲除的老鼠所繁殖的后代不會(huì)發(fā)展為肝癌,。
為了進(jìn)一步研究FGFR4對肝細(xì)胞癌的重要性，他們發(fā)展了一個(gè)抗FGFR4的單克隆抗體(LD1),。LD1能夠抑制FGF1和FGF19結(jié)合到FGFR4,；還能抑制FGFR4介導(dǎo)的信號、集落形成以及體外增生,；也能抑制腫瘤以癌癥潛伏期模式生長,。
結(jié)果發(fā)現(xiàn),，對比于正常組織,，在包括肝癌的幾種類型的癌癥，F(xiàn)GFR4表達(dá)被明顯提高,。
Benjamin C. Lin表示,，該研究闡明了肝細(xì)胞癌的發(fā)展及演化中FGFR4的調(diào)節(jié)作用，而FGFR4很有可能成為一個(gè)重要的癌癥治療靶點(diǎn),。（生物谷Deepblue）
doi: 10.1371/journal.pone.0036713
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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.
