Institute of Cancer Research, Department of Medicine 1, Medical University Vienna, Borschkegasse 8a, 1090 Vienna, Austria.
Curr Pharm Des. 2014;20(17):2881-98. doi: 10.2174/13816128113199990594.
Fibroblast growth factors (FGF) and their tyrosine kinase receptors (FGFR) support cell proliferation, survival and migration during embryonic development, organogenesis and tissue maintenance and their deregulation is frequently observed in cancer development and progression. Consequently, increasing efforts are focusing on the development of strategies to target FGF/FGFR signaling for cancer therapy. Among the FGFRs the family member FGFR4 is least well understood and differs from FGFRs1-3 in several aspects. Importantly, FGFR4 deletion does not lead to an embryonic lethal phenotype suggesting the possibility that its inhibition in cancer therapy might not cause grave adverse effects. In addition, the FGFR4 kinase domain differs sufficiently from those of FGFRs1-3 to permit development of highly specific inhibitors. The oncogenic impact of FGFR4, however, is not undisputed, as the FGFR4-mediated hormonal effects of several FGF ligands may also constitute a tissue-protective tumor suppressor activity especially in the liver. Therefore it is the purpose of this review to summarize all relevant aspects of FGFR4 physiology and pathophysiology and discuss the options of targeting this receptor for cancer therapy.
成纤维细胞生长因子 (FGF) 及其酪氨酸激酶受体 (FGFR) 在胚胎发育、器官发生和组织维持过程中支持细胞增殖、存活和迁移，其失调在癌症的发展和进展中经常观察到。因此，越来越多的人致力于开发针对 FGF/FGFR 信号的策略，以将其作为癌症治疗的靶点。在 FGFR 家族中，FGFR4 成员了解最少，在几个方面与 FGFR1-3 不同。重要的是，FGFR4 缺失不会导致胚胎致死表型，这表明其在癌症治疗中的抑制作用可能不会引起严重的不良反应。此外，FGFR4 的激酶结构域与 FGFR1-3 的激酶结构域有足够的差异，允许开发高度特异性的抑制剂。然而，FGFR4 的致癌作用并非没有争议，因为几种 FGF 配体的 FGFR4 介导的激素作用也可能构成组织保护的肿瘤抑制活性，尤其是在肝脏中。因此，本综述的目的是总结 FGFR4 生理学和病理生理学的所有相关方面，并讨论针对该受体进行癌症治疗的选择。
