Endocrine fibroblast growth factor FGF19 promotes prostate cancer progression.
Endocrine fibroblast growth factor FGF19 promotes prostate cancer progression.
复制标题
DOI：
10.1158/0008-5472.can-12-4108
复制
发表时间：
2013-04-15
期刊：
影响因子：
11.2
通讯作者：
Ittmann M
中科院分区：
文献类型：
--
作者：
Feng S;Dakhova O;Creighton CJ;Ittmann M
前列腺癌（PCa）是最常见的内脏恶性肿瘤，也是美国男性癌症死亡的第二大原因。有广泛的证据表明FGF受体在PCa的发生和进展中是重要的，但特定FGF在这种疾病中的作用尚未完全了解。FGF家族成员FGF 19、FGF 21和FGF 23包含在血清中循环并以内分泌方式起作用的不同亚家族。这些内分泌FGF需要α-Klotho（KL）和/或β-Klotho（KLB），这两种相关的单程跨膜蛋白在其组织分布中受到限制，以作为共受体沿着经典FGF介导有效的生物活性。在这里，我们表明，FGF 19表达在原发性和转移性前列腺癌组织中，它作为一个自分泌生长因子的功能。外源性FGF 19在低配体浓度下促进PCa细胞的生长、侵袭、粘附和集落形成。表达自分泌FGF 19的PCa细胞中的FGF 19沉默降低了体外侵袭和增殖以及体内肿瘤生长。与这些观察结果一致，KL和/或KLB在体外和体内PCa细胞中表达，提高了额外的内分泌FGF也可能在PCa中发挥生物学作用的可能性。我们的研究结果支持这样的概念，即靶向FGFR信号传导的疗法可能对PCa有效，并且它们强调FGF 19在这种情况下是相关的内分泌FGF。
Prostate cancer (PCa) is the most common visceral malignancy and the second leading cause of cancer deaths in US men. There is broad evidence that FGF receptors are important in PCa initiation and progression, but the contribution of particular FGFs in this disease is not fully understood. The FGF family members FGF19, FGF21 and FGF23 comprise a distinct subfamily that circulate in serum and act in an endocrine manner. These endocrine FGFs require α-Klotho (KL) and/or β-Klotho (KLB), two related single-pass transmembrane proteins restricted in their tissue distribution, to act as co-receptors along with classic FGFRs to mediate potent biological activity. Here we show that FGF19 is expressed in primary and metastatic PCa tissues where it functions as an autocrine growth factor. Exogenous FGF19 promoted the growth, invasion, adhesion and colony formation of PCa cells at low ligand concentrations. FGF19 silencing in PCa cells expressing autocrine FGF19 decreased invasion and proliferation in vitro and tumor growth in vivo. Consistent with these observations, KL and/or KLB were expressed in PCa cells in vitro and in vivo, raising the possibility that additional endocrine FGFs may also exert biological effects in PCa. Our findings support the concept that therapies targeting FGFR signaling these therapies may have efficacy in PCa and they highlight FGF19 as a relevant endocrine FGF in this setting.