Endothelial function of von Hippel-Lindau tumor suppressor gene: Control of fibroblast growth factor receptor signaling
Endothelial function of von Hippel-Lindau tumor suppressor gene: Control of fibroblast growth factor receptor signaling
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DOI：
10.1158/0008-5472.can-07-6003
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发表时间：
2008-06-15
期刊：
影响因子：
11.2
通讯作者：
Hsu, Tien
中科院分区：
文献类型：
--
作者：
Champion, Kristen J.;Guinea, Maria;Hsu, Tien
von Hippel-Lindau（VHL）病由VHL肿瘤抑制基因的生殖系和体细胞突变引起，并且以高度血管化的肿瘤为特征。VHL突变导致缺氧诱导因子（HIF）的稳定，其上调促血管生成因子，如血管内皮生长因子（VEGF）。因此，该途径被认为是VHL肿瘤的多血管表型的基础。然而，最近的研究已经确定了新的VHL功能，是独立的HIF-VEGF途径。此外，VHL在肿瘤微环境中的潜在作用，在VHL患者中携带杂合VHL突变，已被忽视。在这里，我们报告了一种新的HIF-独立的VHL功能的内皮细胞。原代人微血管内皮细胞中VHL敲低导致表面成纤维细胞生长因子（FGF）受体的缺陷性周转，增加细胞外信号调节激酶信号传导和ETS 1激活，导致细胞对FGF的反应增加运动性和体外三维索形成。VHL功能丧失内皮细胞中HIF-α的敲低并不妨碍其体外血管生成活性的升高。重要的是，对FGF的升高的血管生成应答在Vhl杂合小鼠中重现。因此，VHL在内皮细胞中的部分功能丧失可能是通过HIF-VEGF非依赖性机制促进肿瘤血管生成的因素。
von Hippel-Lindau (VHL) disease results from germline and somatic mutations in the VHL tumor suppressor gene and is characterized by highly vascularized tumors. VHL mutations lead to stabilization of hypoxia-inducible factor (HIF), which up-regulates proangiogenic factors such as vascular endothelial growth factor (VEGF). This pathway is therefore believed to underlie the hypervascular phenotypes of the VHL tumors. However, recent studies have identified novel VHL functions that are independent of the HIF-VEGF pathway. In addition, a potential role of VHL in the tumor microenvironment, which carries heterozygous VHL mutations in VHL patients, has been overlooked. Here, we report a novel HIF-independent VHL function in the endothelium. VHL knockdown in primary human microvascular endothelial cells caused defective turnover of surface fibroblast growth factor (FGF) receptor, increased extracellular signal-regulated kinase signaling, and ETS1 activation, leading to increased cell motility in response to FGF and three-dimensional cord formation in vitro. HIF-alpha knockdown in VHL loss-of-function endothelial cells does not impede their elevated in vitro angiogenic activity. Importantly, the elevated angiogenic response to FGF is recapitulated in Vhl-heterozygous mice. Thus, partial loss of function of VHL in endothelium may be a contributing factor in tumor angiogenesis through a HIF-VEGF-independent mechanism.