Endothelial function of von Hippel-Lindau tumor suppressor gene: control of fibroblast growth factor receptor signaling.

Abstract:

: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.

journal_name

Cancer Res

journal_title

Cancer research

authors

Champion KJ,Guinea M,Dammai V,Hsu T

doi

10.1158/0008-5472.CAN-07-6003

subject

Has Abstract

pub_date

2008-06-15 00:00:00

pages

4649-57

issue

12

eissn

0008-5472

issn

1538-7445

pii

68/12/4649

journal_volume

68

pub_type

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