VHL Gene Deletion and Enhanced VEGF Gene Expression Detected in the Stromal Cells of Retinal Angioma

Chan, Chi Chao; Vortmeyer, A. O.; Chew, Emily Y.; Green, W. R.; Matteson, Dawn M.; Shen, De Fen; Linehan, W. Marston; Lubensky, Irina A.; Zhuang, Zhengping

doi:10.1001/archopht.117.5.625

Cited by 125 publications

(60 citation statements)

References 32 publications

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“…Hemangioblastoma, uncontrolled vessel growth occurring in the central nervous system and retinas of VHL patients, is the most common VHL-associated tumor (41,42). Interestingly, because loss of heterozygosity of VHL is found only in cells neighboring the overgrown vessels (42)(43)(44), termed stromal cells, it is generally believed that the endothelium plays only a passive role in the disease, responding to the VEGF overproduced by the VHL À/À cells. However, this tumor is exceedingly rare in non-VHL patient population (45), suggesting that heterozygosity of the VHL patient endothelial cells may be a contributing factor.…”

Section: Discussionmentioning

confidence: 99%

Endothelial Function of von Hippel-Lindau Tumor Suppressor Gene: Control of Fibroblast Growth Factor Receptor Signaling

et al. 2008

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Abstractvon 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-A 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.

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Section: Discussionmentioning

confidence: 99%

Endothelial Function of von Hippel-Lindau Tumor Suppressor Gene: Control of Fibroblast Growth Factor Receptor Signaling

et al. 2008

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“…103 Mutations result in upregulation of vascular endothelial growth factor and increased endothelial cell growth and migration. 104 Inheritance is autosomal dominant, but 20% of mutations occur de novo. However, two mutations are required for disease, one germline and one somatic.…”

Section: Von Hippel Lindau Disease (Omim 193300)mentioning

confidence: 99%

Retinal Abnormalities Characteristic of Inherited Renal Disease

Savige

Ratnaike

Colville

2011

Journal of the American Society of Nephrology

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“…These lesions are typically cystic tumors of endothelial cells and lipid-filled stromal cells embedded in capillaries [Kanno et al, 1994;Richard et al, 1998]. Stromal cells may play a neoplastic role by releasing angiogenic factors, like vascular endothelial growth factors (VEGF), whereas vascular cells appear to be nonneoplastic [Chan et al, 1999;Flamme et al, 1998;Lee et al, 1998;Morii et al, 1993;Vortmeyer et al, 1997;Wizigmann-Voos et al, 1995]. CNS hemangioblastomas are typically located in the cerebellum, but can also occur at the brainstem, spinal cord, and rarely, at the lumbosacral nerve roots and supratentorial [Neumann et al, 1995].…”

Section: Introductionmentioning

confidence: 99%

Genetic analysis of von Hippel-Lindau disease

et al. 2010

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Mutations in the von Hippel-Lindau (VHL) gene are responsible for VHL disease, congenital polycythemia, and are found in many sporadic tumor types as well. Reports of VHL mutations are dispersed throughout original articles and databases that have not been recently updated. We compiled a comprehensive mutation table of 1,548 germline and somatic VHL mutations, derived from this protein of only 213 amino acids. We describe detailed phenotype and gene mutation information for 945 VHL families, including 30 previously unpublished kindreds from The Netherlands (six novel mutations). These data represent the most extensive catalog of germline VHL mutations to date. We also review VHL disease, known and theorized pathogenesis of common VHL manifestations, and genotype-phenotype correlations. Analysis of all VHL families, excluding germline mutations resulting in congenital polycythemias, describes the spectrum of mutation types: 52% missense, 13% frameshift, 11% nonsense, 6% in-frame deletions/insertions, 11% large/complete deletions, and 7% splice mutations. This easy-to-use compilation of VHL mutations is intended to facilitate research and function as a necessary adjunct for physicians when providing patient information. Hum Mutat 31:521-537,

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VHL Gene Deletion and Enhanced VEGF Gene Expression Detected in the Stromal Cells of Retinal Angioma

Cited by 125 publications

References 32 publications

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

Retinal Abnormalities Characteristic of Inherited Renal Disease

Genetic analysis of von Hippel-Lindau disease

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