Abstract

Germ line VHL tumor suppressor gene loss-of-function mutations cause von Hippel-Lindau disease, which is associated with an increased risk of central nervous system hemangioblastomas, clear cell renal carcinomas, and pheochromocytomas. Somatic VHL mutations are also common in sporadic clear cell renal carcinomas. The VHL gene product, pVHL, is part of a ubiquitin ligase complex that targets the alpha-subunits of the heterodimeric transcription factor hypoxia-inducible factor (HIF) for polyubiquitylation, and hence, proteasomal degradation, when oxygen is available. pVHL-defective clear cell renal carcinomas overproduce a variety of mRNAs that are under the control of HIF, including the mRNAs that encode vascular endothelial growth factor, platelet-derived growth factor B, and transforming growth factor alpha. In preclinical models, down-regulation of HIF-alpha, especially HIF-2alpha, is both necessary and sufficient for renal tumor suppression by pVHL. These observations are probably relevant to the demonstrated clinical activity of vascular endothelial growth factor antagonists in clear cell renal carcinoma and form a foundation for the testing of additional agents that inhibit HIF, or HIF-responsive gene products, in this disease.

Highlights

  • Germ line von Hippel-Lindau tumor suppressor gene (VHL) tumor suppressor gene loss-of-function mutations cause von Hippel-Lindau disease, which is associated with an increased risk of central nervous system hemangioblastomas, clear cell renal carcinomas, and pheochromocytomas

  • Inactivation of the von Hippel-Lindau tumor suppressor gene (VHL), which is located on chromosome 3p25, plays an important role in hereditary (VHL disease) and sporadic clear cell renal carcinoma, which is the most common form of kidney cancer [1]

  • A total of 40% to 80% of sporadic clear cell renal carcinomas are linked to biallelic VHL inactivation, and in some VHL+/+ clear cell renal carcinomas, little or no VHL mRNA is produced as a result of promoter hypermethylation [1]

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Summary

Open Discussion

Dr Atkins: Is something other than the hypoxia-inducible factor driving the von Hippel-Lindau wild-type clear cell renal cancer?. Dr Kaelin: In most VHL wild-type renal carcinoma cell lines, it looks like HIF is regulated appropriately, meaning at least it is responsive to hypoxia. Dr Kaelin: I cannot prove that VHL loss is an early event versus a late event in sporadic clear cell carcinoma. We know that one of the features of renal cystic diseases is increased proliferation of renal epithelial cells, which might be due to cyclin D1 or transforming growth factor-a Another feature is alterations in epithelial stromal interactions, and there is a role for VHL in the regulation of the extracellular matrix. Dr Kaelin: Emerging data suggest that whether HIF1 can promote or inhibit tumor growth depends on what cell type are you looking at and in what context that cell is growing

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