Pseudohypoxic pathways in renal cell carcinoma.

Mutations of the von Hippel-Lindau (VHL) or fumarate hydratase (FH) genes lead to morphologically different renal cell carcinomas with distinct clinical courses and outcomes. The VHL protein is a part of an ubiquitin ligase complex that targets proteins for proteosomal degradation. FH is one of the mitochondrial enzymes of the Kreb's cycle. Despite two different functionalities and cellular locations, loss of either VHL or FH products has been shown to alter expression levels of hypoxia-inducible factors (HIF-1alpha and HIF-2alpha) and their downstream targets. HIF proteins are key regulators of oxygen homeostasis. Tight regulation of HIF allows for cell survival and growth at the time of hypoxic stress. HIF acts via transcriptional regulation of vascular endothelial growth factor, platelet derived growth factor, endothelial growth factor receptor, glucose transporter protein 1, erythropoietin, and transforming growth factor-alpha. Loss of VHL or FH is thought to result in a pseudohypoxic state so that cellular response pathways mediated by HIF are activated despite normal oxygen conditions. Understanding of these pseudohypoxic pathways has provided a better appreciation of the molecular mechanisms of carcinogenesis in addition to providing a rationale for targeted therapeutic approaches.