The molecular biology of kidney cancer and its clinical translation into treatment strategies
The most common histologic type of kidney cancer is clear cell renal carcinoma. Most clear cell renal carcinomas are linked to somatic inactivation of the von Hippel-Lindau tumor suppressor gene (VHL), either as a result of mutations or, less commonly, hypermethylation. The VHL gene product, pVHL, has multiple functions. The best understood function, and the one most tightly linked to renal carcinogenesis, is to serve as the substrate recognition component of an ubiquitin ligase complex that targets the HIFα transcription factor for destruction when tissue oxygenation is adequate. In hypoxic tumor cells, or in tumor cells lacking functional pVHL, HIFα becomes stabilized, binds to its partner protein HIFβ (also called ARNT), and transcriptionally activates ~100-200 genes that promote adaptation to hypoxia including the genes encoding vascular endothelial growth factor (VEGF) and platelet-derived growth factor B (PDGF B). This probably explains the neoangiogenesis that is typical of clear cell renal carcinomas and their sensitivity to drugs, such as sorafenib, sunitinib, and bevacizumab, that inhibit VEGF or its receptor KDR. In addition to pVHL, HIFα levels are also influenced by activity of the mTOR kinase. pVHL-defective tumor cells are sensitive to mTOR inhibitors in preclinical models and mTOR inhibitors have recently demonstrated activity in the clinic for the treatment of kidney cancer. © 2009 Humana Press.
