Treatment of kidney cancer: insights provided by the VHL tumor-suppressor protein.
Germline inactivation of the VHL tumor suppressor gene is associated with an increased risk of clear cell carcinoma of the kidney in the context of von Hippel-Lindau (VHL) disease. Somatic VHL mutations are also common in nonhereditary (sporadic) clear cell carcinomas. The VHL protein (pVHL) has multiple functions that might be linked to tumor suppression, including targeting the hypoxia inducible factor (HIF) transcription factor for polyubiquitylation and proteasomal degradation. HIF, especially HIF2alpha, appears to play a causal role in clear cell renal carcinogenesis based on genotype-phenotype correlations in VHL disease, laboratory experiments with human VHL-/- renal carcinoma cell lines, and genetically engineered mouse models. Deregulation of HIF almost certainly accounts for the high levels of vascular endothelial growth factor (VEGF) observed in kidney cancer and relates to their sensitivity to VEGF inhibitors. In addition, the beneficial effects of mammalian target of rapamycin (mTOR) inhibitors are likely due to, at least partly, their ability to down-regulate HIF. pVHL, in a HIF-independent manner, also regulates a specialized structure called the primary cilium and regulates apoptosis via factors such as NFkappaB. Loss of the primary cilium probably facilitates the development of preneoplastic renal cysts, whereas increased NFkappaB might contribute to the resistance of kidney cancers to conventional cytotoxic agents.
Kaelin
William G
WG
Howard Hughes Medical Institute, Dana-Farber Cancer Institute and Brigham and Women's Hospital, Harvard Medical School, 44 Binney Street, Mayer 457, Boston, MA 02115, USA. William_Kaelin@dfci.harvard.edu
D000818:Animals; D017209:Apoptosis; D051792:Basic Helix-Loop-Helix Proteins / Q000502:physiology; D002292:Carcinoma, Renal Cell / Q000235:genetics*; D016503:Drug Delivery Systems; D006801:Humans; D051795:Hypoxia-Inducible Factor 1, alpha Subunit / Q000502:physiology; D007680:Kidney Neoplasms / Q000235:genetics*; D051794:Von Hippel-Lindau Tumor Suppressor Protein / Q000502:physiology*; D000099162:Endothelial PAS Domain-Containing Protein 1
D051792:Basic Helix-Loop-Helix Proteins; D051795:Hypoxia-Inducible Factor 1, alpha Subunit; D051794:Von Hippel-Lindau Tumor Suppressor Protein; D000099162:Endothelial PAS Domain-Containing Protein 1; C497442:HIF1A protein, human