title: Hypoxia, Hypoxia-inducible Transcription Factors, and Renal Cancer.
abstract: BACKGROUND
  Renal cancer is a common urologic malignancy, and therapeutic options for metastatic disease are limited. Most clear cell renal cell carcinomas (ccRCC) are associated with loss of von Hippel-Lindau tumor suppressor (pVHL) function and deregulation of hypoxia pathways.
  
  
  OBJECTIVE
  This review summarizes recent evidence from genetic and biological studies showing that hypoxia and hypoxia-related pathways play critical roles in the development and progress of renal cancer.
  
  
  METHODS
  We used a systematic search for articles using the keywords hypoxia, HIF, renal cancer, and VHL.
  
  
  RESULTS
  Identification of the tumor suppressor pVHL has allowed the characterization of important ccRCC-associated pathways. pVHL targets α-subunits of hypoxia-inducible transcription factors (HIF) for proteasomal degradation. The two main HIF-α isoforms have opposing effects on RCC biology, possibly through distinct interactions with additional oncogenes. Furthermore, HIF-1α activity is commonly diminished by chromosomal deletion in ccRCCs, and increased HIF-1 activity reduces tumor burden in xenograft tumor models. Conversely, polymorphisms at the HIF-2α gene locus predispose to the development of ccRCCs, and HIF-2α promotes tumor growth. Genetic studies have revealed a prominent role for chromatin-modifying enzyme genes in ccRCC, and these may further modulate specific aspects of the HIF response. This suggests that, rather than global activation of HIF, specific components of the response are important in promoting kidney cancer. Some of these processes are already targets for current therapeutic strategies, and further dissection of this pathway might yield novel methods of treating RCC.
  
  
  CONCLUSIONS
  In contrast to many tumor types, HIF-1α and HIF-2α have opposing effects in ccRCC biology, with HIF-1α acting as a tumor suppressor and HIF-2α acting as an oncogene. The overall effect of VHL inactivation will depend on fine-tuning of the HIF response.
  
  
  RESULTS
  High levels of hypoxia-inducible transcription factors (HIF) are particularly important in the clear cell type of kidney cancer, in which they are no longer properly regulated by the von Hippel-Lindau protein. The two HIF-α proteins have opposing effects on tumor evolution.
authors: Medizinische Klinik 4 and Translational Research Center, Universitätsklinikum Erlangen und Friedrich-Alexander-Universität (FAU) Erlangen-Nürnberg, Erlangen, Germany. Electronic address: Johannes.Schoedel@uk-erlangen.de.
authors: Johannes
authors: J
authors: Schödel
authors: Medizinische Klinik 4 and Translational Research Center, Universitätsklinikum Erlangen und Friedrich-Alexander-Universität (FAU) Erlangen-Nürnberg, Erlangen, Germany.
authors: Steffen
authors: S
authors: Grampp
authors: Department of Medical Genetics, University of Cambridge, Cambridge Biomedical Campus, Cambridge, UK; Cambridge NIHR Biomedical Research Centre, Addenbrooke's Hospital, Cambridge, UK.
authors: Eamonn R
authors: ER
authors: Maher
authors: Institute of Surgical Pathology, University Hospital Zurich, University of Zurich, Zurich, Switzerland.
authors: Holger
authors: H
authors: Moch
authors: Henry Wellcome Building for Molecular Physiology, University of Oxford, Oxford, UK.
authors: Peter J
authors: PJ
authors: Ratcliffe
authors: Department of Surgery, Urology Service, Memorial Sloan Kettering Cancer Center, NY, NY, USA; Weill Medical College, Cornell University, Memorial Sloan Kettering Cancer Center, NY, NY, USA.
authors: Paul
authors: P
authors: Russo
authors: Henry Wellcome Building for Molecular Physiology, University of Oxford, Oxford, UK.
authors: David R
authors: DR
authors: Mole
mesh_terms: D000818:Animals; D051792:Basic Helix-Loop-Helix Proteins / Q000096:biosynthesis* / Q000235:genetics; D002292:Carcinoma, Renal Cell / Q000235:genetics / Q000378:metabolism* / Q000473:pathology / Q000628:therapy; D015687:Cell Hypoxia; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D051795:Hypoxia-Inducible Factor 1, alpha Subunit / Q000096:biosynthesis* / Q000235:genetics; D007680:Kidney Neoplasms / Q000235:genetics / Q000378:metabolism* / Q000473:pathology / Q000628:therapy; D010100:Oxygen / Q000378:metabolism*; D011379:Prognosis; D015398:Signal Transduction; D059016:Tumor Microenvironment; D015854:Up-Regulation; D051794:Von Hippel-Lindau Tumor Suppressor Protein / Q000235:genetics / Q000378:metabolism; D000099162:Endothelial PAS Domain-Containing Protein 1
chemical_list: D051792:Basic Helix-Loop-Helix Proteins; D051795:Hypoxia-Inducible Factor 1, alpha Subunit; D010100:Oxygen; D051794:Von Hippel-Lindau Tumor Suppressor Protein; D000099162:Endothelial PAS Domain-Containing Protein 1; C497442:HIF1A protein, human; C497446:VHL protein, human
keywords: Clear cell renal cell carcinoma; Hypoxia; Hypoxia-inducible transcription factors; von Hippel-Lindau