Hypoxia inducible factor-2alpha in cancer

Poorly oxygenated (hypoxic) tumors are frequently more aggressive compared to corresponding tumors that are better oxygenated. Adaptation to hypoxia is primarily mediated by two closely related hypoxia inducible transcription factor complexes, HIF-1 and HIF-2, which become stabilized and activated at low oxygen levels. Whether HIF-1 and HIF-2 have different roles in tumorigenesis is an open question and an issue we discuss. With focus on HIF-2, we summarize reported phenotypical changes of HIF genetic models and HIF expression patterns during normal development, in adult non-malignant tissues and in tumors. We further address the much-discussed subject of target gene preferences between HIF-1 and HIF-2, given that both transcription factors bind to the same DNA motif. Finally, we also discuss the observations that the oxygen-sensitive HIF-2alpha subunit is accumulated and active under non-hypoxic conditions as exemplified by HIF-2alpha expressing tumor macrophages and neuroblastoma cells located in seemingly well-vascularized tumor regions and how this phenomenon is related to tumor aggressiveness.