HIF1α and HIF2α: sibling rivalry in hypoxic tumour growth and progression

Hypoxia-inducible factors (HIFs) are broadly expressed in human cancers, and HIF1 alpha and HIF2 alpha were previously suspected to promote tumour progression through largely overlapping functions. However, this relatively simple model has now been challenged in light of recent data from various approaches that reveal unique and sometimes opposing activities of these HIF alpha isoforms in both normal physiology and disease. These effects are mediated in part through the regulation of unique target genes, as well as through direct and indirect interactions with important oncoproteins and tumour suppressors, including MYC and p53. As HIF inhibitors are currently undergoing clinical evaluation as cancer therapeutics, a more thorough understanding of the unique roles performed by HIF1 alpha and HIF2 alpha in human neoplasia is warranted.