Hypoxia inducible factor-2alpha: a critical mediator of aggressive tumor phenotypes.

Intra-tumoral hypoxia (low oxygen [O(2)] level) is an independent indicator of unfavorable patient diagnosis, and increasing evidence demonstrates that hypoxia contributes to a more aggressive tumor phenotype. Adaptation to hypoxia is predominantly regulated by two structurally related hypoxia inducible factors, HIF-1alpha and HIF-2alpha, which activate the expression of genes involved in proliferation, metabolism, angiogenesis, and metastasis. While highly homologous, HIF-1alpha and HIF-2alpha have been shown to have different roles in tumorigenesis dependent on specific tumor microenvironments. Here we summarize recent studies on HIF-2alpha and discuss the potential mechanisms whereby it contributes to tumor aggressiveness.