Targeted replacement of hypoxia-inducible factor-1alpha by a hypoxia-inducible factor-2alpha knock-in allele promotes tumor growth.

Hypoxia-inducible factors (HIF) are essential transcriptional regulators that mediate adaptation to hypoxic stress in rapidly growing tissues such as tumors. HIF activity is regulated by hypoxic stabilization of the related HIF-1alpha and HIF-2alpha subunits, which are frequently overexpressed in cancer cells. To assess the relative tumor-promoting functions of HIF-1alpha and HIF-2alpha directly, we replaced HIF-1alpha expression with HIF-2alpha by creating a novel "knock-in" allele at the Hif-1alpha locus through homologous recombination in primary murine embryonic stem cells. Compared with controls, s.c. teratomas derived from knock-in embryonic stem cells were larger and more proliferative, had increased microvessel density, and exhibited increased expression of vascular endothelial growth factor, transforming growth factor-alpha, and cyclin D1. These and other data indicate that HIF-2alpha promotes tumor growth more effectively than HIF-1alpha in multiple contexts.