HIF-1: Using two hands to flip the angiogenic switch

In brain, breast, and other common human tumors there is a correlation betw een expression of the transcriptional activator hypoxia-inducible factor 1 (HIF-1) and tumor grade and vascularization. HIF-1 stimulates angiogenesis by activating transcription of the gene encoding vascular endothelial growt h factor (VEGF). HIF-1 is a heterodimer consisting of a constitutively-expr essed HIF-1 beta subunit and an O-2- and growth factor-regulated HIF-1 alph a subunit. Recent studies have demonstrated that HIF-1 alpha expression is increased in tumor relative to normal tissue by two mechanisms. First, decr eased intratumoral O-2 concentrations provide a physiological stimulus. Sec ond, genetic alterations that activate oncogene products or inactivate tumo r suppressor gene products increase HIF-1 alpha expression and/or HIF-1 tra nscriptional activity independent of the O-2 concentration. Taken together, these recent data suggest that increased HIF-1 activity provides a molecul ar basis for VEGF-induced angiogenesis and other adaptations of cancer cell s to hypoxia that are critical for establishment of a primary tumor and its progression to the lethal phenotype.