Involvement of hypoxia-inducible factor 1 in human cancer.

Hypoxia-inducible factor 1 (HIF-1) mediates transcriptional responses to hypoxia. HIF-1 is composed of an O2- and growth factor-regulated HIF-1alpha subunit and a constitutively-expressed HIF-1beta subunit. Four lines of evidence indicate that HIF-1 contributes to tumor progression. First, HIF-1 controls the expression of gene products that stimulate angiogenesis, such as vascular endothelial growth factor, and promote metabolic adaptation to hypoxia, such as glucose transporters and glycolytic enzymes, thus providing a molecular basis for involvement of HIF-1 in tumor growth and angiogenesis. Second, in mouse xenograft models, tumor growth and angiogenesis are inhibited by loss of HIF-1 activity and stimulated by HIF-1alpha overexpression. Third, immunohistochemical analyses of human tumor biopsies indicate that HIF-1alpha is overexpressed in common cancers and that the level of expression is correlated with tumor grade, angiogenesis, and mortality. Fourth, in addition to intratumoral hypoxia, genetic alterations in tumor suppressor genes and oncogenes induce HIF-1 activity.