Hypoxia, clonal selection, and the role of HIF-1 in tumor progression

Tumor progression occurs as a result of the clonal selection of cells in wh ich somatic mutations have activated oncogenes or inactivated tumor suppres sor genes leading to increased proliferation and/or survival within the hyp oxic tumor microenvironment. Hypoxia-inducible factor 1 (HIF-1) is a transc ription factor that mediates adaptive responses to reduced O-2 availability , including angiogenesis and glycolysis. Expression of the O-2-regulated HI F-1(alpha) subunit and HIF-1 transcriptional activity are increased dramati cally in hypoxic cells. Recent studies indicate that many common tumor-spec ific genetic alterations also lead to increased HIF-1 alpha expression and/ or activity. Thus, genetic and physiologic alterations within tumors act sy nergistically to increase HIF-1 transcriptional activity, which appears to play a critical role in the development of invasive and metastatic properti es that define the lethal cancer phenotype.