Hypoxia, Clonal Selection, and the Role of HIF-1 in Tumor Progression

Abstract

Tumor progression occurs as a result of the clonal selection of cells in which somatic mutations have activated oncogenes or inactivated tumor suppressor genes leading to increased proliferation and/or survival within the hypoxic tumor microenvironment. Hypoxia-inducible factor 1 (HIF-1) is a transcription factor that mediates adaptive responses to reduced O₂ availability, including angiogenesis and glycolysis. Expression of the O₂-regulated HIF-1α subunit and HIF-1 transcriptional activity are increased dramatically in hypoxic cells. Recent studies indicate that many common tumor-specific genetic alterations also lead to increased HIF-1α expression and/or activity. Thus, genetic and physiologic alterations within tumors act synergistically to increase HIF-1 transcriptional activity, which appears to play a critical role in the development of invasive and metastatic properties that define the lethal cancer phenotype.

KEY WORDS: :

• angiogenesis
• cancer
• glycolysis p53
• Ras
• vascular endothelial growth factor.