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

Crit Rev Biochem Mol Biol. 2000;35(2):71-103. doi: 10.1080/10409230091169186.


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-1alpha 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-1alpha 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.

Publication types

  • Research Support, Non-U.S. Gov't
  • Research Support, U.S. Gov't, P.H.S.
  • Review

MeSH terms

  • Brain Neoplasms / genetics
  • Brain Neoplasms / metabolism
  • Brain Neoplasms / pathology
  • Cell Division
  • Cell Hypoxia
  • Cell Transformation, Neoplastic* / genetics
  • Cell Transformation, Neoplastic* / metabolism
  • Cell Transformation, Neoplastic* / pathology
  • DNA-Binding Proteins / physiology*
  • Genes, Tumor Suppressor / genetics
  • Genes, Tumor Suppressor / physiology
  • Humans
  • Hypoxia-Inducible Factor 1
  • Hypoxia-Inducible Factor 1, alpha Subunit
  • Neoplasm Invasiveness
  • Neoplasm Metastasis
  • Neoplasms / blood supply
  • Neoplasms / metabolism
  • Neoplasms / pathology*
  • Neovascularization, Pathologic
  • Nuclear Proteins / physiology*
  • Oncogenes / genetics
  • Oncogenes / physiology
  • Transcription Factors / physiology*


  • DNA-Binding Proteins
  • HIF1A protein, human
  • Hypoxia-Inducible Factor 1
  • Hypoxia-Inducible Factor 1, alpha Subunit
  • Nuclear Proteins
  • Transcription Factors