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 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.
Semenza
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Institute of Genetic Medicine, Department of Pediatrics, The Johns Hopkins University School of Medicine, Baltimore, Maryland 21287-3914, USA. gsemenza@jhmi.edu
D001932:Brain Neoplasms / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D002455:Cell Division; D015687:Cell Hypoxia; D002471:Cell Transformation, Neoplastic / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D004268:DNA-Binding Proteins / Q000502:physiology*; D016147:Genes, Tumor Suppressor / Q000235:genetics / Q000502:physiology; D006801:Humans; D051793:Hypoxia-Inducible Factor 1; D051795:Hypoxia-Inducible Factor 1, alpha Subunit; D009361:Neoplasm Invasiveness; D009362:Neoplasm Metastasis; D009369:Neoplasms / Q000098:blood supply / Q000378:metabolism / Q000473:pathology*; D009389:Neovascularization, Pathologic; D009687:Nuclear Proteins / Q000502:physiology*; D009857:Oncogenes / Q000235:genetics / Q000502:physiology; D014157:Transcription Factors / Q000502:physiology*
D004268:DNA-Binding Proteins; C497442:HIF1A protein, human; D051793:Hypoxia-Inducible Factor 1; D051795:Hypoxia-Inducible Factor 1, alpha Subunit; D009687:Nuclear Proteins; D014157:Transcription Factors