A role for hypoxia and hypoxia-inducible transcription factors in tumor physiology.
Cumulative acquisition of genetic alterations affecting oncogenes or tumor suppressor genes may select for tumor cell clones with enhanced proliferation and survival potential. As a result oxygen and nutrient consumption increases, leading to a tumor microenvironment characterized by low oxygen tension, low glucose levels, and an acidic pH. Hypoxia-inducible transcription factors (HIF) are activated in response to hypoxia, apparently via reduced activity of the recently identified class of 2-oxoglutarate dependent oxygenases, as well as various tumor specific genetic alterations. A widespread HIF activation can be observed in a variety of malignant tumors. The HIF system induces adaptive responses including angiogenesis, glycolysis, and pH regulation which confer increased resistance towards the hostile tumor microenvironment. Apart from protumorigenic the wide-ranging HIF pathway may also have antitumorigenic components, which might, however, be counteracted by specific genetic mechanisms. Thus mounting evidence suggests that the HIF system plays a decisive role in tumor physiology and progression. Moreover, recent insight into this pathway has opened novel and potentially selective therapeutic approaches.
Acker
Till
T
Edinger Institute, Johann Wolfgang Goethe University, Deutschordenstrasse 46, 60528 Frankfurt, Germany. till.acker@kgu.de
Plate
Karl H
KH
D000818:Animals; D015687:Cell Hypoxia / Q000235:genetics*; D002470:Cell Survival; D004268:DNA-Binding Proteins / Q000235:genetics / Q000502:physiology*; D004487:Edema / Q000503:physiopathology; D005786:Gene Expression Regulation; D018390:Gene Targeting; D016147:Genes, Tumor Suppressor / Q000502:physiology; D006019:Glycolysis; D006801:Humans; D006863:Hydrogen-Ion Concentration; D008957:Models, Genetic; D009369:Neoplasms / Q000098:blood supply / Q000235:genetics / Q000378:metabolism / Q000503:physiopathology*; D009389:Neovascularization, Pathologic / Q000503:physiopathology; D009687:Nuclear Proteins / Q000235:genetics / Q000502:physiology*; D009857:Oncogenes / Q000235:genetics / Q000502:physiology; D010100:Oxygen / Q000378:metabolism* / Q000502:physiology; D014157:Transcription Factors / Q000235:genetics / Q000502:physiology*
D004268:DNA-Binding Proteins; D009687:Nuclear Proteins; D014157:Transcription Factors; D010100:Oxygen