The hypoxic response of tumors is dependent on their microenvironment

Cancer Cell. 2003 Aug;4(2):133-46. doi: 10.1016/s1535-6108(03)00194-6.


To reveal the functional significance of hypoxia and angiogenesis in astrocytoma progression, we created genetically engineered transformed astrocytes from murine primary astrocytes and deleted the hypoxia-responsive transcription factor HIF-1alpha or its target gene, the angiogenic factor VEGF. Growth of HIF-1alpha- and VEGF-deficient transformed astrocytes in the vessel-poor subcutaneous environment results in severe necrosis, reduced growth, and vessel density, whereas when the same cells are placed in the vascular-rich brain parenchyma, the growth of HIF-1alpha knockout, but not VEGF knockout tumors, is reversed: tumors deficient in HIF-1alpha grow faster, and penetrate the brain more rapidly and extensively. These results demonstrate that HIF-1alpha has differential roles in tumor progression, which are greatly dependent on the extant microenvironment of the tumor.

Publication types

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

MeSH terms

  • Animals
  • Astrocytes / metabolism
  • Astrocytes / pathology
  • Astrocytes / transplantation
  • Astrocytoma / blood supply*
  • Astrocytoma / metabolism*
  • Astrocytoma / pathology
  • Brain Neoplasms / blood supply
  • Brain Neoplasms / metabolism*
  • Brain Neoplasms / pathology*
  • Cell Division
  • Cell Transformation, Neoplastic
  • Disease Progression
  • Gene Deletion
  • Hypoxia / metabolism*
  • Hypoxia / pathology*
  • Hypoxia-Inducible Factor 1, alpha Subunit
  • Mice
  • Neoplasm Invasiveness
  • Neoplasm Transplantation
  • Neovascularization, Pathologic*
  • Organ Size
  • Survival Rate
  • Transcription Factors / deficiency
  • Transcription Factors / genetics
  • Transcription Factors / metabolism
  • Tumor Cells, Cultured
  • Vascular Endothelial Growth Factor A / genetics
  • Vascular Endothelial Growth Factor A / metabolism


  • Hypoxia-Inducible Factor 1, alpha Subunit
  • Transcription Factors
  • Vascular Endothelial Growth Factor A