Abstract
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
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Research Support, Non-U.S. Gov't
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Research Support, U.S. Gov't, P.H.S.
MeSH terms
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Animals
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Astrocytes / metabolism
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Astrocytes / pathology
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Astrocytes / transplantation
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Astrocytoma / blood supply*
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Astrocytoma / metabolism*
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Astrocytoma / pathology
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Brain Neoplasms / blood supply
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Brain Neoplasms / metabolism*
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Brain Neoplasms / pathology*
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Cell Division
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Cell Transformation, Neoplastic
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Disease Progression
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Gene Deletion
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Hypoxia / metabolism*
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Hypoxia / pathology*
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Hypoxia-Inducible Factor 1, alpha Subunit
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Mice
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Neoplasm Invasiveness
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Neoplasm Transplantation
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Neovascularization, Pathologic*
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Organ Size
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Survival Rate
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Transcription Factors / deficiency
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Transcription Factors / genetics
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Transcription Factors / metabolism
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Tumor Cells, Cultured
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Vascular Endothelial Growth Factor A / genetics
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Vascular Endothelial Growth Factor A / metabolism
Substances
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Hypoxia-Inducible Factor 1, alpha Subunit
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Transcription Factors
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Vascular Endothelial Growth Factor A