Cancer Cell
Volume 4, Issue 2, August 2003, Pages 133-146
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Article
The hypoxic response of tumors is dependent on their microenvironment

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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-1α or its target gene, the angiogenic factor VEGF. Growth of HIF-1α- 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-1α knockout, but not VEGF knockout tumors, is reversed: tumors deficient in HIF-1α grow faster, and penetrate the brain more rapidly and extensively. These results demonstrate that HIF-1α has differential roles in tumor progression, which are greatly dependent on the extant microenvironment of the tumor.

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