The hypoxic response of tumors is dependent on their microenvironment

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.