title: The hypoxic response of tumors is dependent on their microenvironment.
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.
authors.affiliation: Molecular Biology Section, Division of Biological Sciences, University of California at San Diego, Pacific Hall Room 1212, MC-0366, 9500 Gilman Drive, La Jolla, CA 92093, USA.
authors.forename: Barbara
authors.initials: B
authors.lastname: Blouw
authors.forename: Hanqiu
authors.initials: H
authors.lastname: Song
authors.forename: Tarik
authors.initials: T
authors.lastname: Tihan
authors.forename: Jenel
authors.initials: J
authors.lastname: Bosze
authors.forename: Napoleone
authors.initials: N
authors.lastname: Ferrara
authors.forename: Hans Peter
authors.initials: HP
authors.lastname: Gerber
authors.forename: Randall S
authors.initials: RS
authors.lastname: Johnson
authors.forename: Gabriele
authors.initials: G
authors.lastname: Bergers
mesh_terms: D000818:Animals; D001253:Astrocytes / Q000378:metabolism / Q000473:pathology / Q000637:transplantation; D001254:Astrocytoma / Q000098:blood supply* / Q000378:metabolism* / Q000473:pathology; D001932:Brain Neoplasms / Q000098:blood supply / Q000378:metabolism* / Q000473:pathology*; D002455:Cell Division; D002471:Cell Transformation, Neoplastic; D018450:Disease Progression; D017353:Gene Deletion; D000860:Hypoxia / Q000378:metabolism* / Q000473:pathology*; D051795:Hypoxia-Inducible Factor 1, alpha Subunit; D051379:Mice; D009361:Neoplasm Invasiveness; D009368:Neoplasm Transplantation; D009389:Neovascularization, Pathologic; D009929:Organ Size; D015996:Survival Rate; D014157:Transcription Factors / Q000172:deficiency / Q000235:genetics / Q000378:metabolism; D014407:Tumor Cells, Cultured; D042461:Vascular Endothelial Growth Factor A / Q000235:genetics / Q000378:metabolism
chemical_list: D051795:Hypoxia-Inducible Factor 1, alpha Subunit; D014157:Transcription Factors; D042461:Vascular Endothelial Growth Factor A