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-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.
Blouw
Barbara
B
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.
Song
Hanqiu
H
Tihan
Tarik
T
Bosze
Jenel
J
Ferrara
Napoleone
N
Gerber
Hans Peter
HP
Johnson
Randall S
RS
Bergers
Gabriele
G
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
D051795:Hypoxia-Inducible Factor 1, alpha Subunit; D014157:Transcription Factors; D042461:Vascular Endothelial Growth Factor A