Inhibition of vascular endothelial growth factor (VEGF)-A causes a paradoxical increase in tumor blood flow and up-regulation of VEGF-D.
OBJECTIVE
Vascular endothelial growth factor (VEGF)-A is an important mediator of angiogenesis in almost all solid tumors. The aim of this study was to evaluate the effect of VEGF-A expression on tumor growth, perfusion, and chemotherapeutic efficacy in orthotopic 9L gliosarcomas.


METHODS
Stable 9L cell lines underexpressing and overexpressing VEGF-A were generated. Anatomic, susceptibility contrast, and continuous arterial spin-labeling magnetic resonance imaging were used to quantify the volume, blood volume, and blood flow of tumors orthotopically grown from these and wild-type 9L cells. Histologic, immunohistochemical, and quantitative reverse transcription-PCR analyses were also done on excised tumors. Finally, the effects of carmustine chemotherapy were also evaluated.


RESULTS
Orthotopic tumors underexpressing VEGF-A had slower growth rates (increased median survival), greater blood flow, vessel density, and VEGF-D expression, but no statistical difference in blood volume and chemotherapeutic sensitivity, compared with tumors with wild-type levels of VEGF-A. Tumors overexpressing VEGF-A had faster growth rates, greater blood volume, vessel density, and blood flow but no statistical difference in VEGF-D expression and chemotherapeutic sensitivity compared with wild-type VEGF-A-expressing tumors.


CONCLUSIONS
Blood volume and blood flow are independent and different biomarkers of tumor perfusion. Therefore, both should be measured when characterizing the efficacy of antiangiogenic therapies. Underexpression of VEGF-A does not result in complete inhibition of angiogenesis. Moreover, these tumors have a different perfusion phenotype, suggesting that angiogenesis is mediated by an alternative pathway. The results indicate that VEGF-D is a plausible alternative mediator of this angiogenesis.
Moffat
Bradford A
BA
Department of Radiology, Center for Molecular Imaging, University of Michigan Medical School, Ann Arbor, Michigan 48109-0503, USA.
Chen
Mark
M
Kariaapper
Muhammed S T
MS
Hamstra
Daniel A
DA
Hall
Daniel E
DE
Stojanovska
Jadranka
J
Johnson
Timothy D
TD
Blaivas
Mila
M
Kumar
Mahesh
M
Chenevert
Thomas L
TL
Rehemtulla
Alnawaz
A
Ross
Brian D
BD
D000818:Animals; D018906:Antineoplastic Agents, Alkylating / Q000627:therapeutic use; D001783:Blood Flow Velocity; D001810:Blood Volume; D001932:Brain Neoplasms / Q000098:blood supply* / Q000188:drug therapy / Q000378:metabolism; D002330:Carmustine / Q000627:therapeutic use; D018316:Gliosarcoma / Q000098:blood supply* / Q000188:drug therapy / Q000378:metabolism; D008279:Magnetic Resonance Imaging; D008297:Male; D009389:Neovascularization, Pathologic; D010477:Perfusion; D010641:Phenotype; D016372:RNA, Antisense / Q000378:metabolism; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D051381:Rats; D011916:Rats, Inbred F344; D020133:Reverse Transcriptase Polymerase Chain Reaction; D014407:Tumor Cells, Cultured; D015854:Up-Regulation; D042461:Vascular Endothelial Growth Factor A / Q000037:antagonists & inhibitors / Q000378:metabolism*; D042643:Vascular Endothelial Growth Factor D / Q000235:genetics / Q000378:metabolism*
D018906:Antineoplastic Agents, Alkylating; D016372:RNA, Antisense; D012333:RNA, Messenger; D042461:Vascular Endothelial Growth Factor A; D042643:Vascular Endothelial Growth Factor D; C467498:vascular endothelial growth factor A, rat; D002330:Carmustine