Inhibition of vascular endothelial growth factor (VEGF)-A causes a paradoxical increase in tumor blood flow and up-regulation of VEGF-D.

Abstract

PURPOSE:

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.

EXPERIMENTAL DESIGN:

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.

CONCLUSION:

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.

• Authors: Bradford A Moffat, Mark Chen, Muhammed S T Kariaapper, Daniel A Hamstra, Daniel E Hall, Jadranka Stojanovska, Timothy D Johnson, Mila Blaivas, Mahesh Kumar, Thomas L Chenevert, Alnawaz Rehemtulla, Brian D Ross
• Journal: Clinical cancer research : an official journal of the American Association for Cancer Research (Clin Cancer Res) Vol. 12 Issue 5 Pg. 1525-32 (Mar 01 2006) ISSN: 1078-0432 [Print] United States
• PMID: 16533777 (Publication Type: Journal Article, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't)

Chemical References

• Antineoplastic Agents, Alkylating
• RNA, Antisense
• RNA, Messenger
• Vascular Endothelial Growth Factor A
• Vascular Endothelial Growth Factor D
• vascular endothelial growth factor A, rat
• Carmustine

Topics

• Animals
• Antineoplastic Agents, Alkylating (therapeutic use)
• Blood Flow Velocity
• Blood Volume
• Brain Neoplasms (blood supply, drug therapy, metabolism)
• Carmustine (therapeutic use)
• Gliosarcoma (blood supply, drug therapy, metabolism)
• Magnetic Resonance Imaging
• Male
• Neovascularization, Pathologic
• Perfusion
• Phenotype
• RNA, Antisense (metabolism)
• RNA, Messenger (genetics, metabolism)
• Rats
• Rats, Inbred F344
• Reverse Transcriptase Polymerase Chain Reaction
• Tumor Cells, Cultured
• Up-Regulation
• Vascular Endothelial Growth Factor A (antagonists & inhibitors, metabolism)
• Vascular Endothelial Growth Factor D (genetics, metabolism)