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Inhibition of Vascular Endothelial Growth Factor (VEGF)-A Causes a Paradoxical Increase in Tumor Blood Flow and Up-Regulation of VEGF-D

Authors' Affiliations: Departments of ¹ Radiology, ² Radiation Oncology, ³ Biostatistics, and ⁴ Pathology, Center for Molecular Imaging, University of Michigan Medical School, Ann Arbor, Michigan

Requests for reprints: Brian D. Ross, Center for Molecular Imaging, Department of Radiology, University of Michigan, Ann Arbor, MI 48109-0503; E-mail: bdross{at}umich.edu.

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.

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