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Angiogenesis, Metastasis, and the Cellular Microenvironment

Sustained VEGF Blockade Results in Microenvironmental Sequestration of VEGF by Tumors and Persistent VEGF Receptor-2 Activation

Departments of ¹ Surgery, ² Pathology, and ³ Pediatrics, College of Physicians and Surgeons of Columbia University, New York, New York; and ⁴ Regeneron Pharmaceuticals, Tarrytown, New York

Requests for reprints: Darrell Yamashiro, Pediatric Oncology, Irving Cancer Research Center, 1130 St. Nicholas Avenue, Room 924A, New York, NY 10032. Phone: 212-851-4689; Fax: 212-851-4690. E-mail: dy39{at}columbia.edu

Vascular endothelial growth factor (VEGF) blockade has been validated clinically as a treatment for human cancers, yet virtually all patients eventually develop progressive disease during therapy. In order to dissect this phenomenon, we examined the effect of sustained VEGF blockade in a model of advanced pediatric cancer. Treatment of late-stage hepatoblastoma xenografts resulted in the initial collapse of the vasculature and significant tumor regression. However, during sustained treatment, vessels recovered, concurrent with a striking increase in tumor expression of perlecan, a heparan sulfate proteoglycan. Whereas VEGF mRNA was expressed at the periphery of surviving clusters of tumor cells, both secreted VEGF and perlecan accumulated circumferential to central vessels. Vascular expression of heparanase, VEGF receptor-2 ligand binding, and receptor activation were concurrently maintained despite circulating unbound VEGF Trap. Endothelial survival signaling via Akt persisted. These findings provide a novel mechanism for vascular survival during sustained VEGF blockade and indicate a role for extracellular matrix molecules that sequester and release biologically active VEGF. (Mol Cancer Res 2008;6(1):1–9)