Potent VEGF blockade causes regression of coopted vessels in a model of neuroblastoma

作者：Eugene S. Kim, Anna Serur, Jianzhong Huang, Christina A. Manley, Kimberly W. McCrudden, Jason S. Frischer, Samuel Z. Soffer, Laurence E. Ring, Tamara N. New, Stephanie M. Zabski, John S. Rudge, Jocelyn A. Holash, George D. Yancopoulos, Jessica J. Kandel, Darrell J. Yamashiro · 发表于：Proceedings of the National Academy of Sciences · 年份：2002 · DOI：10.1073/pnas.172398399 · 被引用次数：315 · 研究领域：Neuroblastoma Research and Treatments、Angiogenesis and VEGF in Cancer、Cancer, Hypoxia, and Metabolism

Vascular endothelial growth factor (VEGF) plays a key role in human tumor angiogenesis. We compared the effects of inhibitors of VEGF with different specificities in a xenograft model of neuroblastoma. Cultured human neuroblastoma NGP-GFP cells were implanted intrarenally in nude mice. Three anti-VEGF agents were tested: an anti-human VEGF(165) RNA-based fluoropyrimidine aptamer; a monoclonal anti-human VEGF antibody; and VEGF-Trap, a composite decoy receptor based on VEGFR-1 and VEGFR-2 fused to an Fc segment of IgG1. A wide range of efficacy was observed, with high-dose VEGF-Trap causing the greatest inhibition of tumor growth (81% compared with controls). We examined tumor angiogenesis and found that early in tumor formation, cooption of host vasculature occurs. We postulate that this coopted vasculature serves as a source of blood supply during the initial phase of tumor growth. Subsequently, control tumors undergo vigorous growth and remodeling of vascular networks, which results in disappearance of the coopted vessels. However, if VEGF function is blocked, cooption of host vessels may persist. Persistent cooption, therefore, may represent a novel mechanism by which neuroblastoma can partly evade antiangiogenic therapy and may explain why experimental neuroblastoma is less susceptible to VEGF blockade than a parallel model of Wilms tumor. However, more effective VEGF blockade, as achieved by high doses of VEGF-Trap, can lead to regression of coopted vascular structures. ...