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Angiogenesis, Metastasis, and the Cellular Microenvironment

Vascular Remodeling Marks Tumors That Recur During Chronic Suppression of Angiogenesis¹

Divisions of ¹ Pediatric Surgery, ² Pediatric Oncology and ³ Department of Pathology, Columbia University College of Physicians and Surgeons, New York, NY

Requests for reprints: Jessica J. Kandel, Division of Pediatric Surgery, Columbia University College of Physicians and Surgeons, 3959 Broadway, BHN 214, New York, NY 10032. Tel: (212) 305-5871; Fax: (212) 342-5240. E-mail: jjk47{at}columbia.edu

The potential for avoiding acquired resistance to therapy has been proposed as one compelling theoretical advantage of antiangiogenic therapy based on the normal genetic status of the target vasculature. However, previous work has demonstrated that tumors may resume growth after initial inhibition if antiangiogenic blockade is continued for an extended period. The mechanisms of this recurrent growth are unclear. In these studies, we characterized molecular changes in vasculature during apparent resumption of xenograft growth after initial inhibition by vascular endothelial growth factor blockade, "metronome" topotecan chemotherapy, and combined agents in a xenograft murine model of human Wilms' tumor. Tumors that grew during antiangiogenic blockade developed as viable clusters surrounding strikingly remodeled vessels. These vessels displayed significant increases in diameter and active proliferation of vascular mural cells and expressed platelet-derived growth factor-B, a factor that functions to enhance vascular integrity via stromal cell recruitment. In addition, remodeled vessels were marked by expression of ephrinB2, required for proper assembly of stromal cells into vasculature. Thus, enhanced vascular stability appears to characterize tumor vessel response to chronic antiangiogenesis, features that potentially support increased perfusion and recurrent tumor growth.

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