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Nature Medicine 10, 950 - 958 (2004)
Published online: 29 August 2004 | doi:10.1038/nm1097

Tumor-infiltrating dendritic cell precursors recruited by a bold beta-defensin contribute to vasculogenesis under the influence of Vegf-A

Jose R Conejo-Garcia1,5, Fabian Benencia1,5, Maria-Cecilia Courreges1, Eugene Kang1, Alisha Mohamed-Hadley1, Ronald J Buckanovich1, David O Holtz1, Ann Jenkins1, Hana Na1, Lin Zhang1,2, Daniel S Wagner3, Dionyssios Katsaros4, Richard Caroll2 & George Coukos1,2

The involvement of immune mechanisms in tumor angiogenesis is unclear. Here we describe a new mechanism of tumor vasculogenesis mediated by dendritic cell (DC) precursors through the cooperation of beta-defensins and vascular endothelial growth factor-A (Vegf-A). Expression of mouse beta-defensin-29 recruited DC precursors to tumors and enhanced tumor vascularization and growth in the presence of increased Vegf-A expression. A new leukocyte population expressing DC and endothelial markers was uncovered in mouse and human ovarian carcinomas coexpressing Vegf-A and beta-defensins. Tumor-infiltrating DCs migrated to tumor vessels and independently assembled neovasculature in vivo. Bone marrow–derived DCs underwent endothelial-like differentiation ex vivo, migrated to blood vessels and promoted the growth of tumors expressing high levels of Vegf-A. We show that beta-defensins and Vegf-A cooperate to promote tumor vasculogenesis by carrying out distinct tasks: beta-defensins chemoattract DC precursors through CCR6, whereas Vegf-A primarily induces their endothelial-like specialization and migration to vessels, which is mediated by Vegf receptor-2.

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