Tumor-infiltrating dendritic cell precursors recruited by a beta-defensin contribute to vasculogenesis under the influence of Vegf-A.
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.
Conejo-Garcia
Jose R
JR
Center for Research in Reproduction and Women's Health, University of Pennsylvania Medical Center, BRBII/III, 421 Curie Blvd, Philadelphia, Pennsylvania 19104, USA.
Benencia
Fabian
F
Courreges
Maria-Cecilia
MC
Kang
Eugene
E
Mohamed-Hadley
Alisha
A
Buckanovich
Ronald J
RJ
Holtz
David O
DO
Jenkins
Ann
A
Na
Hana
H
Zhang
Lin
L
Wagner
Daniel S
DS
Katsaros
Dionyssios
D
Caroll
Richard
R
Coukos
George
G
D043925:Angiogenesis Inducing Agents / Q000276:immunology*; D000818:Animals; D002454:Cell Differentiation / Q000276:immunology; D002465:Cell Movement / Q000276:immunology; D003094:Collagen; D003713:Dendritic Cells / Q000276:immunology* / Q000378:metabolism; D004338:Drug Combinations; D005434:Flow Cytometry; D006652:Histological Techniques; D015151:Immunoblotting; D007797:Laminin; D051379:Mice; D009389:Neovascularization, Pathologic / Q000276:immunology*; D011509:Proteoglycans; D019707:Receptors, Chemokine / Q000378:metabolism; D042461:Vascular Endothelial Growth Factor A / Q000378:metabolism*; D023083:beta-Defensins / Q000276:immunology* / Q000378:metabolism
D043925:Angiogenesis Inducing Agents; D004338:Drug Combinations; D007797:Laminin; D011509:Proteoglycans; D019707:Receptors, Chemokine; D042461:Vascular Endothelial Growth Factor A; D023083:beta-Defensins; C467480:vascular endothelial growth factor A, mouse; C059485:matrigel; D003094:Collagen