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

Nature Medicine volume 10, pages 950958 (2004) | Download Citation

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Abstract

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 β-defensins and vascular endothelial growth factor-A (Vegf-A). Expression of mouse β-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 β-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 β-defensins and Vegf-A cooperate to promote tumor vasculogenesis by carrying out distinct tasks: β-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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Acknowledgements

We thank C. H. June and C. B. Thompson for critical review of the manuscript and helpful discussions; S. M. Albelda for the CD31 knock-out mice; P. Terranova for the mouse ID8 cell line; A. D. Miller for the retroviral vector pLXSN; P. D'Amore for the Vegf164 cDNA; and J. M. Palacios for the pCEFL-KZ-HA vector. This work was supported by National Cancer Institute ovarian SPORE P01-CA83638; National Institute of Health R01 CA098951; and grants from the Sidney Kimmel Foundation and the Ovarian Cancer Research Fund, as well as institutional funding by the Abramson Family Cancer Research Institute and the Department of Obstetrics and Gynecology at the University of Pennsylvania. The LCM facility was supported by a generous grant by the Fannie Rippel Foundation. F.B. and M.C.C. were supported by National Institutes of Health Research Grant #D43 TW00671 funded by the Fogarty International Center. F.B. is a member of the Consejo Nacional de Investigaciones Cientificas Argentinas. D.K. was supported by Associazione Italiana per la Ricerca sul Cancro.

Author information

Author notes

    • Jose R Conejo-Garcia
    •  & Fabian Benencia

    These authors contributed equally to this work.

Affiliations

  1. Center for Research in Reproduction and Women's Health, University of Pennsylvania Medical Center, BRBII/III, 421 Curie Blvd, Philadelphia, Pennsylvania 19104, USA.

    • Jose R Conejo-Garcia
    • , Fabian Benencia
    • , Maria-Cecilia Courreges
    • , Eugene Kang
    • , Alisha Mohamed-Hadley
    • , Ronald J Buckanovich
    • , David O Holtz
    • , Ann Jenkins
    • , Hana Na
    • , Lin Zhang
    •  & George Coukos
  2. Abramson Family Cancer Research Institute, University of Pennsylvania Medical Center, BRBII/III, 421 Curie Blvd, Philadelphia, Pennsylvania 19104, USA.

    • Lin Zhang
    • , Richard Caroll
    •  & George Coukos
  3. Department of Cell and Developmental Biology, University of Pennsylvania Medical Center, BRBII/III, 421 Curie Blvd, Philadelphia, Pennsylvania 19104, USA.

    • Daniel S Wagner
  4. Department of Obstetrics and Gynecology, University of Turin, 10126 Turin, Italy.

    • Dionyssios Katsaros

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The authors declare no competing financial interests.

Corresponding author

Correspondence to George Coukos.

Supplementary information

PDF files

  1. 1.

    Supplementary Fig. 1

    Further characterization of β-defensin-29 and CD11c+ cells in tumors.

  2. 2.

    Supplementary Fig. 2

    Bone marrow-derived DCs undergo endothelial specialization in vitro.

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    Supplementary Fig. 3

    Morphological and molecular characterization of vascular differentiation of immature DCs in vitro.

  4. 4.

    Supplementary Fig. 4

    DC precursors in human and mouse tumors.

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    Supplementary Note

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DOI

https://doi.org/10.1038/nm1097