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.
This is a preview of subscription content, access via your institution
Access options
Subscribe to this journal
Receive 12 print issues and online access
$209.00 per year
only $17.42 per issue
Buy this article
- Purchase on Springer Link
- Instant access to full article PDF
Prices may be subject to local taxes which are calculated during checkout
Similar content being viewed by others
References
Banchereau, J. et al. Immunobiology of dendritic cells. Annu. Rev. Immunol. 18, 767–811 (2000).
Bhardwaj, N. Processing and presentation of antigens by dendritic cells: implications for vaccines. Trends Mol. Med. 7, 388–394 (2001).
Steinman, R.M., Turley, S., Mellman, I. & Inaba, K. The induction of tolerance by dendritic cells that have captured apoptotic cells. J. Exp. Med. 191, 411–416 (2000).
Gabrilovich, D.I., Nadaf, S., Corak, J., Berzofsky, J.A. & Carbone, D.P. Dendritic cells in antitumor immune responses. II. Dendritic cells grown from bone marrow precursors, but not mature DC from tumor-bearing mice, are effective antigen carriers in the therapy of established tumors. Cell. Immunol. 170, 111–119 (1996).
Ronchetti, A. et al. Immunogenicity of apoptotic cells in vivo: role of antigen load, antigen-presenting cells, and cytokines. J. Immunol. 163, 130–136 (1999).
Chiodoni, C. et al. Dendritic cells infiltrating tumors cotransduced with granulocyte/macrophage colony-stimulating factor (GM-CSF) and CD40 ligand genes take up and present endogenous tumor-associated antigens, and prime naive mice for a cytotoxic T lymphocyte response. J. Exp. Med. 190, 125–133 (1999).
Hanahan, D. & Folkman, J. Patterns and emerging mechanisms of the angiogenic switch during tumorigenesis. Cell 86, 353–364 (1996).
Gabrilovich, D. et al. Vascular endothelial growth factor inhibits the development of dendritic cells and dramatically affects the differentiation of multiple hematopoietic lineages in vivo. Blood 92, 4150–4166 (1998).
Gabrilovich, D.I. et al. Production of vascular endothelial growth factor by human tumors inhibits the functional maturation of dendritic cells. Nat. Med. 2, 1096–1103 (1996).
Vicari, A.P., Caux, C. & Trinchieri, G. Tumour escape from immune surveillance through dendritic cell inactivation. Semin. Cancer Biol. 12, 33–42 (2002).
Ohm, J.E. & Carbone, D.P. Vegf as a mediator of tumor-associated immunodeficiency. Immunol. Res. 23, 263–272 (2001).
Zhang, L. et al. Intratumoral T cells, recurrence and survival in epithelial ovarian cancer. N. Engl. J. Med. 348, 201–211 (2003).
Yang, D. et al. β-defensins: linking innate and adaptive immunity through dendritic and T cell CCR6. Science 286, 525–528 (1999).
Coussens, L.M. & Werb, Z. Inflammation and cancer. Nature 420, 860–867 (2002).
De Palma, M., Venneri, M.A., Roca, C. & Naldini, L. Targeting exogenous genes to tumor angiogenesis by transplantation of genetically modified hematopoietic stem cells. Nat. Med. 9, 789–795 (2003).
Roby, K.F. et al. Development of a syngeneic mouse model for events related to ovarian cancer. Carcinogenesis 21, 585–591 (2000).
Zhang, L. et al. Generation of a syngeneic mouse model to study the effects of vascular endothelial growth factor in ovarian carcinoma. Am. J. Pathol. 161, 2295–2309 (2002).
Biragyn, A. et al. Mediators of innate immunity that target immature, but not mature, dendritic cells induce antitumor immunity when genetically fused with nonimmunogenic tumor antigens. J. Immunol. 167, 6644–6653 (2001).
St Croix, B. et al. Genes expressed in human tumor endothelium. Science 289, 1197–1202 (2000).
Duncan, G.S. et al. Genetic evidence for functional redundancy of platelet/endothelial cell adhesion molecule-1 (PECAM-1): CD31-deficient mice reveal PECAM-1-dependent and PECAM-1-independent functions. J. Immunol. 162, 3022–3030 (1999).
Vicari, A.P. et al. Reversal of tumor-induced dendritic cell paralysis by CpG immunostimulatory oligonucleotide and anti-interleukin 10 receptor antibody. J. Exp. Med. 196, 541–549 (2002).
Barnden, M.J., Allison, J., Heath, W.R. & Carbone, F.R. Defective TCR expression in transgenic mice constructed using cDNA-based α- and β-chain genes under the control of heterologous regulatory elements. Immunol. Cell Biol. 76, 34–40 (1998).
Lutz, M.B. et al. An advanced culture method for generating large quantities of highly pure dendritic cells from mouse bone marrow. J. Immunol. Methods 223, 77–92 (1999).
Sumpio, B.E., Riley, J.T. & Dardik, A. Cells in focus: endothelial cell. Int. J. Biochem. Cell Biol. 34, 1508–1512 (2002).
Fend, F. et al. Immuno-LCM: laser capture microdissection of immunostained frozen sections for mRNA analysis. Am. J. Pathol. 154, 61–66 (1999).
Ardavin, C. et al. Origin and differentiation of dendritic cells. Trends Immunol. 22, 691–700 (2001).
Mendel, D.B. et al. Development of SU5416, a selective small molecule inhibitor of Vegf receptor tyrosine kinase activity, as an anti-angiogenesis agent. Anticancer Drug Des. 15, 29–41 (2000).
Wu, Z. et al. Engineering disulfide bridges to dissect antimicrobial and chemotactic activities of human β-defensin 3. Proc. Natl. Acad. Sci. USA 100, 8880–8885 (2003).
Zhao, Y., Glesne, D. & Huberman, E. A human peripheral blood monocyte-derived subset acts as pluripotent stem cells. Proc. Natl. Acad. Sci. USA 100, 2426–2431 (2003).
Nakul-Aquaronne, D., Bayle, J. & Frelin, C. Coexpression of endothelial markers and CD14 by cytokine mobilized CD34+ cells under angiogenic stimulation. Cardiovasc. Res. 57, 816–823 (2003).
Fernandez Pujol, B. et al. Dendritic cells derived from peripheral monocytes express endothelial markers and in the presence of angiogenic growth factors differentiate into endothelial-like cells. Eur. J. Cell Biol. 80, 99–110 (2001).
Schmeisser, A. et al. Monocytes coexpress endothelial and macrophagocytic lineage markers and form cord-like structures in Matrigel under angiogenic conditions. Cardiovasc. Res. 49, 671–680 (2001).
Rehman, J., Li, J., Orschell, C.M. & March, K.L. Peripheral blood “endothelial progenitor cells” are derived from monocyte/macrophages and secrete angiogenic growth factors. Circulation 107, 1164–1169 (2003).
Harraz, M., Jiao, C., Hanlon, H.D., Hartley, R.S. & Schatteman, G.C. CD34− blood-derived human endothelial cell progenitors. Stem Cells 19, 304–312 (2001).
Langeggen, H., Berge, K.E., Johnson, E. & Hetland, G. Human umbilical vein endothelial cells express complement receptor 1 (CD35) and complement receptor 4 (CD11c/CD18) in vitro. Inflammation 26, 103–110 (2002).
Peichev, M. et al. Expression of VEGFR-2 and AC133 by circulating human CD34+cells identifies a population of functional endothelial precursors. Blood 95, 952–958 (2000).
Lyden, D. et al. Impaired recruitment of bone-marrow-derived endothelial and hematopoietic precursor cells blocks tumor angiogenesis and growth. Nat. Med. 7, 1194–1201 (2001).
Nowicki, A. et al. Impaired tumor growth in colony-stimulating factor 1 (CSF-1)-deficient, macrophage-deficient op/op mouse: evidence for a role of CSF-1-dependent macrophages in formation of tumor stroma. Int. J. Cancer 65, 112–119 (1996).
Pipp, F. et al. VEGFR-1-selective Vegf homologue PlGF is arteriogenic: evidence for a monocyte-mediated mechanism. Circ. Res. 92, 378–385 (2003).
Moldovan, N.I., Goldschmidt-Clermont, P.J., Parker-Thornburg, J., Shapiro, S.D. & Kolattukudy, P.E. Contribution of monocytes/macrophages to compensatory neovascularization: the drilling of metalloelastase-positive tunnels in ischemic myocardium. Circ. Res. 87, 378–384 (2000).
Schmeisser, A., Graffy, C., Daniel, W.G. & Strasser, R.H. Phenotypic overlap between monocytes and vascular endothelial cells. Adv. Exp. Med. Biol. 522, 59–74 (2003).
Havemann, K., Pujol, B.F. & Adamkiewicz, J. In vitro transformation of monocytes and dendritic cells into endothelial like cells. Adv. Exp. Med. Biol. 522, 47–57 (2003).
Schutte, B.C. et al. Discovery of five conserved β-defensin gene clusters using a computational search strategy. Proc. Natl. Acad. Sci. USA 99, 2129–2133 (2002).
Miller, A.D. & Rosman, G.J. Improved retroviral vectors for gene transfer and expression. Biotechniques 7, 980–982, 984–986, 989–990 (1989).
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
Authors and Affiliations
Corresponding author
Ethics declarations
Competing interests
The authors declare no competing financial interests.
Supplementary information
Supplementary Fig. 1
Further characterization of β-defensin-29 and CD11c+ cells in tumors. (PDF 107 kb)
Supplementary Fig. 2
Bone marrow-derived DCs undergo endothelial specialization in vitro. (PDF 274 kb)
Supplementary Fig. 3
Morphological and molecular characterization of vascular differentiation of immature DCs in vitro. (PDF 94 kb)
Supplementary Fig. 4
DC precursors in human and mouse tumors. (PDF 115 kb)
Rights and permissions
About this article
Cite this article
Conejo-Garcia, J., Benencia, F., Courreges, MC. et al. Tumor-infiltrating dendritic cell precursors recruited by a β-defensin contribute to vasculogenesis under the influence of Vegf-A. Nat Med 10, 950–958 (2004). https://doi.org/10.1038/nm1097
Received:
Accepted:
Published:
Issue Date:
DOI: https://doi.org/10.1038/nm1097
This article is cited by
-
Mechanisms and regulation of defensins in host defense
Signal Transduction and Targeted Therapy (2023)
-
Dendritic cell subsets in cancer immunity and tumor antigen sensing
Cellular & Molecular Immunology (2023)
-
Promising effects of parasite-derived compounds on tumor regression: a systematic review of in vitro and in vivo studies
Environmental Science and Pollution Research (2022)
-
Understanding and addressing barriers to successful adenovirus-based virotherapy for ovarian cancer
Cancer Gene Therapy (2021)
-
Myeloid derived suppressor cells and the release of micro-metastases from dormancy
Clinical & Experimental Metastasis (2021)