Angiogenesis and the development of a vascular network are required for tumour progression, and they involve the release of angiogenic factors, including vascular endothelial growth factor (VEGF-A), from both malignant and stromal cell types1. Infiltration by cells of the myeloid lineage is a hallmark of many tumours, and in many cases the macrophages in these infiltrates express VEGF-A2. Here we show that the deletion of inflammatory-cell-derived VEGF-A attenuates the formation of a typical high-density vessel network, thus blocking the angiogenic switch in solid tumours in mice. Vasculature in tumours lacking myeloid-cell-derived VEGF-A was less tortuous, with increased pericyte coverage and decreased vessel length, indicating vascular normalization. In addition, loss of myeloid-derived VEGF-A decreases the phosphorylation of VEGF receptor 2 (VEGFR2) in tumours, even though overall VEGF-A levels in the tumours are unaffected. However, deletion of myeloid-cell VEGF-A resulted in an accelerated tumour progression in multiple subcutaneous isograft models and an autochthonous transgenic model of mammary tumorigenesis, with less overall tumour cell death and decreased tumour hypoxia. Furthermore, loss of myeloid-cell VEGF-A increased the susceptibility of tumours to chemotherapeutic cytotoxicity. This shows that myeloid-derived VEGF-A is essential for the tumorigenic alteration of vasculature and signalling to VEGFR2, and that these changes act to retard, not promote, tumour progression.
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We thank J. DuRose, N. Ferrara, L. Iruela-Arispe, L. Coussens, M. Karin, V. Nizet and H.-P. Gerber for helpful conversations. Financial support was provided by the Deutsche Forschungsgemeinschaft to C.S. (STO 787/1-1) and A.W. (WE 4275/1-1), a Susan G. Komen Dissertation Research Award (DISS0402406) to A.D., and National Institutes of Health grants CA82515, CA118165 and AI060840 to R.S.J.
Author Contributions C.S. generated isografts, conducted drug treatment studies, performed biochemical experiments, immunohistochemical procedures and histological analysis, and prepared the manuscript. A.D. generated MMTV-PyMT/LysMCre/VEGF+f/+f mice, conducted related tumour palpation/mass studies, initial histology and flow cytometry, and assisted with the manuscript. A.W. generated VEGF-null fibroblasts. N.Z. performed preliminary cDNA studies on MMTV-PyMT/LysMCre/VEGF+f/+f tumours. N.T. assisted with the fluorescein isothiocyanate-dextran angiography. J.I.G. and D.A.C. provided confocal microscopy images and technical advice. R.S.J. supervised and directed the project.
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Stockmann, C., Doedens, A., Weidemann, A. et al. Deletion of vascular endothelial growth factor in myeloid cells accelerates tumorigenesis. Nature 456, 814–818 (2008) doi:10.1038/nature07445
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