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The vascular endothelial growth factor receptor (VEGFR-1) supports growth and survival of human breast carcinoma
Article first published online: 2 MAY 2006
Copyright © 2006 Wiley-Liss, Inc.
International Journal of Cancer
Volume 119, Issue 7, pages 1519–1529, 1 October 2006
How to Cite
Wu, Y., Hooper, A. T., Zhong, Z., Witte, L., Bohlen, P., Rafii, S. and Hicklin, D. J. (2006), The vascular endothelial growth factor receptor (VEGFR-1) supports growth and survival of human breast carcinoma. Int. J. Cancer, 119: 1519–1529. doi: 10.1002/ijc.21865
- Issue published online: 18 JUL 2006
- Article first published online: 2 MAY 2006
- Manuscript Accepted: 12 JAN 2006
- Manuscript Received: 30 AUG 2005
- National Institutes of Health (NHLBI)
- American Cancer Society and Leukemia and Lymphoma Society of America
- VEGFR-1 (Flt-1);
- breast cancer;
- placental growth factor (PlGF)
Vascular endothelial growth factor receptor 1 (VEGFR-1) is present on endothelial cells and subsets of human tumor cells, raising the hypothesis that angiogenic factors may promote tumor growth both by inducing angiogenesis and directly signaling through activation of VEGFR-1 on tumor cells. Here, we report that VEGFR-1 is expressed on a panel of 16 human breast tumor cell lines, and the vasculature and the tumor cell compartment of a subset of breast carcinoma lesions, and that selective signaling through VEGFR-1 on breast cancer cells supports tumor growth through downstream activation of the p44/42 mitogen-activated protein kinase (MAPK) or Akt pathways. Ligand-stimulated proliferation of breast tumor cells was inhibited by specific blockade with an anti-VEGFR-1 neutralizing monoclonal antibody. Treatment with anti-VEGFR-1 mAb significantly suppressed the growth of DU4475, MCF-7, BT-474 and MDA-MB-231 breast xenografts in athymic mice. Histological examination of anti-VEGFR-1 mAb treated tumor xenografts showed a significant reduction of activation of the p44/42 MAPK or Akt pathways in tumor cells resulting in an increase in tumor cell apoptosis. Importantly, cotreatment with mAbs targeting human VEGFR-1 on tumor cells and murine VEGFR-1 on vasculature led to more potent growth inhibition of breast tumor xenografts. The results suggest that VEGF receptors may not only modulate angiogenesis, but also directly influence the growth of VEGF receptor expressing tumors. © 2006 Wiley-Liss, Inc.