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.