Role of placenta growth factor in malignancy and evidence that an antagonistic PlGF/Flt-1 peptide inhibits the growth and metastasis of human breast cancer xenografts

Abstract

The angiogenic growth factor placenta growth factor (PlGF) is implicated in several pathologic processes, including the growth and spread of cancer. We found by immunohistochemistry that 36% to 60% and 65% of primary breast cancers express PlGF and its receptor Flt-1, respectively. These findings suggest that PlGF may be active in tumor growth and metastasis beyond its role in angiogenesis. It was found that exogenously added PlGF (2 nmol/L), in contrast to vascular endothelial growth factor (2 nmol/L), significantly stimulated in vitro motility and invasion of the human breast tumor lines MCF-7 and MDA-MB-231. A PlGF-2/Flt-1-inhibiting peptide, binding peptide 1 (BP1), that binds Flt-1 at or near the heparin-binding site was identified and synthesized. Both PlGF-stimulated motility and invasion were prevented by treatment with BP1 (P < 0.05), as well as by anti-PlGF antibody. Treatment of mice bearing s.c. MDA-MB-231 with BP1 (200 mug i.p., twice per week) decreased the number of spontaneous metastatic lung nodules by 94% (P < 0.02), whereas therapy of animals with orthotopic mammary fat pad tumors decreased pulmonary metastases by 82% (P < 0.02). These results indicate, for the first time, that PlGF stimulates the metastatic phenotype in these breast cancer cells, whereas therapy with a PlGF-2/Flt-1 heparin-blocking peptide reduces the growth and metastasis of human breast cancer xenografts.