title: 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.
authors.affiliation: Garden State Cancer Center, Center for Molecular Medicine and Immunology, 520 Belleville Avenue, Belleville, NJ 07109, USA. ataylor@gscancer.org
authors.forename: Alice P
authors.initials: AP
authors.lastname: Taylor
authors.forename: David M
authors.initials: DM
authors.lastname: Goldenberg
mesh_terms: D000818:Animals; D000911:Antibodies, Monoclonal / Q000627:therapeutic use; D001943:Breast Neoplasms / Q000473:pathology / Q000517:prevention & control*; D002465:Cell Movement; D005434:Flow Cytometry; D018398:Homeodomain Proteins / Q000627:therapeutic use; D006801:Humans; D007124:Immunoenzyme Techniques; D008175:Lung Neoplasms / Q000517:prevention & control* / Q000556:secondary; D008207:Lymphatic Metastasis / Q000517:prevention & control; D051379:Mice; D008819:Mice, Nude; D009361:Neoplasm Invasiveness / Q000473:pathology; D009389:Neovascularization, Pathologic; D010446:Peptide Fragments / Q000627:therapeutic use*; D000072483:Placenta Growth Factor; D011257:Pregnancy Proteins / Q000037:antagonists & inhibitors* / Q000502:physiology*; D015996:Survival Rate; D014157:Transcription Factors / Q000627:therapeutic use; D014183:Transplantation, Heterologous; D040281:Vascular Endothelial Growth Factor Receptor-1 / Q000037:antagonists & inhibitors*
chemical_list: D000911:Antibodies, Monoclonal; C105304:DLX4 protein, human; D018398:Homeodomain Proteins; C000608036:PGF protein, human; D010446:Peptide Fragments; C000608037:Pgf protein, mouse; D011257:Pregnancy Proteins; D014157:Transcription Factors; D000072483:Placenta Growth Factor; C501162:FLT1 protein, human; D040281:Vascular Endothelial Growth Factor Receptor-1