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Research Articles: Therapeutics, Targets, and Development

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

Garden State Cancer Center, Center for Molecular Medicine and Immunology, Belleville, New Jersey

Requests for reprints: Alice P. Taylor, Garden State Cancer Center, Center for Molecular Medicine and Immunology, 520 Belleville Avenue, Belleville, NJ 07109. Phone: 973-844-7009; Fax: 973-844-7020. E-mail: ataylor{at}gscancer.org

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 µg 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. [Mol Cancer Ther 2007;6(2):524–31]

Grant support: Breast Cancer Concept award DAMD17-03-1-0758 from the U.S. Department of Defense (A.P. Taylor) and New Jersey Department of Health and Senior Services grant 05-1842-FS-N-0 (D.M. Goldenberg).

The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked advertisement in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

¹ Supplementary material for this article are available at Molecular Cancer Therapeutics Online (http://mct.aacrjournals.org/).

Received 8/ 2/06; revised 11/ 6/06; accepted 12/13/06.