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PURPOSE: Bone morphogenetic proteins (BMPs) are members of the transforming growth factor-beta family and play an important role in the regulation of embryonic vasculogenesis but their role in postnatal angiogenesis remains to be clarified. In this study we investigated a possible role of BMP-2 in the promotion of tumor angiogenesis. METHODS: We studied the effect of BMP-2 on human dermal microvascular endothelial cells (HDMECs) and examined a possible angiogenic activity of BMP-2 with the mouse sponge assay. The effect of BMP-2 overexpression on tumor vascularization was also analyzed in xenografts of human BMP-2 transfected MCF-7 breast cancer cells (MCF-7/BMP2) in mice. RESULTS: BMP receptor activation selectively induced the phosphorylation of p38 mitogen-activated protein kinase (MAPK) in contrast to the ERK1/2 MAP kinases. In keeping with this finding, BMP-2 had no significant effect on endothelial cell proliferation but promoted HDMEC tube formation in the matrigel assay. The transcription factor inhibitor of differentiation 1 (Id1), which is known to play an important role in neovascularization of tumors, was confirmed as a BMP target in HDMECs. Immunohistochemical analysis of sponge sections revealed that BMP-2 induced vascularization and showed an additive enhancement of angiogenesis with VEGF. In the murine breast cancer xenograft model, human MCF-7 cells with stable overexpression of BMP-2 developed vascularized tumors while empty vector control MCF-7 cells failed to form tumors. CONCLUSIONS: We conclude that activation of the BMP pathway by BMP-2 can promote vascularization and might be involved in tumor angiogenesis possibly by stimulating the Id1 and p38 MAPK pathway.

Original publication

DOI

10.1007/s00432-005-0024-1

Type

Journal article

Journal

J Cancer Res Clin Oncol

Publication Date

11/2005

Volume

131

Pages

741 - 750

Keywords

Animals, Bone Morphogenetic Protein 2, Bone Morphogenetic Protein Receptors, Bone Morphogenetic Proteins, Breast Neoplasms, Cell Line, Tumor, Female, Gene Expression Regulation, Neoplastic, Humans, Immunoblotting, Immunohistochemistry, Mice, Neovascularization, Pathologic, Transfection, Transforming Growth Factor beta, Transplantation, Heterologous, Up-Regulation, p38 Mitogen-Activated Protein Kinases