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Bone morphogenetic protein 2 (BMP-2) and induction of tumor angiogenesis

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Abstract

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.

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Acknowledgements

This work was supported in part by Grants of Cancer Research, UK and Dr. Mildred Scheel Foundation, Germany. We thank Christine Günther for her technical expertise and help in matrigel endothelial cell tube formation assay.

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Authors and Affiliations

  1. Department of Hematology/Oncology, University of Leipzig, 04103, Leipzig, Germany

    Martin Raida & Dietger Niederwieser

  2. Department of Internal Medicine II, Friedrich Schiller University, 07740, Jena, Germany

    Joachim H. Clement

  3. Cancer Research United Kingdom, Molecular Oncology Laboratory, Weatherall Institute of Molecular Medicine, John Radcliffe Hospital, Oxford, OX3 9DS, United Kingdom

    Martin Raida, Russell D. Leek, Kurosh Ameri, Roy Bicknell & Adrian L. Harris

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  1. Martin Raida
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Correspondence to Martin Raida.

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Raida, M., Clement, J.H., Leek, R.D. et al. Bone morphogenetic protein 2 (BMP-2) and induction of tumor angiogenesis. J Cancer Res Clin Oncol 131, 741–750 (2005). https://doi.org/10.1007/s00432-005-0024-1

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  • DOI: https://doi.org/10.1007/s00432-005-0024-1

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