Bone morphogenetic protein 2 (BMP-2) and induction of tumor angiogenesis.
OBJECTIVE
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.
Raida
Martin
M
Department of Hematology/Oncology, University of Leipzig, 04103, Leipzig, Germany. martin.raida@medizin.uni-leipzig.de
Clement
Joachim H
JH
Leek
Russell D
RD
Ameri
Kurosh
K
Bicknell
Roy
R
Niederwieser
Dietger
D
Harris
Adrian L
AL
D000818:Animals; D055396:Bone Morphogenetic Protein 2; D052004:Bone Morphogenetic Protein Receptors / Q000378:metabolism*; D019485:Bone Morphogenetic Proteins / Q000378:metabolism*; D001943:Breast Neoplasms / Q000098:blood supply* / Q000378:metabolism*; D045744:Cell Line, Tumor; D005260:Female; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D015151:Immunoblotting; D007150:Immunohistochemistry; D051379:Mice; D009389:Neovascularization, Pathologic / Q000378:metabolism*; D014162:Transfection; D016212:Transforming Growth Factor beta / Q000378:metabolism*; D014183:Transplantation, Heterologous; D015854:Up-Regulation; D048051:p38 Mitogen-Activated Protein Kinases / Q000378:metabolism
C525718:BMP2 protein, human; C525719:Bmp2 protein, mouse; D055396:Bone Morphogenetic Protein 2; D019485:Bone Morphogenetic Proteins; D016212:Transforming Growth Factor beta; D048051:p38 Mitogen-Activated Protein Kinases; D052004:Bone Morphogenetic Protein Receptors