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Breast cancer cells stimulate osteoprotegerin (OPG) production by endothelial cells through direct cell contact

Reid, P.E., Brown, N.J. and Holen, I. (2009) Breast cancer cells stimulate osteoprotegerin (OPG) production by endothelial cells through direct cell contact. Molecular Cancer, 8 (49). ISSN 1476-4598

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Abstract

Background: Angiogenesis, the sprouting of capillaries from existing blood vessels, is central to tumour growth and progression, however the molecular regulation of this process remains to be fully elucidated. The secreted glycoprotein osteoprotegerin (OPG) is one potential pro-angiogenic factor, and clinical studies have demonstrated endothelial cells within a number of tumour types to express high levels of OPG compared to those in normal tissue. Additionally, OPG can increase endothelial cell survival, proliferation and migration, as well as induce endothelial cell tube formation in vitro. This study aims to elucidate the processes involved in the pro-angiogenic effects of OPG in vitro, and also how OPG levels may be regulated within the tumour microenvironment.

Results: It has previously been demonstrated that OPG can induce tube formation on growth factor reduced matrigel. In this study, we demonstrate that OPG enhances the pro-angiogenic effects of VEGF and that OPG does not stimulate endothelial cell tube formation through activation of the VEGFR2 receptor. We also show that cell contact between HuDMECs and the T47D breast cancer cell line increases endothelial cell OPG mRNA and protein secretion levels in in vitro co-cultures. These increases in endothelial cell OPG secretion were dependent on alpha(nu)beta(3) ligation and NF kappa B activation. In contrast, the pro-angiogenic factors VEGF, bFGF and TGF beta had no effect on HuDMEC OPG levels.

Conclusion: These findings suggest that the VEGF signalling pathway is not involved in mediating the pro-angiogenic effects of OPG on endothelial cells in vitro. Additionally, we show that breast cancer cells cause increased levels of OPG expression by endothelial cells, and that direct contact between endothelial cells and tumour cells is required in order to increase endothelial OPG expression and secretion. Stimulation of OPG secretion was shown to involve alpha(nu)beta(3) ligation and NF kappa B activation.

Item Type: Article
Copyright, Publisher and Additional Information: © 2009 Reid et al; licensee BioMed Central Ltd. This is an Open Access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/2.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.
Keywords: NF-KAPPA-B; CORONARY-ARTERY-DISEASE; IN-VITRO; GROWTH-FACTOR; RECEPTOR ACTIVATOR; SURVIVAL FACTOR; EARLY-ONSET; CALCIFICATION; ANGIOGENESIS; EXPRESSION
Institution: The University of Sheffield
Academic Units: The University of Sheffield > Faculty of Science (Sheffield) > School of Biological Sciences (Sheffield) > Department of Biomedical Science (Sheffield)
The University of Sheffield > Faculty of Medicine, Dentistry and Health (Sheffield) > School of Medicine (Sheffield)
Depositing User: Miss Anthea Tucker
Date Deposited: 07 Sep 2009 11:32
Last Modified: 08 Jun 2014 15:21
Published Version: http://dx.doi.org/10.1186/1476-4598-8-49
Status: Published
Publisher: BioMed Central
Refereed: Yes
Identification Number: 10.1186/1476-4598-8-49
URI: http://eprints.whiterose.ac.uk/id/eprint/9290

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