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a Laboratoire de Médecine Moléculaire and
b Division of Hematology-Oncology, Centre de Cancérologie Charles-Bruneau, Hôpital Sainte-Justine and Université du Québec à Montréal, Montreal, Quebec, Canada;
c Department of Medicine, Lady Davis Institute for Medical Research, Montreal, Quebec, Canada
Key Words. Angiogenesis • Hypoxia • Murine marrow stromal cells • Cell migration • Matrix metalloproteinase
Richard Béliveau, Ph.D., Laboratoire de Médecine Moléculaire, Centre de Recherche de l’Hôpital Sainte-Justine, 3175 Chemin Côte-Sainte-Catherine, Montréal, Québec, Canada, H3T 1C5. Telephone: 514-345-2366; Fax: 514-987-0246; e-mail: oncomol{at}nobel.si.uqam.ca
Recent evidence indicates that bone-marrow-derived stromal cells (MSCs) have a histology coherent with endothelial cells that may enable them to contribute to tumor angiogenesis through yet undefined mechanisms. In this work, we investigated the angiogenic properties of murine MSCs involved in extracellular matrix degradation and in neovascularization that could take place in a hypoxic environment such as that encountered in tumor masses. MSCs were cultured in normoxia (95% air and 5% CO2) or in hypoxia (1% oxygen, 5% CO2, and 94% nitrogen). We found that hypoxic culture conditions rapidly induced MSC migration and three-dimensional capillary-like structure formation on Matrigel. In vitro, MSC migration was induced by growth-factor- and cytokine-enriched conditioned media isolated from U-87 glioma cells as well as from MSCs cultured in hypoxic conditions, suggesting both paracrine and autocrine regulatory mechanisms. Although greater vascular endothelial growth factor levels were secreted by MSCs in hypoxic conditions, this growth factor alone could not explain their greater migration. Interestingly, matrix metalloproteinase (MMP)-2 mRNA expression and protein secretion were downregulated, while those of membrane-type (MT)1-MMP were strongly induced by hypoxia. Functional inhibition of MT1-MMP by a blocking antibody strongly suppressed MSC ability to migrate and generate capillary-like structures. Collectively, these data suggest that MSCs may have the capacity to participate in tumor angiogenesis through regulation of their angiogenic properties under an atmosphere of low oxygen that closely approximates the tumor microenvironment.
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