Hypoxia promotes murine bone-marrow-derived stromal cell migration and tube formation.
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% CO(2)) or in hypoxia (1% oxygen, 5% CO(2), 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.
Laboratoire de Médecine Moléculaire and Division of Hematology-Oncology, Centre de Cancérologie Charles-Bruneau, Hôpital Sainte-Justine and Université du Québec à Montréal, Montreal, Quebec, Canada.
Borhane
B
Annabi
Ying-Ta
YT
Lee
Sandra
S
Turcotte
Emmanuelle
E
Naud
Richard R
RR
Desrosiers
Martin
M
Champagne
Nicoletta
N
Eliopoulos
Jacques
J
Galipeau
Richard
R
Béliveau
D019898:Autocrine Communication; D001854:Bone Marrow Cells / Q000166:cytology / Q000378:metabolism*; D002460:Cell Line; D002465:Cell Movement / Q000502:physiology*; D003094:Collagen; D016207:Cytokines / Q000494:pharmacology; D015536:Down-Regulation / Q000187:drug effects / Q000502:physiology; D004338:Drug Combinations; D004730:Endothelium, Vascular / Q000166:cytology / Q000378:metabolism; D005782:Gels; D006133:Growth Substances / Q000494:pharmacology; D006412:Hematopoietic Stem Cells / Q000166:cytology / Q000378:metabolism; D006801:Humans; D000860:Hypoxia / Q000378:metabolism* / Q000503:physiopathology; D007797:Laminin; D020778:Matrix Metalloproteinase 2 / Q000235:genetics / Q000378:metabolism; D053504:Matrix Metalloproteinases, Membrane-Associated; D008666:Metalloendopeptidases / Q000235:genetics / Q000378:metabolism; D009369:Neoplasms / Q000378:metabolism* / Q000503:physiopathology; D009389:Neovascularization, Pathologic / Q000378:metabolism* / Q000503:physiopathology; D011509:Proteoglycans; D017154:Stromal Cells / Q000166:cytology / Q000378:metabolism*; D015854:Up-Regulation / Q000187:drug effects / Q000502:physiology; D042461:Vascular Endothelial Growth Factor A / Q000378:metabolism
D016207:Cytokines; D004338:Drug Combinations; D005782:Gels; D006133:Growth Substances; D007797:Laminin; D011509:Proteoglycans; D042461:Vascular Endothelial Growth Factor A; C059485:matrigel; D003094:Collagen; D053504:Matrix Metalloproteinases, Membrane-Associated; D008666:Metalloendopeptidases; D020778:Matrix Metalloproteinase 2