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Angiogenesis, Metastasis, and the Cellular Microenvironment

Tumor Environment Dictates Medulloblastoma Cancer Stem Cell Expression and Invasive Phenotype

¹ Laboratoire d'Oncologie Moléculaire, Département de Chimie, Université du Québec à Montréal, ² Centre de Cancérologie Charles-Bruneau, Hôpital Sainte-Justine-UQAM, and ³ Department of Pathology, Hôpital Sainte-Justine, Montreal, Quebec, Canada

Requests for reprints: Richard Béliveau, Laboratoire de Médecine Moléculaire, Université du Québec à Montréal, C.P. 8888, Succursale Centre-ville, Montreal, Quebec, Canada H3C 3P8. Phone: 514-987-3000, ext. 8551; Fax: 514-987-0246. E-mail: oncomol{at}nobel.si.uqam.ca

The neural precursor surface marker CD133 is thought to be enriched in brain cancer stem cells and in radioresistant DAOY medulloblastoma-derived tumor cells. Given that membrane type-1 matrix metalloproteinase (MT1-MMP) expression is a hallmark of highly invasive, radioresistant, and hypoxic brain tumor cells, we sought to determine whether MT1-MMP and other MMPs could regulate the invasive phenotype of CD133(+) DAOY cells. We found that when DAOY medulloblastoma or U87 glioblastoma cells were implanted in nude mice, only those cells specifically implanted in the brain environment generated CD133(+) brain tumors. Vascular endothelial growth factor and basic fibroblast growth factor gene expression increases in correlation with CD133 expression in those tumors. When DAOY cultures were induced to generate in vitro neurosphere-like cells, gene expression of CD133, MT1-MMP, MMP-9, and MDR-1 was induced and correlated with an increase in neurosphere invasiveness. Specific small interfering RNA gene silencing of either MT1-MMP or MMP-9 reduced the capacity of the DAOY monolayers to generate neurospheres and concomitantly abrogated their invasive capacity. On the other hand, overexpression of MT1-MMP in DAOY triggered neurosphere-like formation which was further amplified when cells were cultured in neurosphere medium. Collectively, we show that both MT1-MMP and MMP-9 contribute to the invasive phenotype during CD133(+) neurosphere-like formation in medulloblastoma cells. Increases in MMP-9 may contribute to the opening of the blood-brain barrier, whereas increased MT1-MMP would promote brain tumor infiltration. Our study suggests that MMP-9 or MT1-MMP targeting may reduce the formation of brain tumor stem cells. (Mol Cancer Res 2008;6(6):907–16)