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      A MT1-MMP/NF-κB signaling axis as a checkpoint controller of COX-2 expression in CD133(+) U87 glioblastoma cells

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          Abstract

          Background

          The CD133(+) stem cell population in recurrent gliomas is associated with clinical features such as therapy resistance, blood-brain barrier disruption and, hence, tumor infiltration. Screening of a large panel of glioma samples increasing histological grade demonstrated frequencies of CD133(+) cells which correlated with high expression of cyclooxygenase (COX)-2 and of membrane type-1 matrix metalloproteinase (MT1-MMP).

          Methods

          We used qRT-PCR and immunoblotting to examine the molecular interplay between MT1-MMP and COX-2 gene and protein expression in parental, CD133(+), and neurospheres U87 glioma cell cultures.

          Results

          We found that CD133, COX-2 and MT1-MMP expression were enhanced when glioma cells were cultured in neurosphere conditions. A CD133(+)-enriched U87 glioma cell population, isolated from parental U87 cells with magnetic cell sorting technology, also grew as neurospheres and showed enhanced COX-2 expression. MT1-MMP gene silencing antagonized COX-2 expression in neurospheres, while overexpression of recombinant MT1-MMP directly triggered COX-2 expression in U87 cells independent from MT1-MMP's catalytic function. COX-2 induction by MT1-MMP was also validated in wild-type and in NF-κB p65 -/- mutant mouse embryonic fibroblasts, but was abrogated in NF-κB1 (p50 -/-) mutant cells.

          Conclusion

          We provide evidence for enhanced COX-2 expression in CD133(+) glioma cells, and direct cell-based evidence of NF-κB-mediated COX-2 regulation by MT1-MMP. The biological significance of such checkpoint control may account for COX-2-dependent mechanisms of inflammatory balance responsible of therapy resistance phenotype of cancer stem cells.

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          Most cited references48

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          Analysis of gene expression and chemoresistance of CD133+ cancer stem cells in glioblastoma

          Background Recently, a small population of cancer stem cells in adult and pediatric brain tumors has been identified. Some evidence has suggested that CD133 is a marker for a subset of leukemia and glioblastoma cancer stem cells. Especially, CD133 positive cells isolated from human glioblastoma may initiate tumors and represent novel targets for therapeutics. The gene expression and the drug resistance property of CD133 positive cancer stem cells, however, are still unknown. Results In this study, by FACS analysis we determined the percentage of CD133 positive cells in three primary cultured cell lines established from glioblastoma patients 10.2%, 69.7% and 27.5%, respectively. We also determined the average mRNA levels of markers associated with neural precursors. For example, CD90, CD44, CXCR4, Nestin, Msi1 and MELK mRNA on CD133 positive cells increased to 15.6, 5.7, 337.8, 21.4, 84 and 1351 times, respectively, compared to autologous CD133 negative cells derived from cell line No. 66. Additionally, CD133 positive cells express higher levels of BCRP1 and MGMT mRNA, as well as higher mRNA levels of genes that inhibit apoptosis. Furthermore, CD133 positive cells were significantly resistant to chemotherapeutic agents including temozolomide, carboplatin, paclitaxel (Taxol) and etoposide (VP16) compared to autologous CD133 negative cells. Finally, CD133 expression was significantly higher in recurrent GBM tissue obtained from five patients as compared to their respective newly diagnosed tumors. Conclusion Our study for the first time provided evidence that CD133 positive cancer stem cells display strong capability on tumor's resistance to chemotherapy. This resistance is probably contributed by the CD133 positive cell with higher expression of on BCRP1 and MGMT, as well as the anti-apoptosis protein and inhibitors of apoptosis protein families. Future treatment should target this small population of CD133 positive cancer stem cells in tumors to improve the survival of brain tumor patients.
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            CD133(+) and CD133(-) glioblastoma-derived cancer stem cells show differential growth characteristics and molecular profiles.

            Although glioblastomas show the same histologic phenotype, biological hallmarks such as growth and differentiation properties vary considerably between individual cases. To investigate whether different subtypes of glioblastomas might originate from different cells of origin, we cultured tumor cells from 22 glioblastomas under medium conditions favoring the growth of neural and cancer stem cells (CSC). Secondary glioblastoma (n = 7)-derived cells did not show any growth in the medium used, suggesting the absence of neural stem cell-like tumor cells. In contrast, 11/15 primary glioblastomas contained a significant CD133(+) subpopulation that displayed neurosphere-like, nonadherent growth and asymmetrical cell divisions yielding cells expressing markers characteristic for all three neural lineages. Four of 15 cell lines derived from primary glioblastomas grew adherently in vitro and were driven by CD133(-) tumor cells that fulfilled stem cell criteria. Both subtypes were similarly tumorigenic in nude mice in vivo. Clinically, CD133(-) glioblastomas were characterized by a lower proliferation index, whereas glial fibrillary acidic protein staining was similar. GeneArray analysis revealed 117 genes to be differentially expressed by these two subtypes. Together, our data provide first evidence that CD133(+) CSC maintain only a subset of primary glioblastomas. The remainder stems from previously unknown CD133(-) tumor cells with apparent stem cell-like properties but distinct molecular profiles and growth characteristics in vitro and in vivo.
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              Stem cell marker CD133 affects clinical outcome in glioma patients.

              The CD133 antigen has been identified as a putative stem cell marker in normal and malignant brain tissues. In gliomas, it is used to enrich a subpopulation of highly tumorigenic cancer cells. According to the cancer stem cell hypothesis, CD133-positive cells determine long-term tumor growth and, therefore, are suspected to influence clinical outcome. To date, a correlation between CD133 expression in primary tumor tissues and patients' prognosis has not been reported. To address this question, we analyzed the expression of the CD133 stem cell antigen in a series of 95 gliomas of various grade and histology by immunohistochemistry on cryostat sections. Staining data were correlated with patient outcome. By multivariate survival analysis, we found that both the proportion of CD133-positive cells and their topological organization in clusters were significant (P < 0.001) prognostic factors for adverse progression-free survival and overall survival independent of tumor grade, extent of resection, or patient age. Furthermore, proportion of CD133-positive cells was an independent risk factor for tumor regrowth and time to malignant progression in WHO grade 2 and 3 tumors. These findings constitute the first conclusive evidence that CD133 stem cell antigen expression correlates with patient survival in gliomas, lending support to the current cancer stem cell hypothesis.
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                Author and article information

                Journal
                J Neuroinflammation
                Journal of Neuroinflammation
                BioMed Central
                1742-2094
                2009
                9 March 2009
                : 6
                : 8
                Affiliations
                [1 ]Laboratoire d'Oncologie Moléculaire, Département de Chimie, Centre de Recherche BIOMED, Université du Québec à Montréal, Quebec, Canada
                [2 ]Laboratoire de Médecine Moléculaire, Department of Neurosurgery, CHUM and UQAM, Montreal, Quebec, Canada
                Article
                1742-2094-6-8
                10.1186/1742-2094-6-8
                2655289
                19272160
                60ecbacf-e3eb-47ad-8a98-b4ea6a5d1409
                Copyright © 2009 Annabi 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.

                History
                : 17 February 2009
                : 9 March 2009
                Categories
                Research

                Neurosciences
                Neurosciences

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