MT1-MMP silencing by an shRNA-armed glioma-targeted conditionally replicative adenovirus (CRAd) improves its anti-glioma efficacy in vitro and in vivo. Issue 2 (1st September 2015)

• Record Type: Journal Article
• Authors: Ulasov, Ilya; Borovjagin, Anton V.; Kaverina, Natalya; Schroeder, Brett; Shah, Nameeta; Lin, Biaoyang; Baryshnikov, Anatoly; Cobbs, Charles
• Is Part Of: Cancer letters. Volume 365:Issue 2(2015)
• Page Start: 240
• Page End: 250
• Publication Date: 2015-09-01
• Subjects: Brain tumor -- Adenovirus -- Glioma -- Metalloproteinase; CRAd conditionally replicated adenovirus -- MMP14 metalloproteinase type 14 -- GBM glioblastoma -- CD46 cluster of differentiation 46; Cancer -- Periodicals; Neoplasms -- Periodicals; Cancer -- Périodiques; Electronic journals; 616.994
• DOI: 10.1016/j.canlet.2015.06.002
• Languages: English
• ISSNs: 0304-3835

Abstract

Highlights: GBM exhibits high levels of MMP14 expression. Suppression of MMP14 expression by poly-MMP inhibitor Marimastat inhibits glioma angiogenesis. Adenovirus-mediated delivery of MMP14-specific shRNA improves survival of mice bearing glioma xenografts. Abstract: MMP14 (MT1-MMP) is a cell membrane-associated proteinase of the extracellular matrix, whose biological roles vary from angiogenesis to cell proliferation and survival. We recently found a direct correlation between MMP14 expression levels in brain tumors of glioma patients and the disease progression. By using gene silencing as an experimental approach we found that MMP14 knockdown decreases production of pro-angiogenic factors such as VEGF and IL8 and thereby suppresses angiogenesis in glioma tumors. Although the clinical relevance of MMP14 down-regulation and its possible implications for glioma therapy in humans remain unclear, we observed a significant improvement in animal survival upon down-regulation of MMP14 in murine intracranial glioma xenografts infected with MMP14 shRNA-expressing CRAd. We further found that down-regulation of MMP14 in gliomas by combinational treatment with CRAd-S-5/3 and Marimastat, a chemical inhibitor of metalloproteinases, augments suppression of pro-angiogenic factors, caused by the replication-competent adenovirus. We also demonstrated that delivery of MMP14-targeting shRNA by a fiber-modified adenoviral vector to the glioma cells effectively suppresses their proliferation in vitro and in vivo . Thus our data indicate that inhibition of MMP14 expression in tumors in combination with glioma virotherapy could be effectively utilized to suppress angiogenesis and neovascularization of glioma tumors by decreasing production of pro-angiogenic factors.