title: MT1-MMP silencing by an shRNA-armed glioma-targeted conditionally replicative adenovirus (CRAd) improves its anti-glioma efficacy in vitro and in vivo.
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.
authors.affiliation: Center for Advanced Brain Tumor Center, Swedish Neuroscience Institute, 550 17th Avenue, Seattle, WA 98122, USA; Laboratory of Experimental Diagnostics and Biotherapy, N.N. Blokhin Cancer Research Center (RONC), Moscow 123481, Russia. Electronic address: ulasov75@yahoo.com.
authors.forename: Ilya
authors.initials: I
authors.lastname: Ulasov
authors.affiliation: School of Dentistry, Institute of Oral Health Research, University of Alabama at Birmingham, Birmingham, AL 35205, USA.
authors.forename: Anton V
authors.initials: AV
authors.lastname: Borovjagin
authors.affiliation: Laboratory of Experimental Diagnostics and Biotherapy, N.N. Blokhin Cancer Research Center (RONC), Moscow 123481, Russia.
authors.forename: Natalya
authors.initials: N
authors.lastname: Kaverina
authors.affiliation: College of Medicine, Michigan State University, Grand Rapids, MI 49503, USA.
authors.forename: Brett
authors.initials: B
authors.lastname: Schroeder
authors.affiliation: Center for Advanced Brain Tumor Center, Swedish Neuroscience Institute, 550 17th Avenue, Seattle, WA 98122, USA.
authors.forename: Nameeta
authors.initials: N
authors.lastname: Shah
authors.affiliation: Center for Advanced Brain Tumor Center, Swedish Neuroscience Institute, 550 17th Avenue, Seattle, WA 98122, USA.
authors.forename: Biaoyang
authors.initials: B
authors.lastname: Lin
authors.affiliation: Laboratory of Experimental Diagnostics and Biotherapy, N.N. Blokhin Cancer Research Center (RONC), Moscow 123481, Russia.
authors.forename: Anatoly
authors.initials: A
authors.lastname: Baryshnikov
authors.affiliation: Center for Advanced Brain Tumor Center, Swedish Neuroscience Institute, 550 17th Avenue, Seattle, WA 98122, USA. Electronic address: Charles.Cobbs@Swedish.org.
authors.forename: Charles
authors.initials: C
authors.lastname: Cobbs
mesh_terms: D000256:Adenoviridae / Q000235:genetics*; D000368:Aged; D000818:Animals; D001932:Brain Neoplasms / Q000235:genetics*; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000235:genetics; D018450:Disease Progression; D005260:Female; D015972:Gene Expression Regulation, Neoplastic; D015316:Genetic Therapy; D005822:Genetic Vectors / Q000235:genetics; D005910:Glioma / Q000235:genetics*; D006801:Humans; D006877:Hydroxamic Acids / Q000494:pharmacology; D016209:Interleukin-8 / Q000096:biosynthesis; D008297:Male; D053511:Matrix Metalloproteinase 14 / Q000235:genetics*; D051379:Mice; D008875:Middle Aged; D009368:Neoplasm Transplantation; D009389:Neovascularization, Pathologic / Q000235:genetics; D050130:Oncolytic Virotherapy; D034622:RNA Interference; D034741:RNA, Small Interfering; D014183:Transplantation, Heterologous; D042461:Vascular Endothelial Growth Factor A / Q000096:biosynthesis
chemical_list: C508606:CXCL8 protein, human; D006877:Hydroxamic Acids; D016209:Interleukin-8; D034741:RNA, Small Interfering; C467484:VEGFA protein, human; D042461:Vascular Endothelial Growth Factor A; C100342:marimastat; C507086:MMP14 protein, human; D053511:Matrix Metalloproteinase 14
keywords: Adenovirus; Brain tumor; Glioma; Metalloproteinase