title: ADAM-9 is a novel mediator of tenascin-C-stimulated invasiveness of brain tumor-initiating cells.
abstract: BACKGROUND
  Tenascin-C (TNC), an extracellular matrix protein overexpressed in malignant gliomas, stimulates invasion of conventional glioma cell lines (U251, U87). However, there is a dearth of such information on glioma stemlike cells. Here, we have addressed whether and how TNC may regulate the invasiveness of brain tumor-initiating cells (BTICs) that give rise to glioma progenies.
  
  
  METHODS
  Transwell inserts coated with extracellular matrix proteins were used to determine the role of TNC in BTIC invasion. Microarray analysis, lentiviral constructs, RNA interference-mediated knockdown, and activity assay ascertained the role of proteases in TNC-stimulated BTIC invasion in culture. Involvement of proteases was validated using orthotopic brain xenografts in mice.
  
  
  RESULTS
  TNC stimulated BTIC invasiveness in a metalloproteinase-dependent manner. A global gene expression screen identified the metalloproteinase ADAM-9 as a potential regulator of TNC-stimulated BTIC invasiveness, and this was corroborated by an increase of ADAM-9 protein in 4 glioma patient-derived BTIC lines. Notably, RNA interference to ADAM-9, as well as inhibition of mitogen-activated protein kinase 8 (c-Jun NH2-terminal kinase), attenuated TNC-stimulated ADAM-9 expression, proteolytic activity, and BTIC invasiveness. The relevance of ADAM-9 to tumor invasiveness was validated using resected human glioblastoma specimens and orthotopic xenografts where elevation of ADAM-9 and TNC expression was prominent at the invasive front of the tumor.
  
  
  CONCLUSIONS
  This study has identified TNC as a promoter of the invasiveness of BTICs through a mechanism involving ADAM-9 proteolysis via the c-Jun NH2-terminal kinase pathway.
authors: Department of Clinical Neurosciences, University of Calgary, Calgary, Alberta, Canada (S.S., V.W.Y.); Hotchkiss Brain Institute, University of Calgary, Calgary, Alberta, Canada (S.S., V.W.Y.); The Southern Alberta Cancer Research Institute, University of Calgary, Calgary, Alberta, Canada (F.J.Z., D.S., S.M.R.).
authors: Susobhan
authors: S
authors: Sarkar
authors: Department of Clinical Neurosciences, University of Calgary, Calgary, Alberta, Canada (S.S., V.W.Y.); Hotchkiss Brain Institute, University of Calgary, Calgary, Alberta, Canada (S.S., V.W.Y.); The Southern Alberta Cancer Research Institute, University of Calgary, Calgary, Alberta, Canada (F.J.Z., D.S., S.M.R.).
authors: Franz J
authors: FJ
authors: Zemp
authors: Department of Clinical Neurosciences, University of Calgary, Calgary, Alberta, Canada (S.S., V.W.Y.); Hotchkiss Brain Institute, University of Calgary, Calgary, Alberta, Canada (S.S., V.W.Y.); The Southern Alberta Cancer Research Institute, University of Calgary, Calgary, Alberta, Canada (F.J.Z., D.S., S.M.R.).
authors: Donna
authors: D
authors: Senger
authors: Department of Clinical Neurosciences, University of Calgary, Calgary, Alberta, Canada (S.S., V.W.Y.); Hotchkiss Brain Institute, University of Calgary, Calgary, Alberta, Canada (S.S., V.W.Y.); The Southern Alberta Cancer Research Institute, University of Calgary, Calgary, Alberta, Canada (F.J.Z., D.S., S.M.R.).
authors: Stephen M
authors: SM
authors: Robbins
authors: Department of Clinical Neurosciences, University of Calgary, Calgary, Alberta, Canada (S.S., V.W.Y.); Hotchkiss Brain Institute, University of Calgary, Calgary, Alberta, Canada (S.S., V.W.Y.); The Southern Alberta Cancer Research Institute, University of Calgary, Calgary, Alberta, Canada (F.J.Z., D.S., S.M.R.).
authors: V Wee
authors: VW
authors: Yong
mesh_terms: D051722:ADAM Proteins / Q000378:metabolism*; D000818:Animals; D001932:Brain Neoplasms / Q000378:metabolism / Q000473:pathology*; D045744:Cell Line, Tumor; D005909:Glioblastoma / Q000378:metabolism / Q000473:pathology*; D006801:Humans; D020935:MAP Kinase Signaling System; D008565:Membrane Proteins / Q000378:metabolism*; D051379:Mice; D009361:Neoplasm Invasiveness; D014411:Neoplastic Stem Cells / Q000378:metabolism / Q000473:pathology*; D019063:Tenascin / Q000494:pharmacology / Q000502:physiology*
chemical_list: D008565:Membrane Proteins; D019063:Tenascin; D051722:ADAM Proteins; C098339:ADAM9 protein, human
keywords: extracellular matrix; glioma; metalloproteinases; proteolysis; stem cell
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