title: A role for matrix remodelling proteins in invasive and malignant meningiomas.
abstract: OBJECTIVE
  Meningiomas are one of the most common brain tumours in adults. Invasive and malignant meningiomas present a significant therapeutic challenge due to high recurrence rates and invasion into surrounding bone, brain, neural and soft tissues. Understanding the molecular mechanism of invasion could help in designing novel therapeutic approaches in order to prevent the need for repeat surgery, decrease morbidity and improve patient survival. The aim of this study was to identify the key factors and underlying mechanisms which govern invasive properties of meningiomas.
  
  
  METHODS
  Formalin-fixed paraffin-embedded (FFPE) as well as frozen tumour tissues from bone-invasive, non-invasive and malignant meningiomas were used for RNA microarray, quantitative real-time PCR or Western blot analyses. Malignant meningioma cell lines (F5) were subject to MMP16 downregulation or overexpression and used for in vitro and in vivo functional assays. Subdural xenograft meningioma tumours were generated to study the invasion of tumour cells into brain parenchyma using cell lines with altered MMP16 expression.
  
  
  RESULTS
  We establish that the expression level of MMP16 was significantly elevated in both bone-invasive and brain invasive meningiomas. Gain- and loss-of-function experiments indicated a role for MMP16 in meningioma cell movement, invasion and tumour cell growth. Furthermore, MMP16 was shown to positively regulate MMP2, suggesting this mechanism may modulate meningioma invasion in invasive meningiomas.
  
  
  CONCLUSIONS
  Overall, the results support a role for MMP16 in promoting invasive properties of the meningioma tumours. Further studies to explore the potential value for clinical use of matrix metalloproteinases inhibitors are warranted.
authors.affiliation: Labatt's Brain Tumor Research Center, Hospital for Sick Children, University of Toronto, Toronto, Ontario, Canada.
authors.forename: Shahrzad
authors.initials: S
authors.lastname: Jalali
authors.forename: Sanjay
authors.initials: S
authors.lastname: Singh
authors.forename: Sameer
authors.initials: S
authors.lastname: Agnihotri
authors.forename: Takafumi
authors.initials: T
authors.lastname: Wataya
authors.forename: Fatemeh
authors.initials: F
authors.lastname: Salehi
authors.forename: R
authors.initials: R
authors.lastname: Alkins
authors.forename: Kelly
authors.initials: K
authors.lastname: Burrell
authors.forename: Roya
authors.initials: R
authors.lastname: Navab
authors.forename: Sidney
authors.initials: S
authors.lastname: Croul
authors.forename: Kenneth
authors.initials: K
authors.lastname: Aldape
authors.forename: Gelareh
authors.initials: G
authors.lastname: Zadeh
mesh_terms: D000328:Adult; D000818:Animals; D015153:Blotting, Western; D045744:Cell Line, Tumor; D015972:Gene Expression Regulation, Neoplastic / Q000502:physiology; D064593:Heterografts; D006801:Humans; D053513:Matrix Metalloproteinase 16 / Q000378:metabolism*; D020778:Matrix Metalloproteinase 2 / Q000096:biosynthesis; D008577:Meningeal Neoplasms / Q000378:metabolism / Q000473:pathology*; D008579:Meningioma / Q000378:metabolism / Q000473:pathology*; D051379:Mice; D016688:Mice, Inbred NOD; D016513:Mice, SCID; D009361:Neoplasm Invasiveness; D020411:Oligonucleotide Array Sequence Analysis; D060888:Real-Time Polymerase Chain Reaction; D014162:Transfection
chemical_list: C507102:MMP16 protein, human; D053513:Matrix Metalloproteinase 16; C522361:MMP2 protein, human; D020778:Matrix Metalloproteinase 2
keywords: MMP16; expression profiling; invasion; malignant; matrix metalloproteinase; meningioma