title: Gliomas induce and exploit microglial MT1-MMP expression for tumor expansion.
abstract: Diffuse infiltration of glioma cells into normal brain tissue is considered to be a main reason for the unfavorable outcomes of patients with malignant gliomas. Invasion of glioma cells into the brain parenchyma is facilitated by metalloprotease-mediated degradation of the extracellular matrix. Metalloproteases are released as inactive pro-forms and get activated upon cleavage by membrane bound metalloproteases. Here, we show that membrane type 1 metalloprotease (MT1-MMP) is up-regulated in glioma-associated microglia, but not in the glioma cells. Overexpression of MT1-MMP is even lethal for glioma cells. Glioma-released factors trigger the expression and activity of MT1-MMP via microglial toll-like receptors and the p38 MAPK pathway, as deletion of the toll-like receptor adapter protein MyD88 or p38 inhibition prevented MT1-MMP expression and activity in cultured microglial cells. Microglial MT1-MMP in turn activates glioma-derived pro-MMP-2 and promotes glioma expansion, as shown in an ex vivo model using MT1-MMP-deficient brain tissue and a microglia depletion paradigm. Finally, MyD88 deficiency or microglia depletion largely attenuated glioma expansion in 2 independent in vivo models.
authors.affiliation: Cellular Neuroscience, Max Delbrück Center for Molecular Medicine, 13125 Berlin, Germany.
authors.forename: D S
authors.initials: DS
authors.lastname: Markovic
authors.forename: K
authors.initials: K
authors.lastname: Vinnakota
authors.forename: S
authors.initials: S
authors.lastname: Chirasani
authors.forename: M
authors.initials: M
authors.lastname: Synowitz
authors.forename: H
authors.initials: H
authors.lastname: Raguet
authors.forename: K
authors.initials: K
authors.lastname: Stock
authors.forename: M
authors.initials: M
authors.lastname: Sliwa
authors.forename: S
authors.initials: S
authors.lastname: Lehmann
authors.forename: R
authors.initials: R
authors.lastname: Kälin
authors.forename: N
authors.initials: N
authors.lastname: van Rooijen
authors.forename: K
authors.initials: K
authors.lastname: Holmbeck
authors.forename: F L
authors.initials: FL
authors.lastname: Heppner
authors.forename: J
authors.initials: J
authors.lastname: Kiwit
authors.forename: V
authors.initials: V
authors.lastname: Matyash
authors.forename: S
authors.initials: S
authors.lastname: Lehnardt
authors.forename: B
authors.initials: B
authors.lastname: Kaminska
authors.forename: R
authors.initials: R
authors.lastname: Glass
authors.forename: H
authors.initials: H
authors.lastname: Kettenmann
mesh_terms: D000818:Animals; D015153:Blotting, Western; D001932:Brain Neoplasms / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D045744:Cell Line, Tumor; D004792:Enzyme Precursors / Q000378:metabolism; D005260:Female; D018093:Gelatinases / Q000378:metabolism; D015972:Gene Expression Regulation, Neoplastic; D005910:Glioma / Q000235:genetics / Q000378:metabolism / Q000473:pathology*; D049452:Green Fluorescent Proteins / Q000235:genetics / Q000378:metabolism; D006801:Humans; D007150:Immunohistochemistry; D008297:Male; D053511:Matrix Metalloproteinase 14 / Q000235:genetics / Q000378:metabolism*; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D017628:Microglia / Q000378:metabolism / Q000473:pathology*; D053594:Myeloid Differentiation Factor 88 / Q000235:genetics / Q000378:metabolism; D020133:Reverse Transcriptase Polymerase Chain Reaction; D015398:Signal Transduction; D051193:Toll-Like Receptors / Q000378:metabolism; D047368:Tumor Burden; D048051:p38 Mitogen-Activated Protein Kinases / Q000378:metabolism
chemical_list: D004792:Enzyme Precursors; C507780:Myd88 protein, mouse; D053594:Myeloid Differentiation Factor 88; D051193:Toll-Like Receptors; D049452:Green Fluorescent Proteins; D048051:p38 Mitogen-Activated Protein Kinases; D018093:Gelatinases; C069860:progelatinase; D053511:Matrix Metalloproteinase 14