Gliomas induce and exploit microglial MT1-MMP expression for tumor expansion.
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.
Markovic
D S
DS
Cellular Neuroscience, Max Delbrück Center for Molecular Medicine, 13125 Berlin, Germany.
Vinnakota
K
K
Chirasani
S
S
Synowitz
M
M
Raguet
H
H
Stock
K
K
Sliwa
M
M
Lehmann
S
S
Kälin
R
R
van Rooijen
N
N
Holmbeck
K
K
Heppner
F L
FL
Kiwit
J
J
Matyash
V
V
Lehnardt
S
S
Kaminska
B
B
Glass
R
R
Kettenmann
H
H
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
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