Gliomas induce and exploit microglial MT1-MMP expression for tumor expansion
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Gliomas induce and exploit microglial MT1-MMP expression for tumor expansion. / Markovic, D S; Vinnakota, K; Chirasani, S; Synowitz, M; Raguet, H; Stock, K; Sliwa, M; Lehmann, S; Kälin, R; van Rooijen, N; Holmbeck, K; Heppner, F L; Kiwit, J; Matyash, V; Lehnardt, S; Kaminska, B; Glass, R; Kettenmann, H.
In: Proceedings of the National Academy of Sciences of the United States of America, Vol. 106, No. 30, 28.07.2009, p. 12530-5.Research output: Contribution to journal › Journal article › Research › peer-review
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TY - JOUR
T1 - Gliomas induce and exploit microglial MT1-MMP expression for tumor expansion
AU - Markovic, D S
AU - Vinnakota, K
AU - Chirasani, S
AU - Synowitz, M
AU - Raguet, H
AU - Stock, K
AU - Sliwa, M
AU - Lehmann, S
AU - Kälin, R
AU - van Rooijen, N
AU - Holmbeck, K
AU - Heppner, F L
AU - Kiwit, J
AU - Matyash, V
AU - Lehnardt, S
AU - Kaminska, B
AU - Glass, R
AU - Kettenmann, H
PY - 2009/7/28
Y1 - 2009/7/28
N2 - 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.
AB - 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.
KW - Animals
KW - Blotting, Western
KW - Brain Neoplasms/genetics
KW - Cell Line, Tumor
KW - Enzyme Precursors/metabolism
KW - Female
KW - Gelatinases/metabolism
KW - Gene Expression Regulation, Neoplastic
KW - Glioma/genetics
KW - Green Fluorescent Proteins/genetics
KW - Humans
KW - Immunohistochemistry
KW - Male
KW - Matrix Metalloproteinase 14/genetics
KW - Mice
KW - Mice, Inbred C57BL
KW - Mice, Knockout
KW - Microglia/metabolism
KW - Myeloid Differentiation Factor 88/genetics
KW - Reverse Transcriptase Polymerase Chain Reaction
KW - Signal Transduction
KW - Toll-Like Receptors/metabolism
KW - Tumor Burden
KW - p38 Mitogen-Activated Protein Kinases/metabolism
U2 - 10.1073/pnas.0804273106
DO - 10.1073/pnas.0804273106
M3 - Journal article
C2 - 19617536
VL - 106
SP - 12530
EP - 12535
JO - Proceedings of the National Academy of Sciences of the United States of America
JF - Proceedings of the National Academy of Sciences of the United States of America
SN - 0027-8424
IS - 30
ER -
ID: 201165473