Gliomas induce and exploit microglial MT1-MMP expression for tumor expansion

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

SN - 0027-8424

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

IS - 30

ER -