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

• Published in: Proceedings of the National Academy of Sciences - PNAS 2009-07, Vol.106 (30), p.12530-12535
• Main Authors: 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
• Format: Article
• Language: English
• Subjects: Animals; Biological Sciences; Blotting, Western; Brain; Brain cancer; Brain Neoplasms - genetics; Brain Neoplasms - metabolism; Brain Neoplasms - pathology; Cell death; Cell Line, Tumor; Cells; Endothelial cells; Enzyme Precursors - metabolism; Female; Gelatinases - metabolism; Gelatins; Gene Expression Regulation, Neoplastic; Glioma; Glioma - genetics; Glioma - metabolism; Glioma - pathology; Green Fluorescent Proteins - genetics; Green Fluorescent Proteins - metabolism; Humans; Immunohistochemistry; Male; Matrix Metalloproteinase 14 - genetics; Matrix Metalloproteinase 14 - metabolism; Membranes; Mice; Mice, Inbred C57BL; Mice, Knockout; Microglia; Microglia - metabolism; Microglia - pathology; Myeloid Differentiation Factor 88 - genetics; Myeloid Differentiation Factor 88 - metabolism; p38 Mitogen-Activated Protein Kinases - metabolism; Parenchyma; Reverse Transcriptase Polymerase Chain Reaction; Signal Transduction; Toll like receptors; Toll-Like Receptors - metabolism; Tumor Burden; Tumors
• ISSN: 0027-8424; 1091-6490
• DOI: 10.1073/pnas.0804273106

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.