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

Item Type:	Article
Title:	Gliomas induce and exploit microglial MT1-MMP expression for tumor expansion
Creators Name:	Markovic, D.S. and Vinnakota, K. and Chirasani, S. and Synowitz, M. and Raguet, H. and Stock, K. and Sliwa, M. and Lehmann, S. and Kaelin, R. and van Rooijen, N. and Holmbeck, K. and Heppner, F.L. and Kiwit, J. and Matyash, V. and Lehnardt, S. and Kaminska, B. and Glass, R. and Kettenmann, H.
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.
Keywords:	Brain Tumor, Invasion, Metalloprotease, Toll-Like Receptor, Animals, Mice
Source:	Proceedings of the National Academy of Sciences of the United States of America
ISSN:	0027-8424
Publisher:	National Academy of Sciences
Volume:	106
Number:	30
Page Range:	12530-12535
Date:	28 July 2009
Additional Information:	Copyright (c) 2009 by The National Academy of Sciences
Official Publication:	https://doi.org/10.1073/pnas.0804273106
PubMed:	View item in PubMed

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