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

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Item Type:	Article
Title:	Gliomas induce and exploit microglial MT1-MMP expression for tumor expansion
Creators Name:	Markovic, D.S., Vinnakota, K., Chirasani, S., Synowitz, M., Raguet, H., Stock, K., Sliwa, M., Lehmann, S., Kaelin, R., van Rooijen, N., Holmbeck, K., Heppner, F.L., Kiwit, J., Matyash, V., Lehnardt, S., Kaminska, B., 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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