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61st Annual Meeting of the German Society of Neurosurgery (DGNC) as part of the Neurowoche 2010
Joint Meeting with the Brazilian Society of Neurosurgery on the 20 September 2010

German Society of Neurosurgery (DGNC)

21 - 25 September 2010, Mannheim

Glioma-induced Toll like receptors (TLR) signaling in microglia promotes parenchymal MT1-MMP expression and tumor expansion in vivo

Meeting Abstract

  • Darko Markovic - Helios Kliniken, Dept. of Neurosurgery, Berlin-Buch, Germany; Max Delbrück Center for Molecular Medicine Cellular Neuroscience, Berlin, Germany
  • Michael Synowitz - Max Delbrück Center for Molecular Medicine Cellular Neuroscience, Berlin, Germany; Charité, University Clinics, Dept. of Neurosurgery, Berlin, Germany
  • Rainer Glass - Max Delbrück Center for Molecular Medicine Cellular Neuroscience, Berlin, Germany
  • Helmut Kettenmann - Max Delbrück Center for Molecular Medicine Cellular Neuroscience, Berlin, Germany
  • Jürgen Kiwit - Helios Kliniken, Dept. of Neurosurgery, Berlin-Buch, Germany

Deutsche Gesellschaft für Neurochirurgie. 61. Jahrestagung der Deutschen Gesellschaft für Neurochirurgie (DGNC) im Rahmen der Neurowoche 2010. Mannheim, 21.-25.09.2010. Düsseldorf: German Medical Science GMS Publishing House; 2010. DocV1546

DOI: 10.3205/10dgnc023, URN: urn:nbn:de:0183-10dgnc0238

Published: September 16, 2010

© 2010 Markovic et al.
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Outline

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Objective: We have shown previously that membrane type 1 metalloprotease (MT1-MMP) is upregulated in glioma associated microglia, but not in the glioma cells and that a glioma released factor is stimulating via p38 MAPK overexpression of MT1-MMP in microglia. Now, we investigate with a novel glioma experimental model the possible mediators in microglial expression of MT1-MMP.

Methods: We used immunohistochemistry, in vivo mouse glioma model, 2-photon time lapse microscopy in organotypical brain slice cultures, PCR, and Western Blot in cell culture experiments to demonstrate reduced tumor expansion after interfering with TLR signaling in microglia.

Results: Glioma-released factors trigger the expression and activity of MT1-MMP via microglial TLR and the p38 MAPK pathway since deletion of the TLR 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-matrix metalloproteinase-2 (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, both MyD88-deficiency or microglia depletion largely attenuated glioma expansion in two independent in vivo models.

Conclusions: A glioma released factor is stimulating via TLR's the p38 MAPK overexpression of MT1-MMP, which in turn overproduces active MMP-2.