Gliomas induce and exploit microglial MT1-MMP expression for tumor expansion
Research output: Contribution to journal › Journal article › Research › peer-review
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.
Original language | English |
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Journal | Proceedings of the National Academy of Sciences of the United States of America |
Volume | 106 |
Issue number | 30 |
Pages (from-to) | 12530-5 |
Number of pages | 6 |
ISSN | 0027-8424 |
DOIs | |
Publication status | Published - 28 Jul 2009 |
- Animals, Blotting, Western, Brain Neoplasms/genetics, Cell Line, Tumor, Enzyme Precursors/metabolism, Female, Gelatinases/metabolism, Gene Expression Regulation, Neoplastic, Glioma/genetics, Green Fluorescent Proteins/genetics, Humans, Immunohistochemistry, Male, Matrix Metalloproteinase 14/genetics, Mice, Mice, Inbred C57BL, Mice, Knockout, Microglia/metabolism, Myeloid Differentiation Factor 88/genetics, Reverse Transcriptase Polymerase Chain Reaction, Signal Transduction, Toll-Like Receptors/metabolism, Tumor Burden, p38 Mitogen-Activated Protein Kinases/metabolism
Research areas
ID: 201165473