Gliomas induce and exploit microglial MT1-MMP expression for tumor expansion
Copyright policy )Gliomas induce and exploit microglial MT1-MMP expression for tumor expansion
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.
- Amsterdam UMC Netherlands
- Polish Academy of Learning Poland
- Amsterdam University Medical Centers Netherlands
- Helmholtz Association of German Research Centres Germany
- University of Copenhagen Denmark
Male, p38 Mitogen-Activated Protein Kinases/metabolism, Knockout, Blotting, Western, Green Fluorescent Proteins, Inbred C57BL, Green Fluorescent Proteins/genetics, Cell Line, Microglia/metabolism, Mice, Cell Line, Tumor, Matrix Metalloproteinase 14, Animals, Humans, Gelatinases/metabolism, Enzyme Precursors/metabolism, Myeloid Differentiation Factor 88/genetics, Brain Neoplasms/genetics, Mice, Knockout, Neoplastic, Enzyme Precursors, Tumor, Blotting, Brain Neoplasms, Reverse Transcriptase Polymerase Chain Reaction, Glioma, Glioma/genetics, Immunohistochemistry, Tumor Burden, Gene Expression Regulation, Neoplastic, Mice, Inbred C57BL, Gene Expression Regulation, Gelatinases, Myeloid Differentiation Factor 88, Matrix Metalloproteinase 14/genetics, Toll-Like Receptors/metabolism, Female, Microglia, Western, Signal Transduction
Male, p38 Mitogen-Activated Protein Kinases/metabolism, Knockout, Blotting, Western, Green Fluorescent Proteins, Inbred C57BL, Green Fluorescent Proteins/genetics, Cell Line, Microglia/metabolism, Mice, Cell Line, Tumor, Matrix Metalloproteinase 14, Animals, Humans, Gelatinases/metabolism, Enzyme Precursors/metabolism, Myeloid Differentiation Factor 88/genetics, Brain Neoplasms/genetics, Mice, Knockout, Neoplastic, Enzyme Precursors, Tumor, Blotting, Brain Neoplasms, Reverse Transcriptase Polymerase Chain Reaction, Glioma, Glioma/genetics, Immunohistochemistry, Tumor Burden, Gene Expression Regulation, Neoplastic, Mice, Inbred C57BL, Gene Expression Regulation, Gelatinases, Myeloid Differentiation Factor 88, Matrix Metalloproteinase 14/genetics, Toll-Like Receptors/metabolism, Female, Microglia, Western, Signal Transduction
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