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Updated: Jun 21, 2026
Coculture Assays to Study Macrophage and Microglia Stimulation of Glioblastoma Invasion
Published on: October 20, 2016
Gliomas induce and exploit microglial MT1-MMP expression for tumor expansion
D S Markovic1, K Vinnakota, S Chirasani
1Cellular Neuroscience, Max Delbrück Center for Molecular Medicine, 13125 Berlin, Germany.
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.
Insights
Glioma cell invasion, a cause of poor outcomes, is driven by microglial MT1-MMP. Inhibiting microglial activation pathways significantly reduces glioma expansion in preclinical models.
Area of Science:
- Neuro-oncology
- Cellular Biology
- Immunology
Background:
- Malignant gliomas are aggressive brain tumors with poor patient outcomes.
- Glioma cell infiltration into normal brain tissue is a major cause of treatment failure.
- Metalloproteases facilitate glioma invasion by degrading the extracellular matrix.
Purpose of the Study:
- To investigate the role of membrane type 1 metalloprotease (MT1-MMP) in glioma cell invasion.
- To identify the cellular source and regulatory mechanisms of MT1-MMP in the glioma microenvironment.
- To evaluate the therapeutic potential of targeting MT1-MMP-mediated pathways in glioma.
Main Methods:
- Analysis of MT1-MMP expression in glioma-associated microglia and glioma cells.
- Investigating the signaling pathways (toll-like receptors, p38 MAPK) regulating MT1-MMP in microglia.
- Utilizing ex vivo models with MT1-MMP-deficient brain tissue and in vivo models with microglia depletion.
Main Results:
- MT1-MMP is upregulated in glioma-associated microglia, not glioma cells.
- Glioma-released factors activate microglial MT1-MMP via toll-like receptors and the p38 MAPK pathway.
- Microglial MT1-MMP activates pro-MMP-2, promoting glioma expansion.
- MyD88 deficiency or microglia depletion significantly attenuated glioma expansion in vivo.
Conclusions:
- Microglia-derived MT1-MMP plays a critical role in promoting glioma invasion and expansion.
- Targeting microglial activation pathways, such as those involving MyD88 and p38 MAPK, represents a promising therapeutic strategy for malignant gliomas.
