Artikel
Low grade glioma invasion is dependent on microglia
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Autoren
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D. Markovic
- Neurochirurgie, Helios-Klinikum Berlin-Buch
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C. Sridhar
- Max Delbrück Zentrum Berlin
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S. Michael
- Neurochirurgie, Charité – Universitätsmedizin Berlin
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K. Jürgen
- Neurochirurgie, Helios-Klinikum Berlin-Buch
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G. Rainer
- Max Delbrück Zentrum Berlin
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K. Helmut
- Max Delbrück Zentrum Berlin
| Veröffentlicht: | 20. Mai 2009 |
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Gliederung
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Objective: We have shown previously that the microglia surrounding glioma is promoting glioma invasiveness by activation of MMP-2 (Markovic et al. 2005). Now we investigate whether microglial expression of membrane type 1 metalloprotease (MT1-MMP) is regulated by gliomas.
Methods: We used immunohistochemistry, the in vivo mouse GL261 glioma model, organotypical brain slice cultures, PCR, Western Blot, shRNA microglia transfection and MT1-MMP activity assays in cell culture experiments to demonstrate overexpression of MT1-MMP in microglia after glioma stimulation.
Results: MT1-MMP is upregulated 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 in cultured microglial cells, mainly via a p38 MAP kinase pathway. 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. The antibiotic minocycline, a blood brain barrier penetrating blocker of microglial activation and p38 MAPK signaling pathway, interferes with MT1-MMP expression and activity in glioma associated microglia and attenuates glioma expansion in an in vivo model (GL261).
Conclusions: Glioma released factor is stimulating overexpression of MT1-MMP via p38 MAPK, which in turn leads to overproduction of active MMP-2. Minocycline treatment could have beneficial effects on glioma invasiveness.
