Darko Markovic
The role of microglia in glioma malignancy
darko.markovic@helios-kliniken.de
Glioblastoma multiforme (GBM), the most aggressive and malignant glioma, accounts for more than 50% of all gliomas. With an average survival between 12 to 15 months after standard treatments (surgery, irradiation and chemotherapy) it is the cancer with poorest prognosis among all cancers [1]. Despite therapy, GBM´s are characterized by fast recurrence [2] mostly because of high invasiveness of single glioma cells into the healthy brain parenchyma. Glioma associated microglia and brain macrophages, but not other immune cells (e.g. lymphocytes), are the major cell population infiltrating glioma and can contribute up to 30% of the tumor mass [6, 7]. Importantly, glioma associated microglia and macrophages are promoting invasiveness and growth of gliomas by overexpression of matrix metalloproteinases [4, 5]. MMPs degrade the extracellular matrix [3-5].
Our group is focused on exploring the interaction between glioma and glioma associated microglia and developing potential pharmacological glioma therapy by manipulating glioma induced microglia proinvasive behaviour. We are particularly interested to reveal how glioma cells are exploiting microglia for GBM malignant behaviour, e.g. invasion and migration into healthy brain or avoidance of glioma cell death. In our previous studies we found that inactive proMMP-2 released from glioma cells can be activated by membrane-bound MT1-MMP expressed by microglia. Microglial MT1-MMP and MMP-9 expression is induced by factor(s) released from glioma cells that act via toll-like receptor (TLR)2 signalling and the p38 MAPK pathway [5, 9]. We were able to show that the FDA approved antibiotic minocycline interfered with the p38 pathway by reducing microglial MT1-MMP and MMP-9 expression. As a result, minocycline treatment of mice inoculated with glioma cells led to reduced tumor growth [10].
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3. Kessenbrock, K., V. Plaks, and Z. Werb, Matrix metalloproteinases: regulators of the tumor microenvironment. Cell, 2010. 141(1): p. 52-67.
4. Markovic, D.S., et al., Microglia stimulate the invasiveness of glioma cells by increasing the activity of metalloprotease-2. J Neuropathol Exp Neurol, 2005. 64(9): p. 754-62.
5. Markovic, D.S., et al., Gliomas induce and exploit microglial MT1-MMP expression for tumor expansion. Proc Natl Acad Sci U S A, 2009. 106(30): p. 12530-5.
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9. Vinnakota, K., et al., Toll-like receptor 2 mediates microglia/brain macrophage MT1-MMP expression and glioma expansion. Neuro Oncol, 2013.
10. Markovic, D.S., et al., Minocycline reduces glioma expansion and invasion by attenuating microglial MT1-MMP expression. Brain Behav Immun, 2011. 25(4): p. 624-8.