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Microglia cells - glioma interaction

Scientific focus
Gliomas are the most frequent primary tumours of the central nervous system (CNS). The majority of glioma patients suffers from glioblastoma multiforme, which is the most aggressive form of a glioma, consituting an average survival of only 14 months after diagnosis. A major clinical problem is the diffuse infiltration of the tumour cells into the adjacent brain which makes complete surgical removal impossible. Invasion of glioma cells into the brain parenchyma is facilitated by metalloprotease-mediated degradation of the extracellular matrix. Matrix Metallo-Proteinases (MMP) are released as inactive pro-forms and get activated upon cleavage e.g. by membrane-bound metalloproteases. We have recently shown, that membrane type 1 metalloprotease (MT1-MMP) is upregulated in glioma-associated microglia (the intrinsic immune cells of the brain), but not in the glioma cells proper. Our data indicate that glioma depend on tumour-associated microglia to facilitate tumour-cell invasion (1-5).

Current state of the field
Microglia are the intrinsic immune cells of the brain, they control the innate and the adaptive immune response in the CNS and are activated by inflammatory or other pathological stimuli (6). Activation of microglial toll-like receptors (TLR) triggers the innate immune response and can initiate host-defence and tissue repair mechanisms, but also CNS inflammation, neurodegeneration and trauma (6), (7). Since microglial cells are attracted towards glioma in large numbers - glioma tissue consists up to 30% of microglial cells - and since microglia density in gliomas positively correlates with malignancy, invasiveness and grading of the tumours (8-10), we are investigating if microglia may actively contribute to glioma expansion. We have previously demonstrated that soluble factors released from glioma stimulate microglial TLRs, resulting in microglial MT1-MMP expression via the TLR downstream signalling molecules MyD88 and p38 MAPK. In turn, MT1-MMP expression and activity in these immune cells promotes glioma cell invasion and tumour expansion.

Own contributions
Invasion of glioma cells into the brain parenchyma is induced by metalloprotease-mediated degradation of the extracellular matrix. Matrix metalloproteases (MMP) are released as inactive pro-forms and get activated upon cleavage e.g. by membrane-bound metalloproteases. Recently, we could show that glioma depend on membrane type 1 metalloprotease (MT1-MMP) expression in glioma-associated microglia to facilitate tumor invasion. Our studies suggested that a soluble factor from glioma stimulates microglial TLRs (toll like receptor), triggers MyD88 and p38MAPK signalling and thereby induces microglial MT1-MMP expression. Increased parenchymal MT1-MMP in turn promoted accelerated glioma expansion, presumably also by activation of glioma-derived MMP2. Interfering with microglial TLR-signalling or experimental depletion of microglia in our in vivo glioma models resulted in more than an 70% reduction in glioma volume. Overall, our data indicate that microglia significantly contribute to glioma progression in mouseand rat-glioma models. Furthermore, our data from primary patient material show that our observation is of relevance for human brain tumors (11-15).

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Figure 1

(A) GFP-expressing glioma cells 5days after injection into a cultivated brain slices shows that MT1-MMP (blue) is expressed on microglia and endothelia (labelled by Isolectin-B4;ILB4; red). (B) A microglia depleted brain slice preparation shows MT1-MMP only on endothelial cells (insert in B). The size bars are 35µm

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Figure 2
Glioma exploits microglial MT1-MMP expression

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.

1. Markovic DV, K; Chirasani, S; Synowitz, M; Raguet, H; Stock, K; Sliwa, M ; Lehmann, S ; Kälin, R; van Rooijen, N; Holmbeck, K; Heppner, FL; Kiwit, J; Matyash, V; Lehnardt, S; Kaminska, B; Glass, R * and Kettenmann, H*. (2009) Glioma induce and exploit microglial MT1-MMP expression for tumour expansion. . Proc Natl Acad Sci U S A (2009) vol. 106 (30) pp. 12530-5.
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