Microglia Stimulate the Invasiveness of Glioma Cells by Increasing the Activity of Metalloprotease-2

Marković, Darko; Glaß, Rainer; Synowitz, Michael; Rooijen, Nico van; Kettenmann, Helmut

doi:10.1097/01.jnen.0000178445.33972.a9

Cited by 273 publications

(285 citation statements)

References 29 publications

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“…To verify that the effect of MT1-MMP deletion on glioma growth is mediated by microglial cells, we depleted microglia from the organotypic slice as described earlier (8). We could confirm the previous observation that depletion of microglial cells leads to a reduction of glioma expansion (8) (Fig.…”

Section: Blocking the Mt1-mmp Expression By Shrna In Microglia Resultssupporting

confidence: 70%

“…By applying clodronate-filled liposomes to cultured brain slices, microglial cells were completely abrogated whereas the other cell types were not affected (8). After injection of GFP-expressing GL261 cells into these slices, the glioma cells invaded into the parenchyma.…”

Section: Mt1-mmp Expression Is Associated With the Presence Of Microgmentioning

confidence: 90%

“…*Significant at P Ͻ 0.05. **Significant at P Ͻ 0.01. glioma expansion, we used the organotypic brain slice culture model described earlier (8,17). We compared glioma invasion in brain slice cultures from MT1-MMP ϩ/ϩ MT1-MMP ϩ/Ϫ MT1-MMP Ϫ/Ϫ mice.…”

Section: Blocking the Mt1-mmp Expression By Shrna In Microglia Resultsmentioning

confidence: 99%

“…We compared glioma invasion in brain slice cultures from MT1-MMP ϩ/ϩ MT1-MMP ϩ/Ϫ MT1-MMP Ϫ/Ϫ mice. EGFP-transfected glioma cells were injected and glioma size was quantified as established previously (8,10) by measuring the projected fluorescent area covered by the EGFP-transfected glioma cells within the slice 5 d after injection. These surface measurements give a good correlate for the invasiveness of a tumor (ref.…”

Section: Blocking the Mt1-mmp Expression By Shrna In Microglia Resultsmentioning

confidence: 99%

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Gliomas induce and exploit microglial MT1-MMP expression for tumor expansion

Marković

Vinnakota

Chirasani

et al. 2009

Proc. Natl. Acad. Sci. U.S.A.

341

328

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for highly malignant gliomas (World Health Organization grade III and IV) there is no successful treatment; patients have an average survival time of approximately 1 y after diagnosis. Glioma cells are highly invasive and infiltrate normal brain tissue, and as a result, surgical resection is always incomplete. Degradation of ECM by membrane-bound and secreted metalloproteases facilitates glioma invasion. In particular, the membrane-bound metalloproteases are pivotal for tumor invasion as they very efficiently digest extracellular matrix proteins and also activate secreted metalloproteases (1) like matrix metalloproteinase-2 (MMP-2, also known as gelatinase A), which is one of the major proteases involved in glioma invasion in mouse models (2) and probably also in humans (3). Hence, membrane-inserted metalloproteases like membrane type 1 matrix metalloproteinase (MT1-MMP) can enable gliomas to invade the brain parenchyma as single cells (4).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 (5). Activation of microglial toll-like receptors (TLRs) triggers the innate immune response and can initiate host-defense and tissue repair mechanisms, but also CNS inflammation, neurodegeneration, and trauma (5, 6). As microglial cells are attracted toward glioma in large numbers-glioma tissue consists of as much as 30% microglial cells-and because microglia density in gliomas positively correlates with malignancy, invasiveness, and grading of the tumors (7-9), we investigated if microglia may actively contribute to glioma expansion. Here, we show that soluble factors released from glioma stimulate microglial TLRs, resulting in microglial MT1-MMP expression via the TLR downstream signaling molecules MyD88 and p38 MAPK. In turn, MT1-MMP expression and activity in these immune cells promotes glioma cell invasion and tumor expansion. ResultsGlioma Associated Microglia Over-Express MT1-MMP. We analyzed the expression pattern of the matrix protease MT1-MMP in mouse and human gliomas and found the enzyme to be expressed predominantly in microglial cells closely associated with the tumors. Whereas tumor-free human brain samples showed virtually no MT1-MMP expression, we detected intense MT1-MMP labeling, especially in higher-grade gliomas. Importantly, in human samples, immunolabeling for the microglial marker Iba1 and for MT1-MMP largely overlapped [supporting information (SI) Fig. S1 A-D and Table S1]. Likewise, after injection of a human glioma cell line (U373 cells) into immunodeficient mice, we detected that microglia represent the predominant cell type contributing intratumoral MT1-MMP expression (see Fig. S1E).In our in vivo mouse model, the glioma cells were identified by stable expression of EGFP and microglial cells by immunolabeling for Iba1. In sections obtained from mice 2 weeks after intracerebral injection with isogenic glioma cells (GL261 cells), we found an increased density of mic...

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Section: Blocking the Mt1-mmp Expression By Shrna In Microglia Resultssupporting

confidence: 70%

Section: Mt1-mmp Expression Is Associated With the Presence Of Microgmentioning

confidence: 90%

Section: Blocking the Mt1-mmp Expression By Shrna In Microglia Resultsmentioning

confidence: 99%

Section: Blocking the Mt1-mmp Expression By Shrna In Microglia Resultsmentioning

confidence: 99%

See 2 more Smart Citations

Gliomas induce and exploit microglial MT1-MMP expression for tumor expansion

Marković

Vinnakota

Chirasani

et al. 2009

Proc. Natl. Acad. Sci. U.S.A.

341

328

View full text Add to dashboard Cite

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“…MMP-14 can activate inactive matrix metalloprotease-2 secreted by glioma cells and lead to the break down of the extracellular matrix. Results from in vitro studies support the idea that microglia can promote tumor invasion and growth (Bettinger et al, 2002;Markovic et al, 2005). Perhaps the most convincing evidence of the importance of microglia to glioma formation is from in vivo studies that have shown that tumor cell growth is inhibited in microglia-deficient glioma mouse models (Daginakatte and Gutmann, 2007;Markovic et al, 2009).…”

Section: Microgliamentioning

confidence: 86%

Standard of care therapy for malignant glioma and its effect on tumor and stromal cells

Jones

Holland

2011

Oncogene

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Damage caused by Wegener's granulomatosis and its treatment: Prospective data from the Wegener's Granulomatosis Etanercept Trial (WGET)

Seo

Min

Holbrook

et al. 2005

Arthritis & Rheumatism

174

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Objective. To analyze damage occurring in patients with Wegener's granulomatosis (WG) enrolled in the WG Etanercept Trial (WGET) and to correlate that damage with disease activity, adverse events, and quality of life.Methods. The Vasculitis Damage Index (VDI) was applied to all 180 patients at trial entry and every 6 months throughout the trial. Items of damage were analyzed by presumed etiology (i.e., secondary to WG, to therapy, or both) and time of occurrence. Spearman's rank correlation coefficients were calculated between VDI scores and the Birmingham Vasculitis Activity Score for WG (BVAS/WG), frequency of flares, number of adverse events, and the patients' quality-of-life assessments.Results. The mean VDI score was 1.3 at the study enrollment and 1.8 at the end of the trial. This increase was due to damage that occurred despite (or because of) therapy, including visual impairment, hearing loss, nasal blockade, pulmonary fibrosis, hypertension, renal insufficiency, peripheral neuropathy, gonadal failure, and diabetes mellitus. Only 11% of the enrolled patients had not sustained a single VDI item after 1 year of enrollment. When adjusted for baseline VDI, the baseline BVAS/WG correlated moderately well with the VDI score at 1 year (r ‫؍‬ 0.20, P ‫؍‬ 0.015). Increases in adjusted VDI scores also correlated with the number of adverse events, particularly among patients with limited WG (P ‫؍‬ 0.06).Conclusion. Damage from both active disease and its treatment remain important problems for patients with WG. Despite the dramatic improvements in patient survival achieved over the last several decades, only a few patients with WG emerge from a period of active disease without sustaining some damage from the disease itself, its treatment, or both.

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Microglia Stimulate the Invasiveness of Glioma Cells by Increasing the Activity of Metalloprotease-2

Cited by 273 publications

References 29 publications

Gliomas induce and exploit microglial MT1-MMP expression for tumor expansion

Gliomas induce and exploit microglial MT1-MMP expression for tumor expansion

Standard of care therapy for malignant glioma and its effect on tumor and stromal cells

Damage caused by Wegener's granulomatosis and its treatment: Prospective data from the Wegener's Granulomatosis Etanercept Trial (WGET)

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