Minocycline reduces glioma expansion and invasion by attenuating microglial MT1-MMP expression

Max Delbrück Center for Molecular Medicine, Cellular Neuroscience, Robert Rössle Str. 10, 13125 Berlin, Germany.
Brain Behavior and Immunity (Impact Factor: 5.89). 02/2011; 25(4):624-8. DOI: 10.1016/j.bbi.2011.01.015
Source: PubMed


Glioma cells release soluble factors, which induce the expression of membrane type 1 matrix metalloprotease (MT1-MMP) in tumor associated microglia and then exploit MT1-MMP mediated matrix degradation for invasion. Here, we show that minocycline blocked the increase in MT1-MMP expression and activity in cultivated microglia stimulated with glioma conditioned medium. Glioma growth within an organotypic brain slice preparation was reduced by minocycline and this reduction depended on the presence of microglia. Glioma growth in an experimental mouse model was strongly reduced by the addition of minocycline to drinking water, compared to untreated controls. Coherently, we observed in our orthotopic glioma implantation model, that MT1-MMP was abundantly expressed in glioma associated microglia in controls, but was strongly attenuated in tumors of minocycline treated animals. Overall, our study indicates that the clinically approved antibiotic minocycline is a promising new candidate for adjuvant therapy against malignant gliomas.

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Available from: Katyayni Vinnakota, Dec 13, 2013
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    • "In contrast, we now show that the percentage of F11R+ macrophages are increased in high-grade relative to low-grade glioma and that F11R tumor expression is an independent predictor of patient outcome, regardless of GBM molecular subtype. Taken together with reports revealing that microglia are essential drivers of murine glioma formation and maintenance [1,2,5,8,9], along with studies in other cancer types highlighting the predictive value of stromal gene expression patterns in predicting patient outcome [40,41], the identification of F11R as a marker of a subset of brain macrophages may facilitate the detection of critical microenvironmental factors suitable for future stroma-directed glioma therapy. Similarly, potential derivative microglia/macrophage gene signatures may enable clinically-useful deconvolution of existing complex TCGA datasets for prognostic analysis. "
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    ABSTRACT: Brain tumors (gliomas) contain large populations of infiltrating macrophages and recruited microglia, which in experimental murine glioma models promote tumor formation and progression. Among the barriers to understanding the contributions of these stromal elements to high-grade glioma (glioblastoma; GBM) biology is the relative paucity of tools to characterize infiltrating macrophages and resident microglia. In this study, we leveraged multiple RNA analysis platforms to identify new monocyte markers relevant to GBM patient outcome. High-confidence lists of mouse resident microglia- and bone marrow-derived macrophage-specific transcripts were generated using converging RNA-seq and microarray technologies and validated using qRT-PCR and flow cytometry. Expression of select cell surface markers was analyzed in brain-infiltrating macrophages and resident microglia in an induced GBM mouse model, while allogeneic bone marrow transplantation was performed to trace the origins of infiltrating and resident macrophages. Glioma tissue microarrays were examined by immunohistochemistry, and the Gene Expression Omnibus (GEO) database was queried to determine the prognostic value of identified microglia biomarkers in human GBM. We generated a unique catalog of differentially-expressed bone marrow-derived monocyte and resident microglia transcripts, and demonstrated that brain-infiltrating macrophages acquire F11R expression in GBM and following bone-marrow transplantation. Moreover, mononuclear cell F11R expression positively correlates with human high-grade glioma and additionally serves as a biomarker for GBM patient survival, regardless of GBM molecular subtype. These studies establish F11R as a novel monocyte prognostic marker for GBM critical for defining a subpopulation of stromal cells for future potential therapeutic intervention.
    PLoS ONE 10/2013; 8(10):e77571. DOI:10.1371/journal.pone.0077571 · 3.23 Impact Factor
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    • "The antibiotic minocycline hydrochloride is a small, highly lipophilic molecule that is readily absorbed after oral administration and capable of crossing the BBB. Markovic et al. have shown that minocycline attenuates the protumorigenic effect of GAMs by inhibiting p38 MAP kinase that is responsible for MT1-MMP upregulation in microglia [45]. Besides, the inhibition of p38 MAPK was also shown to reduce the secretion of pro-inflammatory cytokines from microglia and tumor cells, resulting in a decrease of glioma migration [46]. "
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    ABSTRACT: Malignant gliomas are the most common primary brain tumors. Their deadliest manifestation, glioblastoma multiforme (GBM), accounts for 15% of all primary brain tumors and is associated with a median survival of only 15 months even after multimodal therapy. There is substantial presence of microglia and macrophages within and surrounding brain tumors. These immune cells acquire an alternatively activated phenotype with potent tumor-tropic functions that contribute to glioma growth and invasion. In this review, we briefly summarize recent data that has been reported on the interaction of microglia/macrophages with brain tumors and discuss potential application of these findings to the development of future antiglioma therapies.
    Clinical and Developmental Immunology 06/2013; 2013(4):264124. DOI:10.1155/2013/264124 · 2.93 Impact Factor
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    • "Induction of autophagic cell death may therefore help stop tumor development and optimize cancer treatment modalities (Ceteci et al. 2011; Guo et al. 2011; Chen et al. 2012). Interestingly, recent evidence indicates the clinically approved antibiotic minocycline, a highly lipid-soluble antibacterial known for its superior ability to cross the blood-brain barrier, to act as a promising new candidate for adjuvant therapy against malignant gliomas by reducing MT1-MMP expression (Markovic et al. 2011). More importantly, minocycline effectively inhibited tumor growth and induced autophagy in a xenograft tumor model of C6 glioma cells (Liu, Lin, Yu et al. 2011; Liu, Lin, Hsiao et al. 2011). "
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    ABSTRACT: Pre-clinical trials for cancer therapeutics support the anti-neoplastic properties of the lectin from Canavalia ensiformis (Concanavalin-A, ConA) in targeting apoptosis and autophagy in a variety of cancer cells. Given that membrane type-1 matrix metalloproteinase (MT1-MMP), a plasma membrane-anchored matrix metalloproteinase, is a glycoprotein strongly expressed in radioresistant and chemoresistant glioblastoma that mediates pro-apoptotic signalling in brain cancer cells, we investigated whether MT1-MMP could also signal autophagy. Among the four lectins tested, we found that the mannopyranoside/glucopyranoside-binding ConA, which is also well documented to trigger MT1-MMP expression, increases autophagic acidic vacuoles formation as demonstrated by Acridine Orange cell staining. Although siRNA-mediated MT1-MMP gene silencing effectively reversed ConA-induced autophagy, inhibition of the MT1-MMP extracellular catalytic function with Actinonin or Ilomastat did not. Conversely, direct overexpression of the recombinant Wt-MT1-MMP protein triggered proMMP-2 activation and green fluorescent protein-microtubule-associated protein light chain 3 puncta indicative of autophagosomes formation, while deletion of MT1-MMP's cytoplasmic domain disabled such autophagy induction. ConA-treated U87 cells also showed an upregulation of BNIP3 and of autophagy-related gene members autophagy-related protein 3, autophagy-related protein 12 and autophagy-related protein 16-like 1, where respective inductions were reversed when MT1-MMP gene expression was silenced. Altogether, we provide molecular evidence supporting the pro-autophagic mechanism of action of ConA in glioblastoma cells. We also highlight new signal transduction functions of MT1-MMP within apoptotic and autophagic pathways that often characterize cancer cell responses to chemotherapeutic drugs.
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