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Malignant gliomas actively recruit bone marrow stromal cells by secreting angiogenic cytokines

Department of Neurology, Ludwig-Maximilians-University, Klinikum Grosshadern, Marchioninistr. 15, 81377 Munich, Germany.
Journal of Neuro-Oncology (Impact Factor: 2.79). 08/2007; 83(3):241-7. DOI: 10.1007/s11060-007-9332-4
Source: PubMed

ABSTRACT The transplantation of progenitor cells is a promising new approach for the treatment of gliomas. Marrow stromal cells (MSC) are possible candidates for such a cell-based therapy, since they are readily and autologously available and show an extensive tropism to gliomas in vitro and in vivo. However, the signals that guide the MSC are still poorly understood. In this study, we show that gliomas have the capacity to actively attract MSC by secreting a multitude of angiogenic cytokines. We demonstrate that interleukin-8 (IL-8), transforming growth factor-ss1 (TGF-ss1) and neurotrophin-3 (NT-3) contribute to this glioma-directed tropism of human MSC. Together with the finding that vascular endothelial growth factor (VEGF) is another MSC-attracting factor secreted by glioma cells, these data support the hypothesis that gliomas use their angiogenic pathways to recruit mesenchymal progenitor cells.

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Available from: Christian Schichor, Aug 05, 2015
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    • "Recruitment of MSC by experimental implanted vascularizing tumors and their incorporation within the tumor architecture [12] [13] implies that these cells must ultimately respond to inflammation-and tumor-derived growth factor cues [14] [15]. Given their intrinsic immunosuppressive property [16] [17], it is further hypothesized that MSC could contribute to tumor formation and growth in vivo through some paracrine-mediated processes involving , in part, promotion of neovascularization [18]. "
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    ABSTRACT: Human bone marrow-derived mesenchymal stromal cells (MSCs) express Toll-like receptors (TLRs) and produce cytokines and chemokines, all of which contribute to these cells' immunomodulatory and proangiogenic properties. Among the secreted cytokines, colony-stimulating factors (CSFs) regulate angiogenesis through activation of endothelial cell proliferation and migration. Since MSC are recruited within hypoxic tumors where they signal paracrine-regulated angiogenesis, the aim of this study was to evaluate which CSF members are expressed and are inducible in activated MSC. Furthermore, we investigated the JAK/STAT signal transducing pathway that may impact on CSF transcription. MSC were activated with Concanavalin-A (ConA), a TLR-2/6 agonist as well as a membrane type-1 matrix metalloproteinase (MT1-MMP) inducer, and we found increased transcription of granulocyte macrophage-CSF (GM-CSF, CSF-2), granulocyte CSF (G-CSF, CSF-3), and MT1-MMP. Gene silencing of either STAT3 or MT1-MMP prevented ConA-induced phosphorylation of STAT3, and reversed ConA effects on CSF-2 and CSF-3. Treatment with the Janus Kinase (JAK)2 inhibitor AG490 antagonized the ConA induction of MT1-MMP and CSF-2, while the pan-JAK inhibitor Tofacitinib reversed ConA-induced CSF-2 and -3 gene expression. Silencing of JAK2 prevented the ConA-mediated increase of CSF-2, while silencing of JAK1, JAK3 and TYK2 prevented the increase in CSF-3. Given that combined TLR-activation and locally-produced CSF-2 and CSF-3 could regulate immunomodulation and neovascularization, pharmacological targeting of TLR-2/6-induced MT1-MMP/JAK/STAT3 signalling pathway may prevent MSC contribution to tumor development.
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    • "The high concentration of inflammatory chemokines released after tissue damage can indeed control the migration of MSCs, which express receptors for a number of grow factors including PDGF and IGF-1, and chemokines receptors, as CCR2, CCR3, CCR4, and CCL5 (Ponte et al., 2007). On the other hand, strong connections exist between tissue injury, chronic inflammation and cancer, as first described by Mina Bissell's group (Dolberg et al., 1985), so that tumors have been defined " wounds that do not heal " (Dvorak, 1986), where inflammatory cytokines and chemokines are produced and can drive MSC homing (Birnbaum et al., 2007; Dwyer et al., 2007; Menon et al., 2007). "
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    Frontiers in Physiology 09/2012; 3:359. DOI:10.3389/fphys.2012.00359 · 3.50 Impact Factor
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    • "Annabi). tumor-derived growth factor cues [6] [7]. While chronic inflammation has been found to mediate a wide variety of diseases including neoplasms [8], our understanding of the oncogenic adaptation of MSC within an inflammatory microenvironment lacks the identification of molecular contributors and characterization of inflammation-mediated signaling pathways. "
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