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      Pericytes/vessel-associated mural cells (VAMCs) are the major source of key epithelial-mesenchymal transition (EMT) factors SLUG and TWIST in human glioma

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          Abstract

          Epithelial-to-mesenchymal transition (EMT) is supposed to be responsible for increased invasion and metastases in epithelial cancer cells. The activation of EMT genes has further been proposed to be important in the process of malignant transformation of primary CNS tumors. Since the cellular source and clinical impact of EMT factors in primary CNS tumors still remain unclear, we aimed at deciphering their distribution in vivo and clinico-pathological relevance in human gliomas.

          We investigated 350 glioma patients for the expression of the key EMT factors SLUG and TWIST by immunohistochemistry and immunofluorescence related to morpho-genetic alterations such as EGFR-amplification, IDH-1 (R132H) mutation and 1p/19q LOH. Furthermore, transcriptional cluster and survival analyses were performed.

          Our data illustrate that SLUG and TWIST are overexpressed in gliomas showing vascular proliferation such as pilocytic astrocytomas and glioblastomas. EMT factors are exclusively expressed by non-neoplastic pericytes/vessel-associated mural cells (VAMCs). They are not associated with patient survival but correlate with pericytic/VAMC genes in glioblastoma cluster analysis.

          In summary, the upregulation of EMT genes in pilocytic astrocytomas and glioblastomas reflects the level of activation of pericytes/VAMCs in newly formed blood vessels. Our results underscore that the negative prognostic potential of the EMT signature in the group of diffuse gliomas of WHO grade II-IV does most likely not derive from glioma cells but rather reflects the degree of proliferating mural cells thereby constituting a potential target for future alternative treatment approaches.

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          Most cited references31

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          Molecular subclasses of high-grade glioma predict prognosis, delineate a pattern of disease progression, and resemble stages in neurogenesis.

          Previously undescribed prognostic subclasses of high-grade astrocytoma are identified and discovered to resemble stages in neurogenesis. One tumor class displaying neuronal lineage markers shows longer survival, while two tumor classes enriched for neural stem cell markers display equally short survival. Poor prognosis subclasses exhibit markers either of proliferation or of angiogenesis and mesenchyme. Upon recurrence, tumors frequently shift toward the mesenchymal subclass. Chromosomal locations of genes distinguishing tumor subclass parallel DNA copy number differences between subclasses. Functional relevance of tumor subtype molecular signatures is suggested by the ability of cell line signatures to predict neurosphere growth. A robust two-gene prognostic model utilizing PTEN and DLL3 expression suggests that Akt and Notch signaling are hallmarks of poor prognosis versus better prognosis gliomas, respectively.
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            Glioblastoma stem cells generate vascular pericytes to support vessel function and tumor growth.

            Glioblastomas (GBMs) are highly vascular and lethal brain tumors that display cellular hierarchies containing self-renewing tumorigenic glioma stem cells (GSCs). Because GSCs often reside in perivascular niches and may undergo mesenchymal differentiation, we interrogated GSC potential to generate vascular pericytes. Here, we show that GSCs give rise to pericytes to support vessel function and tumor growth. In vivo cell lineage tracing with constitutive and lineage-specific fluorescent reporters demonstrated that GSCs generate the majority of vascular pericytes. Selective elimination of GSC-derived pericytes disrupts the neovasculature and potently inhibits tumor growth. Analysis of human GBM specimens showed that most pericytes are derived from neoplastic cells. GSCs are recruited toward endothelial cells via the SDF-1/CXCR4 axis and are induced to become pericytes predominantly by transforming growth factor β. Thus, GSCs contribute to vascular pericytes that may actively remodel perivascular niches. Therapeutic targeting of GSC-derived pericytes may effectively block tumor progression and improve antiangiogenic therapy. Copyright © 2013 Elsevier Inc. All rights reserved.
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              VEGF inhibits tumor cell invasion and mesenchymal transition through a MET/VEGFR2 complex.

              Inhibition of VEGF signaling leads to a proinvasive phenotype in mouse models of glioblastoma multiforme (GBM) and in a subset of GBM patients treated with bevacizumab. Here, we demonstrate that vascular endothelial growth factor (VEGF) directly and negatively regulates tumor cell invasion through enhanced recruitment of the protein tyrosine phosphatase 1B (PTP1B) to a MET/VEGFR2 heterocomplex, thereby suppressing HGF-dependent MET phosphorylation and tumor cell migration. Consequently, VEGF blockade restores and increases MET activity in GBM cells in a hypoxia-independent manner, while inducing a program reminiscent of epithelial-to-mesenchymal transition highlighted by a T-cadherin to N-cadherin switch and enhanced mesenchymal features. Inhibition of MET in GBM mouse models blocks mesenchymal transition and invasion provoked by VEGF ablation, resulting in substantial survival benefit. Copyright © 2012 Elsevier Inc. All rights reserved.
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                Author and article information

                Journal
                Oncotarget
                Oncotarget
                Oncotarget
                ImpactJ
                Oncotarget
                Impact Journals LLC
                1949-2553
                8 May 2018
                8 May 2018
                : 9
                : 35
                : 24041-24053
                Affiliations
                1 Edinger Institute (Neurological Institute), Goethe University, Frankfurt, Germany
                2 Department of Neuropathology, University of Heidelberg, Heidelberg, Germany
                3 Clinical Cooperation Unit Neuropathology, German Cancer Research Center (DKFZ), Heidelberg, Germany
                4 Charité — Universitätsmedizin Berlin, Corporate Member of Freie Universität Berlin, Humboldt-Universität zu Berlin, and Berlin Institute of Health, Department of Neuropathology, Berlin, Germany
                5 Laboratory of Molecular Neuro-Oncology, Department of Vascular Neurology, Hertie Institute for Clinical Brain Research, University of Tübingen, Tübingen, Germany
                6 German Cancer Consortium (DKTK), Heidelberg, Germany
                7 German Cancer Research Center (DKFZ), Heidelberg, Germany
                8 Department of Radiation Oncology, University of Tübingen, Tübingen, Germany
                9 Carl Gustav Carus Faculty of Medicine, Technische Universität Dresden, Institute for Medical Informatics and Biometry (IMB), Dresden, Germany
                10 National Center for Tumor Diseases (NCT), Dresden, Germany
                11 Institute for Clinical Genetics, Faculty of Medicine Carl Gustav Carus, Dresden University of Technology, Dresden, Germany
                12 NORLUX Neuro-Oncology Laboratory, Luxembourg Institute of Health (LIH), Strassen, Luxembourg
                13 Luxembourg Centre of Neuropathology (LCNP), Dudelange, Luxembourg
                14 Laboratoire National de Santé (LNS), Dudelange, Luxembourg
                15 Luxembourg Centre for Systems Biomedicine (LCSB), University of Luxembourg, Esch-sur-Alzette, Luxembourg
                Author notes
                Correspondence to: Michel Mittelbronn, Michel.Mittelbronn@ 123456lns.etat.lu
                [*]

                These authors have contributed equally to this work

                Article
                25275
                10.18632/oncotarget.25275
                5963615
                56822a44-1d57-4d4a-a798-193979f526e9
                Copyright: © 2018 Mäder et al.

                This is an open-access article distributed under the terms of the Creative Commons Attribution License 3.0 (CC BY 3.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.

                History
                : 21 February 2017
                : 3 April 2018
                Categories
                Research Paper

                Oncology & Radiotherapy
                emt,met,gliomas,pericytes,vessel-associated mural cells
                Oncology & Radiotherapy
                emt, met, gliomas, pericytes, vessel-associated mural cells

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