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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Lisa Mäder1,*, Anna E. Blank1,*, David Capper2,3,4, Janina Jansong5, Peter Baumgarten1, Naita M. Wirsik1, Cornelia Zachskorn1,6,7, Jakob Ehlers4,8, Michael Seifert9,10, Barbara Klink11, Stefan Liebner1, Simone Niclou12, Ulrike Naumann5, Patrick N. Harter1,6,7 and Michel Mittelbronn1,6,7,12,13,14,15
1Edinger Institute (Neurological Institute), Goethe University, Frankfurt, Germany
2Department of Neuropathology, University of Heidelberg, Heidelberg, Germany
3Clinical Cooperation Unit Neuropathology, German Cancer Research Center (DKFZ), Heidelberg, Germany
4Charité — Universitätsmedizin Berlin, Corporate Member of Freie Universität Berlin, Humboldt-Universität zu Berlin, and Berlin Institute of Health, Department of Neuropathology, Berlin, Germany
5Laboratory of Molecular Neuro-Oncology, Department of Vascular Neurology, Hertie Institute for Clinical Brain Research, University of Tübingen, Tübingen, Germany
6German Cancer Consortium (DKTK), Heidelberg, Germany
7German Cancer Research Center (DKFZ), Heidelberg, Germany
8Department of Radiation Oncology, University of Tübingen, Tübingen, Germany
9Carl Gustav Carus Faculty of Medicine, Technische Universität Dresden, Institute for Medical Informatics and Biometry (IMB), Dresden, Germany
10National Center for Tumor Diseases (NCT), Dresden, Germany
11Institute for Clinical Genetics, Faculty of Medicine Carl Gustav Carus, Dresden University of Technology, Dresden, Germany
12NORLUX Neuro-Oncology Laboratory, Luxembourg Institute of Health (LIH), Strassen, Luxembourg
13Luxembourg Centre of Neuropathology (LCNP), Dudelange, Luxembourg
14Laboratoire National de Santé (LNS), Dudelange, Luxembourg
15Luxembourg Centre for Systems Biomedicine (LCSB), University of Luxembourg, Esch-sur-Alzette, Luxembourg
*These authors have contributed equally to this work
Michel Mittelbronn, email: [email protected]
Keywords: EMT; MET; gliomas; pericytes; vessel-associated mural cells
Received: February 21, 2017 Accepted: April 03, 2018 Published: May 08, 2018
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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