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

// Lisa Mader 1, * , Anna E. Blank 1, * , David Capper 2, 3, 4 , Janina Jansong 5 , Peter Baumgarten 1 , Naita M. Wirsik 1 , Cornelia Zachskorn 1, 6, 7 , Jakob Ehlers 4, 8 , Michael Seifert 9, 10 , Barbara Klink 11 , Stefan Liebner 1 , Simone Niclou 12 , Ulrike Naumann 5 , Patrick N. Harter 1, 6, 7 and Michel Mittelbronn 1, 6, 7, 12, 13, 14, 15 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 Charite — Universitatsmedizin Berlin, Corporate Member of Freie Universitat Berlin, Humboldt-Universitat 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 Tubingen, Tubingen, Germany 6 German Cancer Consortium (DKTK), Heidelberg, Germany 7 German Cancer Research Center (DKFZ), Heidelberg, Germany 8 Department of Radiation Oncology, University of Tubingen, Tubingen, Germany 9 Carl Gustav Carus Faculty of Medicine, Technische Universitat 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 Sante (LNS), Dudelange, Luxembourg 15 Luxembourg Centre for Systems Biomedicine (LCSB), University of Luxembourg, Esch-sur-Alzette, Luxembourg * These authors have contributed equally to this work Correspondence to: Michel Mittelbronn, email: Michel.Mittelbronn@lns.etat.lu Keywords: EMT; MET; gliomas; pericytes; vessel-associated mural cells Received: February 21, 2017     Accepted: April 03, 2018     Published: May 08, 2018 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.