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      EMT‐ and MET‐related processes in nonepithelial tumors: importance for disease progression, prognosis, and therapeutic opportunities

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          Abstract

          The epithelial‐to mesenchymal (EMT) process is increasingly recognized for playing a key role in the progression, dissemination, and therapy resistance of epithelial tumors. Accumulating evidence suggests that EMT inducers also lead to a gain in mesenchymal properties and promote malignancy of nonepithelial tumors. In this review, we present and discuss current findings, illustrating the importance of EMT inducers in tumors originating from nonepithelial/mesenchymal tissues, including brain tumors, hematopoietic malignancies, and sarcomas. Among these tumors, the involvement of mesenchymal transition has been most extensively investigated in glioblastoma, providing proof for cell autonomous and microenvironment‐derived stimuli that provoke EMT‐like processes that regulate stem cell, invasive, and immunogenic properties as well as therapy resistance. The involvement of prominent EMT transcription factor families, such as TWIST, SNAI, and ZEB, in promoting therapy resistance and tumor aggressiveness has also been reported in lymphomas, leukemias, and sarcomas. A reverse process, resembling mesenchymal‐to‐epithelial transition (MET), seems particularly relevant for sarcomas, where (partial) epithelial differentiation is linked to less aggressive tumors and a better patient prognosis. Overall, a hybrid model in which more stable epithelial and mesenchymal intermediates exist likely extends to the biology of tumors originating from sources other than the epithelium. Deeper investigation and understanding of the EMT/MET machinery in nonepithelial tumors will shed light on the pathogenesis of these tumors, potentially paving the way toward the identification of clinically relevant biomarkers for prognosis and future therapeutic targets.

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          Most cited references103

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          Epithelial-mesenchymal transitions in development and disease.

          The epithelial to mesenchymal transition (EMT) plays crucial roles in the formation of the body plan and in the differentiation of multiple tissues and organs. EMT also contributes to tissue repair, but it can adversely cause organ fibrosis and promote carcinoma progression through a variety of mechanisms. EMT endows cells with migratory and invasive properties, induces stem cell properties, prevents apoptosis and senescence, and contributes to immunosuppression. Thus, the mesenchymal state is associated with the capacity of cells to migrate to distant organs and maintain stemness, allowing their subsequent differentiation into multiple cell types during development and the initiation of metastasis.
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            The cell biology of neurogenesis.

            During the development of the mammalian central nervous system, neural stem cells and their derivative progenitor cells generate neurons by asymmetric and symmetric divisions. The proliferation versus differentiation of these cells and the type of division are closely linked to their epithelial characteristics, notably, their apical-basal polarity and cell-cycle length. Here, we discuss how these features change during development from neuroepithelial to radial glial cells, and how this transition affects cell fate and neurogenesis.
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              The transcriptional network for mesenchymal transformation of brain tumors

              Inference of transcriptional networks that regulate transitions into physiologic or pathologic cellular states remains a central challenge in systems biology. A mesenchymal phenotype is the hallmark of tumor aggressiveness in human malignant glioma but the regulatory programs responsible for implementing the associated molecular signature are largely unknown. Here, we show that reverse-engineering and unbiased interrogation of a glioma-specific regulatory network reveal the transcriptional module that activates expression of mesenchymal genes in malignant glioma. Two transcription factors (C/EBPβ and Stat3) emerge as synergistic initiators and master regulators of mesenchymal transformation. Ectopic co-expression of C/EBPβ and Stat3 reprograms neural stem cells along the aberrant mesenchymal lineage whereas elimination of the two factors in glioma cells leads to collapse of the mesenchymal signature and reduces tumor aggressiveness. In human glioma, expression of C/EBPβ and Stat3 correlates with mesenchymal differentiation and predicts poor clinical outcome. These results reveal that activation of a small regulatory module is necessary and sufficient to initiate and maintain an aberrant phenotypic state in cancer cells.
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                Author and article information

                Contributors
                f.a.e.kruyt@umcg.nl
                Journal
                Mol Oncol
                Mol Oncol
                10.1002/(ISSN)1878-0261
                MOL2
                Molecular Oncology
                John Wiley and Sons Inc. (Hoboken )
                1574-7891
                1878-0261
                19 June 2017
                July 2017
                : 11
                : 7 , Special Issue: Epithelial‐to‐Mesenchymal Transition in Cancer ( doiID: 10.1002/mol2.2017.11.issue-7 )
                : 860-877
                Affiliations
                [ 1 ] Department of Neurosurgery Medical FacultyHeinrich‐Heine University DüsseldorfGermany
                [ 2 ] Department of BiomedicineUniversity of Bergen Norway
                [ 3 ] Department of Medical OncologyUniversity of Groningen University Medical Center GroningenThe Netherlands
                Author notes
                [*] [* ] Correspondence

                F. A. E. Kruyt, Department of Medical Oncology, University of Groningen, University Medical Center Groningen, Hanzeplein 1, 9713 GZ Groningen, The Netherlands

                Fax: +31 50 3614862

                Tel: +31 50 3615531

                E‐mail: f.a.e.kruyt@ 123456umcg.nl

                Article
                MOL212085
                10.1002/1878-0261.12085
                5496495
                28556516
                8d446553-e92c-4be2-97db-36a6a6d46f28
                © 2017 The Authors. Published by FEBS Press and John Wiley & Sons Ltd.

                This is an open access article under the terms of the Creative Commons Attribution License, which permits use, distribution and reproduction in any medium, provided the original work is properly cited.

                History
                : 14 March 2017
                : 16 May 2017
                : 18 May 2017
                Page count
                Figures: 3, Tables: 0, Pages: 18, Words: 12563
                Funding
                Funded by: Strategic Research Fund of the Heinrich‐Heine University Dusseldorf
                Categories
                Review
                Reviews
                Custom metadata
                2.0
                mol212085
                July 2017
                Converter:WILEY_ML3GV2_TO_NLMPMC version:5.1.2 mode:remove_FC converted:04.07.2017

                Oncology & Radiotherapy
                cancer stem cell,epithelial,glioblastoma,leukemia,mesenchymal,sarcoma
                Oncology & Radiotherapy
                cancer stem cell, epithelial, glioblastoma, leukemia, mesenchymal, sarcoma

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