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      Soft Tissue Sarcoma Cancer Stem Cells: An Overview

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          Abstract

          Soft tissue sarcomas (STSs) are an uncommon group of solid tumors that can arise throughout the human lifespan. Despite their commonality as non-bony cancers that develop from mesenchymal cell precursors, they are heterogeneous in their genetic profiles, histology, and clinical features. This has made it difficult to identify a single target or therapy specific to STSs. And while there is no one cell of origin ascribed to all STSs, the cancer stem cell (CSC) principle—that a subpopulation of tumor cells possesses stem cell-like properties underlying tumor initiation, therapeutic resistance, disease recurrence, and metastasis—predicts that ultimately it should be possible to identify a feature common to all STSs that could function as a therapeutic Achilles' heel. Here we review the published evidence for CSCs in each of the most common STSs, then focus on the methods used to study CSCs, the developmental signaling pathways usurped by CSCs, and the epigenetic alterations critical for CSC identity that may be useful for further study of STS biology. We conclude with discussion of some challenges to the field and future directions.

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          Generation of neurons and astrocytes from isolated cells of the adult mammalian central nervous system.

          Neurogenesis in the mammalian central nervous system is believed to end in the period just after birth; in the mouse striatum no new neurons are produced after the first few days after birth. In this study, cells isolated from the striatum of the adult mouse brain were induced to proliferate in vitro by epidermal growth factor. The proliferating cells initially expressed nestin, an intermediate filament found in neuroepithelial stem cells, and subsequently developed the morphology and antigenic properties of neurons and astrocytes. Newly generated cells with neuronal morphology were immunoreactive for gamma-aminobutyric acid and substance P, two neurotransmitters of the adult striatum in vivo. Thus, cells of the adult mouse striatum have the capacity to divide and differentiate into neurons and astrocytes.
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            Reconstructing and reprogramming the tumor-propagating potential of glioblastoma stem-like cells.

            Developmental fate decisions are dictated by master transcription factors (TFs) that interact with cis-regulatory elements to direct transcriptional programs. Certain malignant tumors may also depend on cellular hierarchies reminiscent of normal development but superimposed on underlying genetic aberrations. In glioblastoma (GBM), a subset of stem-like tumor-propagating cells (TPCs) appears to drive tumor progression and underlie therapeutic resistance yet remain poorly understood. Here, we identify a core set of neurodevelopmental TFs (POU3F2, SOX2, SALL2, and OLIG2) essential for GBM propagation. These TFs coordinately bind and activate TPC-specific regulatory elements and are sufficient to fully reprogram differentiated GBM cells to "induced" TPCs, recapitulating the epigenetic landscape and phenotype of native TPCs. We reconstruct a network model that highlights critical interactions and identifies candidate therapeutic targets for eliminating TPCs. Our study establishes the epigenetic basis of a developmental hierarchy in GBM, provides detailed insight into underlying gene regulatory programs, and suggests attendant therapeutic strategies. PAPERCLIP: Copyright © 2014 Elsevier Inc. All rights reserved.
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              Chromatin signatures of pluripotent cell lines.

              Epigenetic genome modifications are thought to be important for specifying the lineage and developmental stage of cells within a multicellular organism. Here, we show that the epigenetic profile of pluripotent embryonic stem cells (ES) is distinct from that of embryonic carcinoma cells, haematopoietic stem cells (HSC) and their differentiated progeny. Silent, lineage-specific genes replicated earlier in pluripotent cells than in tissue-specific stem cells or differentiated cells and had unexpectedly high levels of acetylated H3K9 and methylated H3K4. Unusually, in ES cells these markers of open chromatin were also combined with H3K27 trimethylation at some non-expressed genes. Thus, pluripotency of ES cells is characterized by a specific epigenetic profile where lineage-specific genes may be accessible but, if so, carry repressive H3K27 trimethylation modifications. H3K27 methylation is functionally important for preventing expression of these genes in ES cells as premature expression occurs in embryonic ectoderm development (Eed)-deficient ES cells. Our data suggest that lineage-specific genes are primed for expression in ES cells but are held in check by opposing chromatin modifications.
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                Author and article information

                Contributors
                Journal
                Front Oncol
                Front Oncol
                Front. Oncol.
                Frontiers in Oncology
                Frontiers Media S.A.
                2234-943X
                26 October 2018
                2018
                : 8
                : 475
                Affiliations
                [1] 1Division of Hematology-Oncology, Department of Pediatrics, Duke University Medical Center , Durham, NC, United States
                [2] 2Department of Hematology-Oncology, Bambino Gesù Pediatric Hospital, IRCCS , Rome, Italy
                [3] 3Department of Pharmacology & Cancer Biology, Duke University Medical Center , Durham, NC, United States
                Author notes

                Edited by: Thomas G. P. Grünewald, Ludwig-Maximilians-Universität München, Germany

                Reviewed by: Dominique Heymann, University of Nantes, France; Barak Rotblat, Ben-Gurion University of the Negev, Israel

                *Correspondence: Corinne M. Linardic linar001@ 123456mc.duke.edu

                This article was submitted to Molecular and Cellular Oncology, a section of the journal Frontiers in Oncology

                †These authors have contributed equally to this work

                ‡These authors have contributed equally to this work

                Article
                10.3389/fonc.2018.00475
                6212576
                30416982
                2f469e0c-030b-4f2a-bed2-c0199bae1522
                Copyright © 2018 Genadry, Pietrobono, Rota and Linardic.

                This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) and the copyright owner(s) are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.

                History
                : 18 March 2018
                : 05 October 2018
                Page count
                Figures: 1, Tables: 1, Equations: 0, References: 269, Pages: 17, Words: 16460
                Funding
                Funded by: St. Baldrick's Foundation 10.13039/100006058
                Funded by: Associazione Italiana per la Ricerca sul Cancro 10.13039/501100005010
                Award ID: 15312
                Funded by: Hyundai Hope On Wheels 10.13039/100008258
                Categories
                Oncology
                Review

                Oncology & Radiotherapy
                stemness,cancer stem cells,sarcoma,epigenetic plasticity,developmental pathways,soft tissue sarcoma

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