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      Cancer Stem Cells in Soft-Tissue Sarcomas

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          Abstract

          Soft tissue sarcomas (STS) are a rare group of mesenchymal solid tumors with heterogeneous genetic profiles and clinical features. Systemic chemotherapy is the backbone treatment for advanced STS; however, STS frequently acquire resistance to standard therapies, which highlights the need to improve treatments and identify novel therapeutic targets. Increases in the knowledge of the molecular pathways that drive sarcomas have brought to light different molecular alterations that cause tumor initiation and progression. These findings have triggered a breakthrough of targeted therapies that are being assessed in clinical trials. Cancer stem cells (CSCs) exhibit mesenchymal stem cell (MSC) features and represent a subpopulation of tumor cells that play an important role in tumor progression, chemotherapy resistance, recurrence and metastasis. In fact, CSCs phenotypes have been identified in sarcomas, allied to drug resistance and tumorigenesis. Herein, we will review the published evidence of CSCs in STS, discussing the molecular characteristic of CSCs, the commonly used isolation techniques and the new possibilities of targeting CSCs as a way to improve STS treatment and consequently patient outcome.

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          Most cited references111

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          Machine Learning Identifies Stemness Features Associated with Oncogenic Dedifferentiation

          Cancer progression involves the gradual loss of a differentiated phenotype and acquisition of progenitor and stem-cell-like features. Here, we provide novel stemness indices for assessing the degree of oncogenic dedifferentiation. We used an innovative one-class logistic regression (OCLR) machine-learning algorithm to extract transcriptomic and epigenetic feature sets derived from non-transformed pluripotent stem cells and their differentiated progeny. Using OCLR, we were able to identify previously undiscovered biological mechanisms associated with the dedifferentiated oncogenic state. Analyses of the tumor microenvironment revealed unanticipated correlation of cancer stemness with immune checkpoint expression and infiltrating immune cells. We found that the dedifferentiated oncogenic phenotype was generally most prominent in metastatic tumors. Application of our stemness indices to single-cell data revealed patterns of intra-tumor molecular heterogeneity. Finally, the indices allowed for the identification of novel targets and possible targeted therapies aimed at tumor differentiation.
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            Targeting mTOR for cancer therapy

            Mechanistic target of rapamycin (mTOR) is a protein kinase regulating cell growth, survival, metabolism, and immunity. mTOR is usually assembled into several complexes such as mTOR complex 1/2 (mTORC1/2). In cooperation with raptor, rictor, LST8, and mSin1, key components in mTORC1 or mTORC2, mTOR catalyzes the phosphorylation of multiple targets such as ribosomal protein S6 kinase β-1 (S6K1), eukaryotic translation initiation factor 4E binding protein 1 (4E-BP1), Akt, protein kinase C (PKC), and type-I insulin-like growth factor receptor (IGF-IR), thereby regulating protein synthesis, nutrients metabolism, growth factor signaling, cell growth, and migration. Activation of mTOR promotes tumor growth and metastasis. Many mTOR inhibitors have been developed to treat cancer. While some of the mTOR inhibitors have been approved to treat human cancer, more mTOR inhibitors are being evaluated in clinical trials. Here, we update recent advances in exploring mTOR signaling and the development of mTOR inhibitors for cancer therapy. In addition, we discuss the mechanisms underlying the resistance to mTOR inhibitors in cancer cells.
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              Aldehyde dehydrogenase 1A1 in stem cells and cancer

              The human genome contains 19 putatively functional aldehyde dehydrogenase (ALDH) genes, which encode enzymes critical for detoxification of endogenous and exogenous aldehyde substrates through NAD(P)+-dependent oxidation. ALDH1 has three main isotypes, ALDH1A1, ALDH1A2, and ALDH1A3, and is a marker of normal tissue stem cells (SC) and cancer stem cells (CSC), where it is involved in self-renewal, differentiation and self-protection. Experiments with murine and human cells indicate that ALDH1 activity, predominantly attributed to isotype ALDH1A1, is tissue- and cancer-specific. High ALDH1 activity and ALDH1A1 overexpression are associated with poor cancer prognosis, though high ALDH1 and ALDH1A1 levels do not always correlate with highly malignant phenotypes and poor clinical outcome. In cancer therapy, ALDH1A1 provides a useful therapeutic CSC target in tissue types that normally do not express high levels of ALDH1A1, including breast, lung, esophagus, colon and stomach. Here we review the functions and mechanisms of ALDH1A1, the key ALDH isozyme linked to SC populations and an important contributor to CSC function in cancers, and we outline its potential in future anticancer strategies.
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                Author and article information

                Journal
                Cells
                Cells
                cells
                Cells
                MDPI
                2073-4409
                10 June 2020
                June 2020
                : 9
                : 6
                : 1449
                Affiliations
                [1 ]Institute of Biomedicine of Seville (IBIS, HUVR, CSIC, Universidad de Sevilla), 41013 Sevilla, Spain; paula.mrtnez.delgado@ 123456gmail.com (P.M.-D.); serelac@ 123456hotmail.it (S.L.); marlopalv4@ 123456gmail.com (M.L.-A.); joseluciniomondaza@ 123456gmail.com (J.L.M.-H.); elena.blancoalcaina@ 123456gmail.com (E.B.-A.); sanchezbustospaloma@ 123456gmail.com (P.S.-B.); nhindi@ 123456mustbesevilla.org (N.H.); david.moura@ 123456usal.es (D.S.M.)
                [2 ]Health Research Institute of the Balearic Islands (IdISBa) and Molecular Diagnosis Unit, Son Espases University Hospital, 07120 Palma de Mallorca, Spain; antonia.obrador@ 123456ssib.es
                [3 ]Medical Oncology Department, University Hospital Virgen del Rocio, 41013 Seville, Spain
                Author notes
                [* ]Correspondence: jmartin@ 123456mustbesevilla.org ; Tel.: +34-95-592-3113
                [†]

                These authors contributed equally to this work.

                Author information
                https://orcid.org/0000-0001-8313-7587
                https://orcid.org/0000-0002-4630-2077
                https://orcid.org/0000-0002-6514-2419
                Article
                cells-09-01449
                10.3390/cells9061449
                7349510
                32532153
                1b88670c-4fd5-4313-ade0-31e64ab33a24
                © 2020 by the authors.

                Licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license ( http://creativecommons.org/licenses/by/4.0/).

                History
                : 14 May 2020
                : 08 June 2020
                Categories
                Review

                cancer stem cells,tumor-initiating cells,soft-tissue sarcoma,chemotherapy resistance,stemness,tumor heterogeneity,genetic and epigenetic plasticity

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