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      High Expression of CD109 Antigen Regulates the Phenotype of Cancer Stem-Like Cells/Cancer-Initiating Cells in the Novel Epithelioid Sarcoma Cell Line ESX and Is Related to Poor Prognosis of Soft Tissue Sarcoma

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          Epithelioid sarcoma (ES) is a relatively rare, highly malignant soft tissue sarcoma. The mainstay of treatment is resection or amputation. Currently other therapeutic options available for this disease are limited. Therefore, a novel therapeutic option needs to be developed. In the present study, we established a new human ES cell line (ESX) and analyzed the characteristics of its cancer stem-like cells/cancer-initiating cells (CSCs/CICs) based on ALDH1 activity. We demonstrated that a subpopulation of ESX cells with high ALDH1 activity (ALDH high cells) correlated with enhanced clonogenic ability, sphere-formation ability, and invasiveness in vitro and showed higher tumorigenicity in vivo. Next, using gene expression profiling, we identified CD109, a GPI-anchored protein upregulated in the ALDH high cells. CD109 mRNA was highly expressed in various sarcoma cell lines, but weakly expressed in normal adult tissues. CD109-positive cells in ESX predominantly formed spheres in culture, whereas siCD109 reduced ALDH1 expression and inhibited the cell proliferation in vitro. Subsequently, we evaluated the expression of CD109 protein in 80 clinical specimens of soft tissue sarcoma. We found a strong correlation between CD109 protein expression and the prognosis ( P = 0.009). In conclusion, CD109 might be a CSC/CIC marker in epithelioid sarcoma. Moreover, CD109 is a promising prognostic biomarker and a molecular target of cancer therapy for sarcomas including ES.

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          Most cited references 41

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          Functional expression cloning of Nanog, a pluripotency sustaining factor in embryonic stem cells.

          Embryonic stem (ES) cells undergo extended proliferation while remaining poised for multilineage differentiation. A unique network of transcription factors may characterize self-renewal and simultaneously suppress differentiation. We applied expression cloning in mouse ES cells to isolate a self-renewal determinant. Nanog is a divergent homeodomain protein that directs propagation of undifferentiated ES cells. Nanog mRNA is present in pluripotent mouse and human cell lines, and absent from differentiated cells. In preimplantation embryos, Nanog is restricted to founder cells from which ES cells can be derived. Endogenous Nanog acts in parallel with cytokine stimulation of Stat3 to drive ES cell self-renewal. Elevated Nanog expression from transgene constructs is sufficient for clonal expansion of ES cells, bypassing Stat3 and maintaining Oct4 levels. Cytokine dependence, multilineage differentiation, and embryo colonization capacity are fully restored upon transgene excision. These findings establish a central role for Nanog in the transcription factor hierarchy that defines ES cell identity.
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            Formation of pluripotent stem cells in the mammalian embryo depends on the POU transcription factor Oct4.

            Oct4 is a mammalian POU transcription factor expressed by early embryo cells and germ cells. We report that the activity of Oct4 is essential for the identity of the pluripotential founder cell population in the mammalian embryo. Oct4-deficient embryos develop to the blastocyst stage, but the inner cell mass cells are not pluripotent. Instead, they are restricted to differentiation along the extraembryonic trophoblast lineage. Furthermore, in the absence of a true inner cell mass, trophoblast proliferation is not maintained in Oct4-/- embryos. Expansion of trophoblast precursors is restored, however, by an Oct4 target gene product, fibroblast growth factor-4. Therefore, Oct4 also determines paracrine growth factor signaling from stem cells to the trophectoderm.
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              Stem cells, the molecular circuitry of pluripotency and nuclear reprogramming.

              Reprogramming of somatic cells to a pluripotent embryonic stem cell-like state has been achieved by nuclear transplantation of a somatic nucleus into an enucleated egg and most recently by introducing defined transcription factors into somatic cells. Nuclear reprogramming is of great medical interest, as it has the potential to generate a source of patient-specific cells. Here, we review strategies to reprogram somatic cells to a pluripotent embryonic state and discuss our understanding of the molecular mechanisms of reprogramming based on recent insights into the regulatory circuitry of the pluripotent state.

                Author and article information

                Role: Editor
                PLoS One
                PLoS ONE
                PLoS ONE
                Public Library of Science (San Francisco, USA )
                20 December 2013
                : 8
                : 12
                [1 ]Department of Orthopedic Surgery, Sapporo Medical University School of Medicine, Chuo-ku, Sapporo, Japan
                [2 ]Department of Pathology, Sapporo Medical University School of Medicine, Chuo-ku, Sapporo, Japan
                [3 ]Department of Surgical Pathology, Sapporo Medical University School of Medicine, Chuo-ku, Sapporo, Japan
                [4 ]Department of Orthopedic Surgery, Fukuoka University School of Medicine, Nanakuma, Jonan Ward, Fukuoka, Japan
                [5 ]Department of Pathology, Fukuoka University School of Medicine, Nanakuma, Jonan Ward, Fukuoka, Japan
                [6 ]Department of Public Health, Sapporo Medical University School of Medicine, Chuo-ku, Sapporo, Japan
                Wayne State University School of Medicine, United States of America
                Author notes

                Competing Interests: The authors have declared that no competing interests exist.

                Conceived and designed the experiments: ME T. Tsukahara VK T. Torigoe TW TY NS. Performed the experiments: ME T. Tsukahara MM M. Kano KM AT TK HA KY. Analyzed the data: ME T. Tsukahara TS TH NS. Contributed reagents/materials/analysis tools: M. Kaya SN JN HI. Wrote the manuscript: ME T. Tsukahara NS.


                This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.

                Supported by grants from JSPS KAKENHI (21249025, 20390403, 22689041), Management Expenses Grants from the Government to the National Cancer Center (23-A-10, 23-A-44), NOASTEC (H24-S-5) and Suhara Memorial Foundation (H24-12). The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.
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