title: Identification and analysis of CXCR4-positive synovial sarcoma-initiating cells.
abstract: Synovial sarcoma accounts for almost 10% of all soft tissue sarcomas, and its prognosis is poor with 5-year survival rates at 36%. Thus, new treatments and therapeutic targets for synovial sarcoma are required. Tumor-initiating cells have been defined by the ability for self-renewal and multipotent differentiation, and they exhibit higher tumorigenic capacity, chemoresistance and radiation resistance, expecting to be a new therapeutic target. In synovial sarcoma, the presence of such stemness remains largely unclear; thus, we analyzed whether synovial sarcoma possessed tumor-initiating cells and explored specific markers, and we discovered that synovial sarcoma cell lines possessed heterogeneity by way of containing a sphere-forming subpopulation highly expressing NANOG, OCT4 and SOX2. By expression microarray analysis, CXCR4 was identified to be highly expressed in the sphere subpopulation and correlated with stem-cell-associated markers. Inhibition of CXCR4 suppressed the cell proliferation of synovial sarcoma cell lines in vitro. The tumor-initiating ability of CXCR4-positive cells was demonstrated by xenograft propagation assay. CXCR4-positive cells showed higher tumorigenicity than negative ones and possessed both self-renewal and multipotent differentiation ability. Immunohistochemical analysis of 39 specimens of synovial sarcoma patients revealed that CXCR4 strongly correlated with poor prognosis of synovial sarcoma. Thus, we conclude that CXCR4 is the marker of synovial sarcoma-initiating cells, a new biomarker for prognosis and a new potential therapeutic target.
authors.affiliation: Department of Translational Pathology, Hokkaido University Graduate School of Medicine, Sapporo, Japan.
authors.forename: T
authors.initials: T
authors.lastname: Kimura
authors.affiliation: Department of Translational Pathology, Hokkaido University Graduate School of Medicine, Sapporo, Japan.
authors.forename: L
authors.initials: L
authors.lastname: Wang
authors.affiliation: Department of Stem Cell Regulation, Medical Research Institute, Tokyo Medical and Dental University (TMDU), Yushima, Bunkyo-ku, Tokyo, Japan.
authors.forename: K
authors.initials: K
authors.lastname: Tabu
authors.affiliation: Department of Cancer Pathology, Hokkaido University Graduate School of Medicine, Sapporo, Japan.
authors.forename: M
authors.initials: M
authors.lastname: Tsuda
authors.affiliation: Department of Cancer Pathology, Hokkaido University Graduate School of Medicine, Sapporo, Japan.
authors.forename: M
authors.initials: M
authors.lastname: Tanino
authors.affiliation: Department of Anatomic Pathology, Graduate School of Medical Sciences, Kyushu University, Higashi-ku, Fukuoka City, Japan.
authors.forename: A
authors.initials: A
authors.lastname: Maekawa
authors.affiliation: Department of Translational Pathology, Hokkaido University Graduate School of Medicine, Sapporo, Japan.
authors.forename: H
authors.initials: H
authors.lastname: Nishihara
authors.affiliation: Division of Orthopedics, National Hospital Organization Hokkaido Cancer Center, Sapporo, Japan.
authors.forename: H
authors.initials: H
authors.lastname: Hiraga
authors.affiliation: Department of Stem Cell Regulation, Medical Research Institute, Tokyo Medical and Dental University (TMDU), Yushima, Bunkyo-ku, Tokyo, Japan.
authors.forename: T
authors.initials: T
authors.lastname: Taga
authors.affiliation: Department of Anatomic Pathology, Graduate School of Medical Sciences, Kyushu University, Higashi-ku, Fukuoka City, Japan.
authors.forename: Y
authors.initials: Y
authors.lastname: Oda
authors.affiliation: Department of Cancer Pathology, Hokkaido University Graduate School of Medicine, Sapporo, Japan.
authors.forename: S
authors.initials: S
authors.lastname: Tanaka
mesh_terms: D000818:Animals; D014408:Biomarkers, Tumor / Q000032:analysis; D045744:Cell Line, Tumor; D005260:Female; D006801:Humans; D051379:Mice; D014411:Neoplastic Stem Cells / Q000737:chemistry*; D015514:Oncogene Proteins, Fusion / Q000502:physiology; D011379:Prognosis; D019718:Receptors, CXCR4 / Q000032:analysis* / Q000502:physiology; D013584:Sarcoma, Synovial / Q000276:immunology / Q000473:pathology*
chemical_list: D014408:Biomarkers, Tumor; C527276:CXCR4 protein, human; D015514:Oncogene Proteins, Fusion; D019718:Receptors, CXCR4; C587877:SS18-SSX1 fusion protein