title: Ewing's sarcoma precursors are highly enriched in embryonic osteochondrogenic progenitors.
abstract: Ewing's sarcoma is a highly malignant bone tumor found in children and adolescents, and the origin of this malignancy is not well understood. Here, we introduced a Ewing's sarcoma-associated genetic fusion of the genes encoding the RNA-binding protein EWS and the transcription factor ETS (EWS-ETS) into a fraction of cells enriched for osteochondrogenic progenitors derived from the embryonic superficial zone (eSZ) of long bones collected from late gestational murine embryos. EWS-ETS fusions efficiently induced Ewing's sarcoma-like small round cell sarcoma formation by these cells. Analysis of the eSZ revealed a fraction of a precursor cells that express growth/differentiation factor 5 (Gdf5), the transcription factor Erg, and parathyroid hormone-like hormone (Pthlh), and selection of the Pthlh-positive fraction alone further enhanced EWS-ETS-dependent tumor induction. Genes downstream of the EWS-ETS fusion protein were quite transcriptionally active in eSZ cells, especially in regions in which the chromatin structure of the ETS-responsive locus was open. Inhibition of β-catenin, poly (ADP-ribose) polymerase 1 (PARP1), or enhancer of zeste homolog 2 (EZH2) suppressed cell growth in a murine model of Ewing's sarcoma, suggesting the utility of the current system as a preclinical model. These results indicate that eSZ cells are highly enriched in precursors to Ewing's sarcoma and provide clues to the histogenesis of Ewing's sarcoma in bone.
authors.forename: Miwa
authors.initials: M
authors.lastname: Tanaka
authors.forename: Yukari
authors.initials: Y
authors.lastname: Yamazaki
authors.forename: Yohei
authors.initials: Y
authors.lastname: Kanno
authors.forename: Katsuhide
authors.initials: K
authors.lastname: Igarashi
authors.forename: Ken-ichi
authors.initials: K
authors.lastname: Aisaki
authors.forename: Jun
authors.initials: J
authors.lastname: Kanno
authors.forename: Takuro
authors.initials: T
authors.lastname: Nakamura
mesh_terms: D000818:Animals; D001859:Bone Neoplasms / Q000209:etiology / Q000235:genetics / Q000473:pathology*; D019902:Chondrocytes / Q000473:pathology; D004195:Disease Models, Animal; D053595:Embryonic Stem Cells / Q000473:pathology; D005260:Female; D020869:Gene Expression Profiling; D050939:Gene Fusion; D006801:Humans; D051379:Mice; D008807:Mice, Inbred BALB C; D014411:Neoplastic Stem Cells / Q000473:pathology*; D010006:Osteoblasts / Q000473:pathology; D011247:Pregnancy; D050783:Proto-Oncogene Proteins c-ets / Q000235:genetics; D034802:RNA-Binding Protein EWS / Q000235:genetics; D012512:Sarcoma, Ewing / Q000209:etiology / Q000235:genetics / Q000473:pathology*; D060449:Wnt Signaling Pathway / Q000235:genetics; D051176:beta Catenin / Q000235:genetics
chemical_list: C495267:CTNNB1 protein, mouse; D050783:Proto-Oncogene Proteins c-ets; D034802:RNA-Binding Protein EWS; D051176:beta Catenin