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: Miwa Tanaka, Yukari Yamazaki, Yohei Kanno, Katsuhide Igarashi, Ken-ichi Aisaki, Jun Kanno, Takuro Nakamura
• Journal: The Journal of clinical investigation (J Clin Invest) Vol. 124 Issue 7 Pg. 3061-74 (Jul 2014) ISSN: 1558-8238 [Electronic] United States
• PMID: 24911143 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• CTNNB1 protein, mouse
• Proto-Oncogene Proteins c-ets
• RNA-Binding Protein EWS
• beta Catenin

Topics

• Animals
• Bone Neoplasms (etiology, genetics, pathology)
• Chondrocytes (pathology)
• Disease Models, Animal
• Embryonic Stem Cells (pathology)
• Female
• Gene Expression Profiling
• Gene Fusion
• Humans
• Mice
• Mice, Inbred BALB C
• Neoplastic Stem Cells (pathology)
• Osteoblasts (pathology)
• Pregnancy
• Proto-Oncogene Proteins c-ets (genetics)
• RNA-Binding Protein EWS (genetics)
• Sarcoma, Ewing (etiology, genetics, pathology)
• Wnt Signaling Pathway (genetics)
• beta Catenin (genetics)