This Article Full Text Full Text (PDF) Supplementary Data Alert me when this article is cited Alert me if a correction is posted Services Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Citing Articles Citing Articles via HighWire Citing Articles via Google Scholar Google Scholar Articles by Riggi, N. Articles by Stamenkovic, I. Search for Related Content PubMed PubMed Citation Articles by Riggi, N. Articles by Stamenkovic, I.

EWS-FLI-1 Expression Triggers a Ewing's Sarcoma Initiation Program in Primary Human Mesenchymal Stem Cells

¹ Division of Experimental Pathology, Institute of Pathology, and ² Department of Pediatric Surgery, University of Lausanne, Lausanne, Switzerland; ³ Department of Orthopedics, University of Geneva, Geneva, Switzerland; and ⁴ Department of Genetics Biology and Biochemistry, University of Turin, Turin, Italy

Requests for reprints: Ivan Stamenkovic, Experimental Pathology, University of Lausanne, Lausanne, Switzerland. Phone: 41-21-314-7136; Fax: 41-21-314-7110; E-mail: Ivan.Stamenkovic{at}chuv.ch.

Key Words: mesenchymal stem cells • EWS-FLI-1 • Ewing's sarcoma • IGF-I • EZH2

Ewing's sarcoma family tumors (ESFT) express the EWS-FLI-1 fusion gene generated by the chromosomal translocation t(11;22)(q24;q12). Expression of the EWS-FLI-1 fusion protein in a permissive cellular environment is believed to play a key role in ESFT pathogenesis. However, EWS-FLI-1 induces growth arrest or apoptosis in differentiated primary cells, and the identity of permissive primary human cells that can support its expression and function has until now remained elusive. Here we show that expression of EWS-FLI-1 in human mesenchymal stem cells (hMSC) is not only stably maintained without inhibiting proliferation but also induces a gene expression profile bearing striking similarity to that of ESFT, including genes that are among the highest ESFT discriminators. Expression of EWS-FLI-1 in hMSCs may recapitulate the initial steps of Ewing's sarcoma development, allowing identification of genes that play an important role early in its pathogenesis. Among relevant candidate transcripts induced by EWS-FLI-1 in hMSCs, we found the polycomb group gene EZH2, which we show to play a critical role in Ewing's sarcoma growth. These observations are consistent with our recent findings using mouse mesenchymal progenitor cells and provide compelling evidence that hMSCs are candidate cells of origin of ESFT. [Cancer Res 2008;68(7):2176–85]

This article has been cited by other articles:

				E. G. Coles, E. R. Lawlor, and M. Bronner-Fraser EWS-FLI1 Causes Neuroepithelial Defects and Abrogates Emigration of Neural Crest Stem Cells Stem Cells, September 1, 2008; 26(9): 2237 - 2244. [Abstract] [Full Text] [PDF]