EWS-FLI-1 Expression Triggers a Ewing's Sarcoma Initiation Program in Primary Human Mesenchymal Stem Cells
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 gr...
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| Veröffentlicht in: | Cancer research (Chicago, Ill.) Ill.), 2008-04, Vol.68 (7), p.2176-2185 |
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| creator | RIGGI, Nicolo SUVA, Mario-Luca STAMENKOVIC, Ivan SUVA, Domizio CIRONI, Luisa PROVERO, Paolo TERCIER, Stéphane JOSEPH, Jean-Marc STEHLE, Jean-Christophe BAUMER, Karine KINDLER, Vincent |
| description | 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. |
| doi_str_mv | 10.1158/0008-5472.can-07-1761 |
| format | Article |
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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.</description><identifier>ISSN: 0008-5472</identifier><identifier>EISSN: 1538-7445</identifier><identifier>DOI: 10.1158/0008-5472.can-07-1761</identifier><identifier>PMID: 18381423</identifier><identifier>CODEN: CNREA8</identifier><language>eng</language><publisher>Philadelphia, PA: American Association for Cancer Research</publisher><subject>Animals ; Antineoplastic agents ; Biological and medical sciences ; Bone Neoplasms - genetics ; Bone Neoplasms - metabolism ; Bone Neoplasms - pathology ; Cell Differentiation - physiology ; Diseases of the osteoarticular system ; Enhancer of Zeste Homolog 2 Protein ; Gene Expression Profiling ; Gene Expression Regulation, Neoplastic - genetics ; Histone-Lysine N-Methyltransferase ; Humans ; Immunocompromised Host ; Medical sciences ; Mesenchymal Stromal Cells - metabolism ; Mesenchymal Stromal Cells - pathology ; Mice ; Oncogene Proteins, Fusion - biosynthesis ; Oncogene Proteins, Fusion - genetics ; Pharmacology. Drug treatments ; Phenotype ; Polycomb Repressive Complex 2 ; Proteins - genetics ; Proto-Oncogene Protein c-fli-1 - biosynthesis ; Proto-Oncogene Protein c-fli-1 - genetics ; RNA, Messenger - biosynthesis ; RNA, Messenger - genetics ; RNA-Binding Protein EWS ; Sarcoma, Ewing - genetics ; Sarcoma, Ewing - metabolism ; Sarcoma, Ewing - pathology ; Soft Tissue Neoplasms - genetics ; Soft Tissue Neoplasms - metabolism ; Soft Tissue Neoplasms - pathology ; Tumors ; Tumors of striated muscle and skeleton</subject><ispartof>Cancer research (Chicago, Ill.), 2008-04, Vol.68 (7), p.2176-2185</ispartof><rights>2008 INIST-CNRS</rights><lds50>peer_reviewed</lds50><oa>free_for_read</oa><woscitedreferencessubscribed>false</woscitedreferencessubscribed><citedby>FETCH-LOGICAL-c535t-750b8811b10079a7007b53b3995d37a89c10f8c2d011f015efbc3e41e0beb4b73</citedby><cites>FETCH-LOGICAL-c535t-750b8811b10079a7007b53b3995d37a89c10f8c2d011f015efbc3e41e0beb4b73</cites></display><links><openurl>$$Topenurl_article</openurl><openurlfulltext>$$Topenurlfull_article</openurlfulltext><thumbnail>$$Tsyndetics_thumb_exl</thumbnail><link.rule.ids>314,780,784,3356,27924,27925</link.rule.ids><backlink>$$Uhttp://pascal-francis.inist.fr/vibad/index.php?action=getRecordDetail&idt=20301906$$DView record in Pascal Francis$$Hfree_for_read</backlink><backlink>$$Uhttps://www.ncbi.nlm.nih.gov/pubmed/18381423$$D View this record in MEDLINE/PubMed$$Hfree_for_read</backlink></links><search><creatorcontrib>RIGGI, Nicolo</creatorcontrib><creatorcontrib>SUVA, Mario-Luca</creatorcontrib><creatorcontrib>STAMENKOVIC, Ivan</creatorcontrib><creatorcontrib>SUVA, Domizio</creatorcontrib><creatorcontrib>CIRONI, Luisa</creatorcontrib><creatorcontrib>PROVERO, Paolo</creatorcontrib><creatorcontrib>TERCIER, Stéphane</creatorcontrib><creatorcontrib>JOSEPH, Jean-Marc</creatorcontrib><creatorcontrib>STEHLE, Jean-Christophe</creatorcontrib><creatorcontrib>BAUMER, Karine</creatorcontrib><creatorcontrib>KINDLER, Vincent</creatorcontrib><title>EWS-FLI-1 Expression Triggers a Ewing's Sarcoma Initiation Program in Primary Human Mesenchymal Stem Cells</title><title>Cancer research (Chicago, Ill.)</title><addtitle>Cancer Res</addtitle><description>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.</description><subject>Animals</subject><subject>Antineoplastic agents</subject><subject>Biological and medical sciences</subject><subject>Bone Neoplasms - genetics</subject><subject>Bone Neoplasms - metabolism</subject><subject>Bone Neoplasms - pathology</subject><subject>Cell Differentiation - physiology</subject><subject>Diseases of the osteoarticular system</subject><subject>Enhancer of Zeste Homolog 2 Protein</subject><subject>Gene Expression Profiling</subject><subject>Gene Expression Regulation, Neoplastic - genetics</subject><subject>Histone-Lysine N-Methyltransferase</subject><subject>Humans</subject><subject>Immunocompromised Host</subject><subject>Medical sciences</subject><subject>Mesenchymal Stromal Cells - metabolism</subject><subject>Mesenchymal Stromal Cells - pathology</subject><subject>Mice</subject><subject>Oncogene Proteins, Fusion - biosynthesis</subject><subject>Oncogene Proteins, Fusion - genetics</subject><subject>Pharmacology. Drug treatments</subject><subject>Phenotype</subject><subject>Polycomb Repressive Complex 2</subject><subject>Proteins - genetics</subject><subject>Proto-Oncogene Protein c-fli-1 - biosynthesis</subject><subject>Proto-Oncogene Protein c-fli-1 - genetics</subject><subject>RNA, Messenger - biosynthesis</subject><subject>RNA, Messenger - genetics</subject><subject>RNA-Binding Protein EWS</subject><subject>Sarcoma, Ewing - genetics</subject><subject>Sarcoma, Ewing - metabolism</subject><subject>Sarcoma, Ewing - pathology</subject><subject>Soft Tissue Neoplasms - genetics</subject><subject>Soft Tissue Neoplasms - metabolism</subject><subject>Soft Tissue Neoplasms - pathology</subject><subject>Tumors</subject><subject>Tumors of striated muscle and skeleton</subject><issn>0008-5472</issn><issn>1538-7445</issn><fulltext>true</fulltext><rsrctype>article</rsrctype><creationdate>2008</creationdate><recordtype>article</recordtype><sourceid>EIF</sourceid><recordid>eNpFkEtLAzEQgIMoWh8_QclFPUVnmo3JHqVUW6gPqOIxJGm2RvZRky3qv3eXFr3MA76ZZD5CThGuEIW6BgDFRCaHV87UDCRDeYM7ZICCKyazTOySwR9zQA5T-uhagSD2yQEqrjAb8gH5GL_N2d1sypCOv1fRpxSamr7EsFz6mKih469QLy8TnZvomsrQaR3aYNqeeo7NMpqKhr4MlYk_dLKuTE0ffPK1e_-pTEnnra_oyJdlOiZ7hSmTP9nmI_J6N34ZTdjs6X46up0xJ7homRRglUK0CCBzI7toBbc8z8WCS6Nyh1AoN1wAYgEofGEd9xl6sN5mVvIjcrHZu4rN59qnVlchue4HpvbNOmkJmQAu8w4UG9DFJqXoC73anKERdC9Z9wJ1L1CPbh81SN1L7ubOtg-sbeUX_1Nbqx1wvgVMcqYsoqldSH_cEDhgDjf8F8rmg_8</recordid><startdate>20080401</startdate><enddate>20080401</enddate><creator>RIGGI, Nicolo</creator><creator>SUVA, Mario-Luca</creator><creator>STAMENKOVIC, Ivan</creator><creator>SUVA, Domizio</creator><creator>CIRONI, Luisa</creator><creator>PROVERO, Paolo</creator><creator>TERCIER, Stéphane</creator><creator>JOSEPH, Jean-Marc</creator><creator>STEHLE, Jean-Christophe</creator><creator>BAUMER, Karine</creator><creator>KINDLER, Vincent</creator><general>American Association for Cancer Research</general><scope>IQODW</scope><scope>CGR</scope><scope>CUY</scope><scope>CVF</scope><scope>ECM</scope><scope>EIF</scope><scope>NPM</scope><scope>AAYXX</scope><scope>CITATION</scope><scope>7X8</scope></search><sort><creationdate>20080401</creationdate><title>EWS-FLI-1 Expression Triggers a Ewing's Sarcoma Initiation Program in Primary Human Mesenchymal Stem Cells</title><author>RIGGI, Nicolo ; SUVA, Mario-Luca ; STAMENKOVIC, Ivan ; SUVA, Domizio ; CIRONI, Luisa ; PROVERO, Paolo ; TERCIER, Stéphane ; JOSEPH, Jean-Marc ; STEHLE, Jean-Christophe ; BAUMER, Karine ; KINDLER, Vincent</author></sort><facets><frbrtype>5</frbrtype><frbrgroupid>cdi_FETCH-LOGICAL-c535t-750b8811b10079a7007b53b3995d37a89c10f8c2d011f015efbc3e41e0beb4b73</frbrgroupid><rsrctype>articles</rsrctype><prefilter>articles</prefilter><language>eng</language><creationdate>2008</creationdate><topic>Animals</topic><topic>Antineoplastic agents</topic><topic>Biological and medical sciences</topic><topic>Bone Neoplasms - genetics</topic><topic>Bone Neoplasms - metabolism</topic><topic>Bone Neoplasms - pathology</topic><topic>Cell Differentiation - physiology</topic><topic>Diseases of the osteoarticular system</topic><topic>Enhancer of Zeste Homolog 2 Protein</topic><topic>Gene Expression Profiling</topic><topic>Gene Expression Regulation, Neoplastic - genetics</topic><topic>Histone-Lysine N-Methyltransferase</topic><topic>Humans</topic><topic>Immunocompromised Host</topic><topic>Medical sciences</topic><topic>Mesenchymal Stromal Cells - metabolism</topic><topic>Mesenchymal Stromal Cells - pathology</topic><topic>Mice</topic><topic>Oncogene Proteins, Fusion - biosynthesis</topic><topic>Oncogene Proteins, Fusion - genetics</topic><topic>Pharmacology. Drug treatments</topic><topic>Phenotype</topic><topic>Polycomb Repressive Complex 2</topic><topic>Proteins - genetics</topic><topic>Proto-Oncogene Protein c-fli-1 - biosynthesis</topic><topic>Proto-Oncogene Protein c-fli-1 - genetics</topic><topic>RNA, Messenger - biosynthesis</topic><topic>RNA, Messenger - genetics</topic><topic>RNA-Binding Protein EWS</topic><topic>Sarcoma, Ewing - genetics</topic><topic>Sarcoma, Ewing - metabolism</topic><topic>Sarcoma, Ewing - pathology</topic><topic>Soft Tissue Neoplasms - genetics</topic><topic>Soft Tissue Neoplasms - metabolism</topic><topic>Soft Tissue Neoplasms - pathology</topic><topic>Tumors</topic><topic>Tumors of striated muscle and skeleton</topic><toplevel>peer_reviewed</toplevel><toplevel>online_resources</toplevel><creatorcontrib>RIGGI, Nicolo</creatorcontrib><creatorcontrib>SUVA, Mario-Luca</creatorcontrib><creatorcontrib>STAMENKOVIC, Ivan</creatorcontrib><creatorcontrib>SUVA, Domizio</creatorcontrib><creatorcontrib>CIRONI, Luisa</creatorcontrib><creatorcontrib>PROVERO, Paolo</creatorcontrib><creatorcontrib>TERCIER, Stéphane</creatorcontrib><creatorcontrib>JOSEPH, Jean-Marc</creatorcontrib><creatorcontrib>STEHLE, Jean-Christophe</creatorcontrib><creatorcontrib>BAUMER, Karine</creatorcontrib><creatorcontrib>KINDLER, Vincent</creatorcontrib><collection>Pascal-Francis</collection><collection>Medline</collection><collection>MEDLINE</collection><collection>MEDLINE (Ovid)</collection><collection>MEDLINE</collection><collection>MEDLINE</collection><collection>PubMed</collection><collection>CrossRef</collection><collection>MEDLINE - Academic</collection><jtitle>Cancer research (Chicago, Ill.)</jtitle></facets><delivery><delcategory>Remote Search Resource</delcategory><fulltext>fulltext</fulltext></delivery><addata><au>RIGGI, Nicolo</au><au>SUVA, Mario-Luca</au><au>STAMENKOVIC, Ivan</au><au>SUVA, Domizio</au><au>CIRONI, Luisa</au><au>PROVERO, Paolo</au><au>TERCIER, Stéphane</au><au>JOSEPH, Jean-Marc</au><au>STEHLE, Jean-Christophe</au><au>BAUMER, Karine</au><au>KINDLER, Vincent</au><format>journal</format><genre>article</genre><ristype>JOUR</ristype><atitle>EWS-FLI-1 Expression Triggers a Ewing's Sarcoma Initiation Program in Primary Human Mesenchymal Stem Cells</atitle><jtitle>Cancer research (Chicago, Ill.)</jtitle><addtitle>Cancer Res</addtitle><date>2008-04-01</date><risdate>2008</risdate><volume>68</volume><issue>7</issue><spage>2176</spage><epage>2185</epage><pages>2176-2185</pages><issn>0008-5472</issn><eissn>1538-7445</eissn><coden>CNREA8</coden><abstract>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.</abstract><cop>Philadelphia, PA</cop><pub>American Association for Cancer Research</pub><pmid>18381423</pmid><doi>10.1158/0008-5472.can-07-1761</doi><tpages>10</tpages><oa>free_for_read</oa></addata></record> |
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| subjects | Animals Antineoplastic agents Biological and medical sciences Bone Neoplasms - genetics Bone Neoplasms - metabolism Bone Neoplasms - pathology Cell Differentiation - physiology Diseases of the osteoarticular system Enhancer of Zeste Homolog 2 Protein Gene Expression Profiling Gene Expression Regulation, Neoplastic - genetics Histone-Lysine N-Methyltransferase Humans Immunocompromised Host Medical sciences Mesenchymal Stromal Cells - metabolism Mesenchymal Stromal Cells - pathology Mice Oncogene Proteins, Fusion - biosynthesis Oncogene Proteins, Fusion - genetics Pharmacology. Drug treatments Phenotype Polycomb Repressive Complex 2 Proteins - genetics Proto-Oncogene Protein c-fli-1 - biosynthesis Proto-Oncogene Protein c-fli-1 - genetics RNA, Messenger - biosynthesis RNA, Messenger - genetics RNA-Binding Protein EWS Sarcoma, Ewing - genetics Sarcoma, Ewing - metabolism Sarcoma, Ewing - pathology Soft Tissue Neoplasms - genetics Soft Tissue Neoplasms - metabolism Soft Tissue Neoplasms - pathology Tumors Tumors of striated muscle and skeleton |
| title | EWS-FLI-1 Expression Triggers a Ewing's Sarcoma Initiation Program in Primary Human Mesenchymal Stem Cells |
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