Modeling initiation of Ewing sarcoma in human neural crest cells.
Ewing sarcoma family tumors (ESFT) are aggressive bone and soft tissue tumors that express EWS-ETS fusion genes as driver mutations. Although the histogenesis of ESFT is controversial, mesenchymal (MSC) and/or neural crest (NCSC) stem cells have been implicated as cells of origin. For the current st...
| Main Authors: | , , , , , , , |
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| Format: | Article |
| Language: | English |
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Public Library of Science (PLoS)
2011-04-01
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| Series: | PLoS ONE |
| Online Access: | http://europepmc.org/articles/PMC3084816?pdf=render |
| _version_ | 1818839937625096192 |
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| author | Cornelia von Levetzow Xiaohua Jiang Ynnez Gwye Gregor von Levetzow Long Hung Aaron Cooper Jessie Hao-Ru Hsu Elizabeth R Lawlor |
| author_facet | Cornelia von Levetzow Xiaohua Jiang Ynnez Gwye Gregor von Levetzow Long Hung Aaron Cooper Jessie Hao-Ru Hsu Elizabeth R Lawlor |
| author_sort | Cornelia von Levetzow |
| collection | DOAJ |
| description | Ewing sarcoma family tumors (ESFT) are aggressive bone and soft tissue tumors that express EWS-ETS fusion genes as driver mutations. Although the histogenesis of ESFT is controversial, mesenchymal (MSC) and/or neural crest (NCSC) stem cells have been implicated as cells of origin. For the current study we evaluated the consequences of EWS-FLI1 expression in human embryonic stem cell-derived NCSC (hNCSC). Ectopic expression of EWS-FLI1 in undifferentiated hNCSC and their neuro-mesenchymal stem cell (hNC-MSC) progeny was readily tolerated and led to altered expression of both well established as well as novel EWS-FLI1 target genes. Importantly, whole genome expression profiling studies revealed that the molecular signature of established ESFT is more similar to hNCSC than any other normal tissue, including MSC, indicating that maintenance or reactivation of the NCSC program is a feature of ESFT pathogenesis. Consistent with this hypothesis, EWS-FLI1 induced hNCSC genes as well as the polycomb proteins BMI-1 and EZH2 in hNC-MSC. In addition, up-regulation of BMI-1 was associated with avoidance of cellular senescence and reversible silencing of p16. Together these studies confirm that, unlike terminally differentiated cells but consistent with bone marrow-derived MSC, NCSC tolerate expression of EWS-FLI1 and ectopic expression of the oncogene initiates transition to an ESFT-like state. In addition, to our knowledge this is the first demonstration that EWS-FLI1-mediated induction of BMI-1 and epigenetic silencing of p16 might be critical early initiating events in ESFT tumorigenesis. |
| first_indexed | 2024-12-19T04:02:14Z |
| format | Article |
| id | doaj.art-60c32db8fc7b4c2c8959a9a49c4ab72a |
| institution | Directory Open Access Journal |
| issn | 1932-6203 |
| language | English |
| last_indexed | 2024-12-19T04:02:14Z |
| publishDate | 2011-04-01 |
| publisher | Public Library of Science (PLoS) |
| record_format | Article |
| series | PLoS ONE |
| spelling | doaj.art-60c32db8fc7b4c2c8959a9a49c4ab72a2022-12-21T20:36:38ZengPublic Library of Science (PLoS)PLoS ONE1932-62032011-04-0164e1930510.1371/journal.pone.0019305Modeling initiation of Ewing sarcoma in human neural crest cells.Cornelia von LevetzowXiaohua JiangYnnez GwyeGregor von LevetzowLong HungAaron CooperJessie Hao-Ru HsuElizabeth R LawlorEwing sarcoma family tumors (ESFT) are aggressive bone and soft tissue tumors that express EWS-ETS fusion genes as driver mutations. Although the histogenesis of ESFT is controversial, mesenchymal (MSC) and/or neural crest (NCSC) stem cells have been implicated as cells of origin. For the current study we evaluated the consequences of EWS-FLI1 expression in human embryonic stem cell-derived NCSC (hNCSC). Ectopic expression of EWS-FLI1 in undifferentiated hNCSC and their neuro-mesenchymal stem cell (hNC-MSC) progeny was readily tolerated and led to altered expression of both well established as well as novel EWS-FLI1 target genes. Importantly, whole genome expression profiling studies revealed that the molecular signature of established ESFT is more similar to hNCSC than any other normal tissue, including MSC, indicating that maintenance or reactivation of the NCSC program is a feature of ESFT pathogenesis. Consistent with this hypothesis, EWS-FLI1 induced hNCSC genes as well as the polycomb proteins BMI-1 and EZH2 in hNC-MSC. In addition, up-regulation of BMI-1 was associated with avoidance of cellular senescence and reversible silencing of p16. Together these studies confirm that, unlike terminally differentiated cells but consistent with bone marrow-derived MSC, NCSC tolerate expression of EWS-FLI1 and ectopic expression of the oncogene initiates transition to an ESFT-like state. In addition, to our knowledge this is the first demonstration that EWS-FLI1-mediated induction of BMI-1 and epigenetic silencing of p16 might be critical early initiating events in ESFT tumorigenesis.http://europepmc.org/articles/PMC3084816?pdf=render |
| spellingShingle | Cornelia von Levetzow Xiaohua Jiang Ynnez Gwye Gregor von Levetzow Long Hung Aaron Cooper Jessie Hao-Ru Hsu Elizabeth R Lawlor Modeling initiation of Ewing sarcoma in human neural crest cells. PLoS ONE |
| title | Modeling initiation of Ewing sarcoma in human neural crest cells. |
| title_full | Modeling initiation of Ewing sarcoma in human neural crest cells. |
| title_fullStr | Modeling initiation of Ewing sarcoma in human neural crest cells. |
| title_full_unstemmed | Modeling initiation of Ewing sarcoma in human neural crest cells. |
| title_short | Modeling initiation of Ewing sarcoma in human neural crest cells. |
| title_sort | modeling initiation of ewing sarcoma in human neural crest cells |
| url | http://europepmc.org/articles/PMC3084816?pdf=render |
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