Inducible expression of chimeric EWS/ETS proteins confers Ewing's family tumor-like phenotypes to human mesenchymal progenitor cells

Yoshitaka Miyagawa, Hajime Okita, Hideki Nakaijima, Yasuomi Horiuchi, Ban Sato, Tomoko Taguchi, Masashi Toyoda, Yohko U. Katagiri, Junichiro Fujimoto, Jun Ichi Hata, Akihiro Umezawa, Nobutaka Kiyokawa

Research output: Contribution to journalArticle

67 Citations (Scopus)

Abstract

Ewing's family tumor (EFT) is a rare pediatric tumor of unclear origin that occurs in bone and soft tissue. Specific chromosomal translocations found in EFT cause EWS to fuse to a subset of ets transcription factor genes (ETS), generating chimeric EWS/ETS proteins. These proteins are believed to play a crucial role in the onset and progression of EFT. However, the mechanisms responsible for the EWS/ETS-mediated onset remain unclear. Here we report the establishment of a tetracycline-controlled EWS/ETS-inducible system in human bone marrow-derived mesenchymal progenitor cells (MPCs). Ectopic expression of both EWS/FLI1 and EWS/ERG proteins resulted in a dramatic change of morphology, i.e., from a mesenchymal spindle shape to a small round-to-polygonal cell, one of the characteristics of EFT. EWS/ETS also induced immunophenotypic changes in MPCs, including the disappearance of the mesenchyme-positive markers CD10 and CD13 and the up-regulation of the EFT-positive markers CD54, CD99, CD117, and CD271. Furthermore, a prominent shift from the gene expression profile of MPCs to that of EFT was observed in the presence of EWS/ETS. Together with the observation that EWS/ETS enhances the ability of cells to invade Matrigel, these results suggest that EWS/ETS proteins contribute to alterations of cellular features and confer an EFT-like phenotype to human MPCs.

Original languageEnglish
Pages (from-to)2125-2137
Number of pages13
JournalMolecular and Cellular Biology
Volume28
Issue number7
DOIs
Publication statusPublished - 2008 Apr
Externally publishedYes

Fingerprint

RNA-Binding Protein EWS
Ewing's Sarcoma
Mesenchymal Stromal Cells
Phenotype
Proto-Oncogene Proteins c-ets
Genetic Translocation
Aptitude
Mesoderm
Tumor Biomarkers
Tetracycline
Transcriptome
Up-Regulation
Bone Marrow
Pediatrics
Bone and Bones

ASJC Scopus subject areas

  • Molecular Biology
  • Genetics
  • Cell Biology

Cite this

Inducible expression of chimeric EWS/ETS proteins confers Ewing's family tumor-like phenotypes to human mesenchymal progenitor cells. / Miyagawa, Yoshitaka; Okita, Hajime; Nakaijima, Hideki; Horiuchi, Yasuomi; Sato, Ban; Taguchi, Tomoko; Toyoda, Masashi; Katagiri, Yohko U.; Fujimoto, Junichiro; Hata, Jun Ichi; Umezawa, Akihiro; Kiyokawa, Nobutaka.

In: Molecular and Cellular Biology, Vol. 28, No. 7, 04.2008, p. 2125-2137.

Research output: Contribution to journalArticle

Miyagawa, Y, Okita, H, Nakaijima, H, Horiuchi, Y, Sato, B, Taguchi, T, Toyoda, M, Katagiri, YU, Fujimoto, J, Hata, JI, Umezawa, A & Kiyokawa, N 2008, 'Inducible expression of chimeric EWS/ETS proteins confers Ewing's family tumor-like phenotypes to human mesenchymal progenitor cells', Molecular and Cellular Biology, vol. 28, no. 7, pp. 2125-2137. https://doi.org/10.1128/MCB.00740-07
Miyagawa, Yoshitaka ; Okita, Hajime ; Nakaijima, Hideki ; Horiuchi, Yasuomi ; Sato, Ban ; Taguchi, Tomoko ; Toyoda, Masashi ; Katagiri, Yohko U. ; Fujimoto, Junichiro ; Hata, Jun Ichi ; Umezawa, Akihiro ; Kiyokawa, Nobutaka. / Inducible expression of chimeric EWS/ETS proteins confers Ewing's family tumor-like phenotypes to human mesenchymal progenitor cells. In: Molecular and Cellular Biology. 2008 ; Vol. 28, No. 7. pp. 2125-2137.
@article{248f12b81a4b4a22a1d2b9811d6ee796,
title = "Inducible expression of chimeric EWS/ETS proteins confers Ewing's family tumor-like phenotypes to human mesenchymal progenitor cells",
abstract = "Ewing's family tumor (EFT) is a rare pediatric tumor of unclear origin that occurs in bone and soft tissue. Specific chromosomal translocations found in EFT cause EWS to fuse to a subset of ets transcription factor genes (ETS), generating chimeric EWS/ETS proteins. These proteins are believed to play a crucial role in the onset and progression of EFT. However, the mechanisms responsible for the EWS/ETS-mediated onset remain unclear. Here we report the establishment of a tetracycline-controlled EWS/ETS-inducible system in human bone marrow-derived mesenchymal progenitor cells (MPCs). Ectopic expression of both EWS/FLI1 and EWS/ERG proteins resulted in a dramatic change of morphology, i.e., from a mesenchymal spindle shape to a small round-to-polygonal cell, one of the characteristics of EFT. EWS/ETS also induced immunophenotypic changes in MPCs, including the disappearance of the mesenchyme-positive markers CD10 and CD13 and the up-regulation of the EFT-positive markers CD54, CD99, CD117, and CD271. Furthermore, a prominent shift from the gene expression profile of MPCs to that of EFT was observed in the presence of EWS/ETS. Together with the observation that EWS/ETS enhances the ability of cells to invade Matrigel, these results suggest that EWS/ETS proteins contribute to alterations of cellular features and confer an EFT-like phenotype to human MPCs.",
author = "Yoshitaka Miyagawa and Hajime Okita and Hideki Nakaijima and Yasuomi Horiuchi and Ban Sato and Tomoko Taguchi and Masashi Toyoda and Katagiri, {Yohko U.} and Junichiro Fujimoto and Hata, {Jun Ichi} and Akihiro Umezawa and Nobutaka Kiyokawa",
year = "2008",
month = "4",
doi = "10.1128/MCB.00740-07",
language = "English",
volume = "28",
pages = "2125--2137",
journal = "Molecular and Cellular Biology",
issn = "0270-7306",
publisher = "American Society for Microbiology",
number = "7",

}

TY - JOUR

T1 - Inducible expression of chimeric EWS/ETS proteins confers Ewing's family tumor-like phenotypes to human mesenchymal progenitor cells

AU - Miyagawa, Yoshitaka

AU - Okita, Hajime

AU - Nakaijima, Hideki

AU - Horiuchi, Yasuomi

AU - Sato, Ban

AU - Taguchi, Tomoko

AU - Toyoda, Masashi

AU - Katagiri, Yohko U.

AU - Fujimoto, Junichiro

AU - Hata, Jun Ichi

AU - Umezawa, Akihiro

AU - Kiyokawa, Nobutaka

PY - 2008/4

Y1 - 2008/4

N2 - Ewing's family tumor (EFT) is a rare pediatric tumor of unclear origin that occurs in bone and soft tissue. Specific chromosomal translocations found in EFT cause EWS to fuse to a subset of ets transcription factor genes (ETS), generating chimeric EWS/ETS proteins. These proteins are believed to play a crucial role in the onset and progression of EFT. However, the mechanisms responsible for the EWS/ETS-mediated onset remain unclear. Here we report the establishment of a tetracycline-controlled EWS/ETS-inducible system in human bone marrow-derived mesenchymal progenitor cells (MPCs). Ectopic expression of both EWS/FLI1 and EWS/ERG proteins resulted in a dramatic change of morphology, i.e., from a mesenchymal spindle shape to a small round-to-polygonal cell, one of the characteristics of EFT. EWS/ETS also induced immunophenotypic changes in MPCs, including the disappearance of the mesenchyme-positive markers CD10 and CD13 and the up-regulation of the EFT-positive markers CD54, CD99, CD117, and CD271. Furthermore, a prominent shift from the gene expression profile of MPCs to that of EFT was observed in the presence of EWS/ETS. Together with the observation that EWS/ETS enhances the ability of cells to invade Matrigel, these results suggest that EWS/ETS proteins contribute to alterations of cellular features and confer an EFT-like phenotype to human MPCs.

AB - Ewing's family tumor (EFT) is a rare pediatric tumor of unclear origin that occurs in bone and soft tissue. Specific chromosomal translocations found in EFT cause EWS to fuse to a subset of ets transcription factor genes (ETS), generating chimeric EWS/ETS proteins. These proteins are believed to play a crucial role in the onset and progression of EFT. However, the mechanisms responsible for the EWS/ETS-mediated onset remain unclear. Here we report the establishment of a tetracycline-controlled EWS/ETS-inducible system in human bone marrow-derived mesenchymal progenitor cells (MPCs). Ectopic expression of both EWS/FLI1 and EWS/ERG proteins resulted in a dramatic change of morphology, i.e., from a mesenchymal spindle shape to a small round-to-polygonal cell, one of the characteristics of EFT. EWS/ETS also induced immunophenotypic changes in MPCs, including the disappearance of the mesenchyme-positive markers CD10 and CD13 and the up-regulation of the EFT-positive markers CD54, CD99, CD117, and CD271. Furthermore, a prominent shift from the gene expression profile of MPCs to that of EFT was observed in the presence of EWS/ETS. Together with the observation that EWS/ETS enhances the ability of cells to invade Matrigel, these results suggest that EWS/ETS proteins contribute to alterations of cellular features and confer an EFT-like phenotype to human MPCs.

UR - http://www.scopus.com/inward/record.url?scp=41149089612&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=41149089612&partnerID=8YFLogxK

U2 - 10.1128/MCB.00740-07

DO - 10.1128/MCB.00740-07

M3 - Article

VL - 28

SP - 2125

EP - 2137

JO - Molecular and Cellular Biology

JF - Molecular and Cellular Biology

SN - 0270-7306

IS - 7

ER -