Inducible expression of chimeric EWS/ETS proteins confers Ewing's family tumor-like phenotypes to human mesenchymal progenitor cells.
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.
Miyagawa
Yoshitaka
Y
Department of Developmental Biology, National Research Institute for Child Health and Development, 2-10-1, Okura, Setagaya-ku, Tokyo 157-8535, Japan.
Okita
Hajime
H
Nakaijima
Hideki
H
Horiuchi
Yasuomi
Y
Sato
Ban
B
Taguchi
Tomoko
T
Toyoda
Masashi
M
Katagiri
Yohko U
YU
Fujimoto
Junichiro
J
Hata
Jun-Ichi
J
Umezawa
Akihiro
A
Kiyokawa
Nobutaka
N
D015703:Antigens, CD / Q000096:biosynthesis; D002461:Cell Line, Transformed / Q000166:cytology / Q000378:metabolism; D002465:Cell Movement; D048430:Cell Shape; D003094:Collagen; D004318:Doxycycline / Q000494:pharmacology; D004338:Drug Combinations; D015972:Gene Expression Regulation, Neoplastic; D005813:Genes, Synthetic; D006801:Humans; D016130:Immunophenotyping; D007797:Laminin; D059630:Mesenchymal Stem Cells / Q000166:cytology* / Q000187:drug effects / Q000378:metabolism; D014411:Neoplastic Stem Cells / Q000166:cytology* / Q000378:metabolism; D015514:Oncogene Proteins, Fusion / Q000235:genetics / Q000502:physiology*; D011509:Proteoglycans; D051789:Proto-Oncogene Protein c-fli-1 / Q000235:genetics / Q000502:physiology*; D034802:RNA-Binding Protein EWS; D011993:Recombinant Fusion Proteins / Q000502:physiology; D012512:Sarcoma, Ewing / Q000378:metabolism / Q000473:pathology*; D013752:Tetracycline / Q000494:pharmacology; D014157:Transcription Factors / Q000235:genetics / Q000502:physiology*
D015703:Antigens, CD; D004338:Drug Combinations; C450460:EWS-ERG fusion protein, human; C106031:EWS-FLI fusion protein; D007797:Laminin; D015514:Oncogene Proteins, Fusion; D011509:Proteoglycans; D051789:Proto-Oncogene Protein c-fli-1; D034802:RNA-Binding Protein EWS; D011993:Recombinant Fusion Proteins; D014157:Transcription Factors; C059485:matrigel; D003094:Collagen; D013752:Tetracycline; D004318:Doxycycline