TY - JOUR
T1 - Characterization of common marmoset dysgerminoma-like tumor induced by the lentiviral expression of reprogramming factors
AU - Yamaguchi, Saori
AU - Marumoto, Tomotoshi
AU - Nii, Takenobu
AU - Kawano, Hirotaka
AU - Liao, Jiyuan
AU - Nagai, Yoko
AU - Okada, Michiyo
AU - Takahashi, Atsushi
AU - Inoue, Hiroyuki
AU - Sasaki, Erika
AU - Fujii, Hiroshi
AU - Okano, Shinji
AU - Ebise, Hayao
AU - Sato, Tetsuya
AU - Suyama, Mikita
AU - Okano, Hideyuki
AU - Miura, Yoshie
AU - Tani, Kenzaburo
PY - 2014/4
Y1 - 2014/4
N2 - Recent generation of induced pluripotent stem (iPSCs) has made a significant impact on the field of human regenerative medicine. Prior to the clinical application of iPSCs, testing of their safety and usefulness must be carried out using reliable animal models of various diseases. In order to generate iPSCs from common marmoset (CM; Callithrix jacchus), one of the most useful experimental animals, we have lentivirally transduced reprogramming factors, including POU5F1 (also known as OCT3/4), SOX2, KLF4, and c-MYC into CM fibroblasts. The cells formed round colonies expressing embryonic stem cell markers, however, they showed an abnormal karyotype denoted as 46, X, del(4q), +mar, and formed human dysgerminoma-like tumors in SCID mice, indicating that the transduction of reprogramming factors caused unexpected tumorigenesis of CM cells. Moreover, CM dysgerminoma-like tumors were highly sensitive to DNA-damaging agents, irradiation, and fibroblast growth factor receptor inhibitor, and their growth was dependent on c-MYC expression. These results indicate that DNA-damaging agents, irradiation, fibroblast growth factor receptor inhibitor, and c-MYC-targeted therapies might represent effective treatment strategies for unexpected tumors in patients receiving iPSC-based therapy. Reprogramming factors for iPSC generation can be oncogenic, and thus reprogramming factor transduced cells might have tumorigenic potential. Here we characterized common marmoset dysgerminoma like tumor, CM DGs, generated by the lentivirally transduced reprogramming factors into fibroblasts. The growth of CM DGs was dependent on c-MYC expression and bFGF signaling. Moreover CM DGs were highly sensitive to DNA damaging agents, irradiation and FGFR inhibitors. Therefore irradiation, DNA damaging agents and FGFR inhibitors might be effective for controlling reprogramming factor related tumors that may be found in patients treated with iPSC-based medicine.
AB - Recent generation of induced pluripotent stem (iPSCs) has made a significant impact on the field of human regenerative medicine. Prior to the clinical application of iPSCs, testing of their safety and usefulness must be carried out using reliable animal models of various diseases. In order to generate iPSCs from common marmoset (CM; Callithrix jacchus), one of the most useful experimental animals, we have lentivirally transduced reprogramming factors, including POU5F1 (also known as OCT3/4), SOX2, KLF4, and c-MYC into CM fibroblasts. The cells formed round colonies expressing embryonic stem cell markers, however, they showed an abnormal karyotype denoted as 46, X, del(4q), +mar, and formed human dysgerminoma-like tumors in SCID mice, indicating that the transduction of reprogramming factors caused unexpected tumorigenesis of CM cells. Moreover, CM dysgerminoma-like tumors were highly sensitive to DNA-damaging agents, irradiation, and fibroblast growth factor receptor inhibitor, and their growth was dependent on c-MYC expression. These results indicate that DNA-damaging agents, irradiation, fibroblast growth factor receptor inhibitor, and c-MYC-targeted therapies might represent effective treatment strategies for unexpected tumors in patients receiving iPSC-based therapy. Reprogramming factors for iPSC generation can be oncogenic, and thus reprogramming factor transduced cells might have tumorigenic potential. Here we characterized common marmoset dysgerminoma like tumor, CM DGs, generated by the lentivirally transduced reprogramming factors into fibroblasts. The growth of CM DGs was dependent on c-MYC expression and bFGF signaling. Moreover CM DGs were highly sensitive to DNA damaging agents, irradiation and FGFR inhibitors. Therefore irradiation, DNA damaging agents and FGFR inhibitors might be effective for controlling reprogramming factor related tumors that may be found in patients treated with iPSC-based medicine.
KW - Common marmoset
KW - FGFR
KW - Regenerating medicine
KW - Reprogramming factor
KW - Tumorigenesis
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UR - http://www.scopus.com/inward/citedby.url?scp=84898474409&partnerID=8YFLogxK
U2 - 10.1111/cas.12367
DO - 10.1111/cas.12367
M3 - Article
C2 - 24521492
AN - SCOPUS:84898474409
SN - 1347-9032
VL - 105
SP - 402
EP - 408
JO - Cancer science
JF - Cancer science
IS - 4
ER -
