TY - JOUR
T1 - Aurora-A overexpression is linked to development of aggressive teratomas derived from human iPS cells
AU - Ohmine, Seiga
AU - Salisbury, Jeffrey L.
AU - Ingle, James
AU - Pettinato, Giuseppe
AU - Haddox, Candace L.
AU - Haddad, Tufia
AU - Galanis, Evanthia
AU - Ikeda, Yasuhiro
AU - D'Assoro, Antonino B.
N1 - Publisher Copyright:
© 2018 Elsevier B.V. All rights reserved.
PY - 2018/4
Y1 - 2018/4
N2 - The discovery of human induced pluripotent stem cells (hiPSCs) is a promising advancement in the field of regenerative and personalized medicine. Expression of SOX2, KLF4, OCT4 and MYC transcription factors induces the nuclear reprogramming of somatic cells into hiPSCs that share striking similarities with human embryonic stem cells (hESCs). However, several studies have demonstrated that hESCs and hiPSCs could lead to teratoma formation in vivo, thus limiting their current clinical applications. Aberrant cell cycle regulation of hESCs is linked to centrosome amplification, which may account, for their enhanced chromosomal instability (CIN), and thus increase their tumorigenicity. Significantly, the tumor suppressor p53 plays a key role as a 'guardian of reprogramming', safeguarding genomic integrity during hiPSC reprogramming. Nevertheless, the molecular mechanisms leading to development of CIN during reprogramming and increased tumorigenic potential of hiPSCs remains to be fully elucidated. In the present study, we analyzed CIN in hiPSCs derived from keratinocytes and established that chromosomal and mitotic aberrations were linked to centrosome amplification, Aurora-A overexpression, abrogation of p53-mediated G1/S cell cycle checkpoint and loss of Rb tumor-suppressor function. When hiPSCs were transplanted into the kidney capsules of immunocompromised mice, they developed high-grade teratomas characterized by the presence of cells that exhibited non-uniform shapes and sizes, high nuclear pleomorphism and centrosome amplification. Significantly, ex vivo cells derived from teratomas exhibited high self-renewal capacity that was linked to Aurora-A kinase activity and gave rise to lung metastasis when injected into the tail vein of immunocompromised mice. Collectively, these findings demonstrated a high risk for malignancy of hiPSCs that exhibit Aurora-A overexpression, loss of Rb function, centrosome amplification and CIN. Based on these findings, we proposed that Aurora-A-Targeted therapy could represent a promising prophylactic therapeutic strategy to decrease the likelihood of CIN and development of aggressive teratomas derived from hiPSCs.
AB - The discovery of human induced pluripotent stem cells (hiPSCs) is a promising advancement in the field of regenerative and personalized medicine. Expression of SOX2, KLF4, OCT4 and MYC transcription factors induces the nuclear reprogramming of somatic cells into hiPSCs that share striking similarities with human embryonic stem cells (hESCs). However, several studies have demonstrated that hESCs and hiPSCs could lead to teratoma formation in vivo, thus limiting their current clinical applications. Aberrant cell cycle regulation of hESCs is linked to centrosome amplification, which may account, for their enhanced chromosomal instability (CIN), and thus increase their tumorigenicity. Significantly, the tumor suppressor p53 plays a key role as a 'guardian of reprogramming', safeguarding genomic integrity during hiPSC reprogramming. Nevertheless, the molecular mechanisms leading to development of CIN during reprogramming and increased tumorigenic potential of hiPSCs remains to be fully elucidated. In the present study, we analyzed CIN in hiPSCs derived from keratinocytes and established that chromosomal and mitotic aberrations were linked to centrosome amplification, Aurora-A overexpression, abrogation of p53-mediated G1/S cell cycle checkpoint and loss of Rb tumor-suppressor function. When hiPSCs were transplanted into the kidney capsules of immunocompromised mice, they developed high-grade teratomas characterized by the presence of cells that exhibited non-uniform shapes and sizes, high nuclear pleomorphism and centrosome amplification. Significantly, ex vivo cells derived from teratomas exhibited high self-renewal capacity that was linked to Aurora-A kinase activity and gave rise to lung metastasis when injected into the tail vein of immunocompromised mice. Collectively, these findings demonstrated a high risk for malignancy of hiPSCs that exhibit Aurora-A overexpression, loss of Rb function, centrosome amplification and CIN. Based on these findings, we proposed that Aurora-A-Targeted therapy could represent a promising prophylactic therapeutic strategy to decrease the likelihood of CIN and development of aggressive teratomas derived from hiPSCs.
KW - Aurora-A
KW - Cell cycle checkpoint
KW - HiPSCs
KW - Metastasis
KW - Teratoma
UR - http://www.scopus.com/inward/record.url?scp=85042804555&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=85042804555&partnerID=8YFLogxK
U2 - 10.3892/or.2018.6239
DO - 10.3892/or.2018.6239
M3 - Article
C2 - 29393405
AN - SCOPUS:85042804555
SN - 1021-335X
VL - 39
SP - 1725
EP - 1730
JO - Oncology reports
JF - Oncology reports
IS - 4
ER -