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Cell, Volume 156, Issue 4, 663-677, 13 February 2014
Authors
Kotaro Ohnishi,
Katsunori Semi,
Takuya Yamamoto,
Masahito Shimizu,
Akito Tanaka,
Kanae Mitsunaga,
Keisuke Okita,
Kenji Osafune,
Yuko Arioka,
Toshiyuki Maeda,
Hidenobu Soejima,
Hisataka Moriwaki,
Shinya Yamanaka,
Knut Woltjen,
Yasuhiro Yamada
Summary
Cancer is believed to arise primarily through
accumulation of genetic mutations. Although induced pluripotent stem
cell (iPSC) generation does not require changes in genomic sequence,
iPSCs acquire unlimited growth potential, a characteristic shared with
cancer cells. Here, we describe a murine system in which reprogramming
factor expression in vivo can be controlled temporally with doxycycline
(Dox). Notably, transient expression of reprogramming factors in vivo
results in tumor development in various tissues consisting of
undifferentiated dysplastic cells exhibiting global changes in DNA
methylation patterns. The Dox-withdrawn tumors arising in the kidney
share a number of characteristics with Wilms tumor, a common pediatric
kidney cancer. We also demonstrate that iPSCs derived from Dox-withdrawn
kidney tumor cells give rise to nonneoplastic kidney cells in mice,
proving that they have not undergone irreversible genetic
transformation. These findings suggest that epigenetic regulation
associated with iPSC derivation may drive development of particular
types of cancer.
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