title: Premature termination of reprogramming in vivo leads to cancer development through altered epigenetic regulation.
abstract: 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 The Dox-withdrawn tumors arising in the kidney share a number of characteristics with Wilms tumor, a common pediatric kidney cancer. We also demonstrate that iPSCs derived from Dox-withdrawn kidney tumor cells give rise to nonneoplastic kidney cells in mice, proving that they have not undergone irreversible genetic transformation.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.
authors: Center for iPS Cell Research and Application (CiRA), Kyoto University, Kyoto 606-8507, Japan; Department of Medicine, Gifu University Graduate School of Medicine, Gifu 501-1194, Japan.
authors: Kotaro
authors: K
authors: Ohnishi
authors: Center for iPS Cell Research and Application (CiRA), Kyoto University, Kyoto 606-8507, Japan; Institute for Integrated Cell-Material Sciences (WPI-iCeMS), Kyoto University, Kyoto 606-8507, Japan.
authors: Katsunori
authors: K
authors: Semi
authors: Center for iPS Cell Research and Application (CiRA), Kyoto University, Kyoto 606-8507, Japan; Institute for Integrated Cell-Material Sciences (WPI-iCeMS), Kyoto University, Kyoto 606-8507, Japan.
authors: Takuya
authors: T
authors: Yamamoto
authors: Department of Medicine, Gifu University Graduate School of Medicine, Gifu 501-1194, Japan.
authors: Masahito
authors: M
authors: Shimizu
authors: Center for iPS Cell Research and Application (CiRA), Kyoto University, Kyoto 606-8507, Japan.
authors: Akito
authors: A
authors: Tanaka
authors: Center for iPS Cell Research and Application (CiRA), Kyoto University, Kyoto 606-8507, Japan.
authors: Kanae
authors: K
authors: Mitsunaga
authors: Center for iPS Cell Research and Application (CiRA), Kyoto University, Kyoto 606-8507, Japan.
authors: Keisuke
authors: K
authors: Okita
authors: Center for iPS Cell Research and Application (CiRA), Kyoto University, Kyoto 606-8507, Japan.
authors: Kenji
authors: K
authors: Osafune
authors: Center for iPS Cell Research and Application (CiRA), Kyoto University, Kyoto 606-8507, Japan.
authors: Yuko
authors: Y
authors: Arioka
authors: Division of Molecular Genetics and Epigenetics, Department of Biomolecular Sciences, Faculty of Medicine, Saga University, Saga 849-8501, Japan.
authors: Toshiyuki
authors: T
authors: Maeda
authors: Division of Molecular Genetics and Epigenetics, Department of Biomolecular Sciences, Faculty of Medicine, Saga University, Saga 849-8501, Japan.
authors: Hidenobu
authors: H
authors: Soejima
authors: Department of Medicine, Gifu University Graduate School of Medicine, Gifu 501-1194, Japan.
authors: Hisataka
authors: H
authors: Moriwaki
authors: Center for iPS Cell Research and Application (CiRA), Kyoto University, Kyoto 606-8507, Japan; Institute for Integrated Cell-Material Sciences (WPI-iCeMS), Kyoto University, Kyoto 606-8507, Japan; Gladstone Institute of Cardiovascular Disease, San Francisco, CA 94158, USA.
authors: Shinya
authors: S
authors: Yamanaka
authors: Center for iPS Cell Research and Application (CiRA), Kyoto University, Kyoto 606-8507, Japan; Hakubi Center for Advanced Research, Kyoto University, Kyoto 606-8507, Japan.
authors: Knut
authors: K
authors: Woltjen
authors: Center for iPS Cell Research and Application (CiRA), Kyoto University, Kyoto 606-8507, Japan; Institute for Integrated Cell-Material Sciences (WPI-iCeMS), Kyoto University, Kyoto 606-8507, Japan; PRESTO, Japan Science and Technology Agency, 4-1-8 Honcho Kawaguchi, Saitama, 332-0012, Japan. Electronic address: y-yamada@cira.kyoto-u.ac.jp.
authors: Yasuhiro
authors: Y
authors: Yamada
mesh_terms: D000818:Animals; D065150:Cellular Reprogramming; D019175:DNA Methylation; D004318:Doxycycline / Q000494:pharmacology; D044127:Epigenesis, Genetic; D015972:Gene Expression Regulation, Neoplastic; D057026:Induced Pluripotent Stem Cells / Q000166:cytology / Q000378:metabolism; D007680:Kidney Neoplasms / Q000139:chemically induced / Q000473:pathology*; D051379:Mice; D008822:Mice, Transgenic; D014157:Transcription Factors / Q000378:metabolism
chemical_list: D014157:Transcription Factors; D004318:Doxycycline