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.
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.
Cell. 2014 Feb 13;156(4):663-77. doi: 10.1016/j.cell.2014.01.005.
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 The Dox-withdrawn tumors arising in the kidney share a number of characteristics with Wilms tumor, a common pediatric kidney cancer. We also demonstrate that iPSCs derived from Dox-withdrawn kidney tumor cells give rise to nonneoplastic kidney cells in mice, proving that they have not undergone irreversible genetic transformation.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.
癌症被认为主要是通过遗传突变的积累而产生的。虽然诱导多能干细胞（iPSC）的产生并不需要改变基因组序列，但 iPSC 获得了无限的生长潜力，这一特征与癌细胞相同。在这里，我们描述了一种在体内可以用强力霉素（Dox）来控制重编程因子表达的小鼠系统。值得注意的是，体内重编程因子的瞬时表达会导致各种组织中未分化的畸形细胞肿瘤的发展，这些细胞表现出 DNA 甲基化模式的全局变化。从肾脏中撤出 Dox 的肿瘤与儿童常见的肾母细胞瘤（Wilms 肿瘤）具有许多共同特征。我们还证明，从 Dox 撤出的肾肿瘤细胞衍生的 iPSC 在小鼠中产生非肿瘤性肾细胞，证明它们没有经历不可逆转的遗传转化。这些发现表明，与 iPSC 衍生相关的表观遗传调控可能会促使特定类型的癌症的发展。
