In vitro evidence for senescent multinucleated melanocytes as a source for tumor-initiating cells.
In vitro evidence for senescent multinucleated melanocytes as a source for tumor-initiating cells.
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DOI：
10.1038/cddis.2015.71
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发表时间：
2015-04-02
影响因子：
9
通讯作者：
Meierjohann S
中科院分区：
文献类型：
--
作者：
Leikam C;Hufnagel AL;Otto C;Murphy DJ;Mühling B;Kneitz S;Nanda I;Schmid M;Wagner TU;Haferkamp S;Bröcker EB;Schartl M;Meierjohann S
黑素细胞中的致癌信号传导导致癌基因诱导的衰老（OIS），这是一种稳定的细胞周期停滞，通常以双核或多核表型为特征，被认为是癌症进展的障碍。然而，长期以来人们一直坚信衰老是一个真正不可逆转的过程，但最近却受到了挑战。尽管如此，尚不清楚被驱动进入 OIS 的细胞是否会发展为癌症，从而构成潜在威胁。在这里，我们发现黑色素瘤癌基因 N-RAS61K 在色素细胞中的延长表达通过触发衰老细胞中肿瘤起始单核干细胞的出现来克服 OIS。该后代是去分化的、高度增殖的、抗失巢凋亡的，并诱导快速生长的转移性肿瘤。我们的数据描述了被癌基因驱动进入衰老状态的分化细胞利用这种衰老状态作为肿瘤转化的触发因素，从而产生高度侵袭性的肿瘤起始细胞。这些观察结果为在细胞水平上逃避 OIS 并随后发生转化提供了第一个体外实验证据。
Oncogenic signaling in melanocytes results in oncogene-induced senescence (OIS), a stable cell-cycle arrest frequently characterized by a bi- or multinuclear phenotype that is considered as a barrier to cancer progression. However, the long-sustained conviction that senescence is a truly irreversible process has recently been challenged. Still, it is not known whether cells driven into OIS can progress to cancer and thereby pose a potential threat. Here, we show that prolonged expression of the melanoma oncogene N-RAS61K in pigment cells overcomes OIS by triggering the emergence of tumor-initiating mononucleated stem-like cells from senescent cells. This progeny is dedifferentiated, highly proliferative, anoikis-resistant and induces fast growing, metastatic tumors. Our data describe that differentiated cells, which are driven into senescence by an oncogene, use this senescence state as trigger for tumor transformation, giving rise to highly aggressive tumor-initiating cells. These observations provide the first experimental in vitro evidence for the evasion of OIS on the cellular level and ensuing transformation.