Whitehead Institute for Biomedical Research, Cambridge, MA 02142, USA.
Cell. 2013 Jul 3;154(1):61-74. doi: 10.1016/j.cell.2013.06.005.
The recent discovery that normal and neoplastic epithelial cells re-enter the stem cell state raised the intriguing possibility that the aggressiveness of carcinomas derives not from their existing content of cancer stem cells (CSCs) but from their proclivity to generate new CSCs from non-CSC populations. Here, we demonstrate that non-CSCs of human basal breast cancers are plastic cell populations that readily switch from a non-CSC to CSC state. The observed cell plasticity is dependent on ZEB1, a key regulator of the epithelial-mesenchymal transition. We find that plastic non-CSCs maintain the ZEB1 promoter in a bivalent chromatin configuration, enabling them to respond readily to microenvironmental signals, such as TGFβ. In response, the ZEB1 promoter converts from a bivalent to active chromatin configuration, ZEB1 transcription increases, and non-CSCs subsequently enter the CSC state. Our findings support a dynamic model in which interconversions between low and high tumorigenic states occur frequently, thereby increasing tumorigenic and malignant potential.
最近的发现表明，正常和肿瘤上皮细胞重新进入干细胞状态，这提出了一个有趣的可能性，即癌细胞的侵袭性不是来自其现有的癌症干细胞（CSC）含量，而是来自其从非 CSC 群体产生新的 CSC 的倾向。在这里，我们证明了人基底乳腺癌的非 CSC 是具有可塑性的细胞群体，它们很容易从非 CSC 状态转变为 CSC 状态。观察到的细胞可塑性依赖于 ZEB1，这是上皮-间充质转化的关键调节剂。我们发现，具有可塑性的非 CSC 保持 ZEB1 启动子处于双价染色质构型，使它们能够对 TGFβ等微环境信号做出快速反应。作为响应，ZEB1 启动子从双价转变为活性染色质构型，ZEB1 转录增加，随后非 CSC 进入 CSC 状态。我们的研究结果支持一个动态模型，其中低和高肿瘤发生状态之间经常发生相互转换，从而增加了肿瘤发生和恶性的潜力。
