Dedifferentiation process driven by TGF-beta signaling enhances stem cell properties in human colorectal cancer
Dedifferentiation process driven by TGF-beta signaling enhances stem cell properties in human colorectal cancer
复制标题
DOI：
10.1038/s41388-018-0480-0
复制
发表时间：
2019-02-07
期刊：
影响因子：
8
通讯作者：
Akashi, Koichi
中科院分区：
文献类型：
--
作者：
Nakano, Michitaka;Kikushige, Yoshikane;Akashi, Koichi
癌症干细胞 (CSC) 具有自我更新的能力和分化为非 CSC 的潜力。最近发现的 CSC 和非 CSC 之间的动态平衡揭示了非 CSC 中获得 CSC 样特性作为癌症进展的重要过程的重要性。获得 CSC 样特性的机制主要是在上皮-间质转化的背景下进行研究。在这里，我们证明去分化过程可能是人类结直肠癌细胞获得 CSC 样特性的另一种机制。通过探索从CD44(+) CSCs发育而来的类器官的单细胞基因表达分析，我们确定TWIST1是维持癌细胞未分化状态的关键分子。与这一发现一致的是，我们利用基于微阵列的基因表达分析和定量病理成像系统发现，TWIST1的调节因子TGF-β信号通路在人结直肠癌未分化CD44(+) CSCs中被特异性激活。此外，我们发现TGF-β的外部刺激和TWIST1的诱导将CD44(-)非CSC转化为未分化的CD44(+)CSC，导致异种移植模型中CSC的显着增加。这项研究强烈表明，TGF-β 信号驱动的去分化可增强人类结直肠癌的干细胞特性。
Cancer stem cells (CSCs) possess the capacity for self-renewal and the potential to differentiate into non-CSCs. The recent discoveries of dynamic equilibrium between CSCs and non-CSCs revealed the significance of acquiring CSC-like properties in non-CSCs as an important process in progression of cancer. The mechanism underlying acquisition of CSC-like properties has mainly been investigated in the context of epithelial-mesenchymal transition. Here, we demonstrate the dedifferentiation process may be an alternative mechanism in acquisition of CSC-like properties in human colorectal cancer cells. By exploring the single-cell gene expression analysis of organoids developed from CD44(+) CSCs, we identified TWIST1 as a key molecule for maintaining the undifferentiated state of cancer cells. Consistent with the finding, we found that TGF-beta signaling pathway, a regulator of TWIST1, was specifically activated in the undifferentiated CD44(+) CSCs in human colorectal cancer using microarray-based gene expression analysis and quantitative pathology imaging system. Furthermore, we showed that external stimulation with TGF-beta and the induction of TWIST1 converted CD44(-) non-CSCs into the undifferentiated CD44(+) CSCs, leading to the significant increment of CSCs in xenograft models. This study strongly suggests dedifferentiation driven by TGF-beta signaling enhances stem cell properties in human colorectal cancer.