Division of Genome Stability Research, National Cancer Center Research Institute, 5-1-1 Tsukiji, Chuo-ku, Tokyo 104-0045, Japan.
J Biol Chem. 2012 Oct 26;287(44):36777-91. doi: 10.1074/jbc.M112.372557. Epub 2012 Sep 7.
Stem cell maintenance depends on their surrounding microenvironment, and aberrancies in the environment have been associated with tumorigenesis. However, it remains to be elucidated whether an environmental aberrancy can act as a carcinogenic stress for cellular transformation of differentiating stem cells into cancer stem cells. Here, utilizing mouse embryonic stem cells as a model, it was illustrated that environmental aberrancy during differentiation leads to the emergence of pluripotent cells showing cancerous characteristics. Analogous to precancerous stages, DNA lesions were spontaneously accumulated during embryonic stem cell differentiation under aberrational environments, which activates barrier responses such as senescence and apoptosis. However, overwhelming such barrier responses, piled-up spheres were subsequently induced from the previously senescent cells. The sphere cells exhibit aneuploidy and dysfunction of the Arf-p53 module as well as enhanced tumorigenicity and a strong self-renewal capacity, suggesting development of cancerous stem cells. Our current study suggests that stem cells differentiating in an aberrational environment are at risk of cellular transformation into malignant counterparts.
干细胞的维持依赖于其周围的微环境，而环境异常与肿瘤发生有关。然而，环境异常是否可以作为一种致癌应激，将分化的干细胞转化为癌症干细胞，仍有待阐明。在这里，利用小鼠胚胎干细胞作为模型，说明了分化过程中的环境异常会导致出现具有癌症特征的多能细胞。类似于癌前阶段，在异常环境下胚胎干细胞分化过程中会自发积累 DNA 损伤，从而激活衰老和凋亡等屏障反应。然而，这些屏障反应被压倒后，先前衰老的细胞会随后诱导出堆积的球体。这些球体细胞表现出非整倍体和 Arf-p53 模块功能障碍，以及增强的肿瘤发生能力和强大的自我更新能力，提示癌症干细胞的发展。我们的研究表明，在异常环境中分化的干细胞有转化为恶性细胞的风险。
