Institute of Clinical Medical Sciences, China-Japan Friendship Hospital, Beijing 100029, PR China.
Cell Death Dis. 2013 Oct 17;4(10):e857. doi: 10.1038/cddis.2013.340.
Cancer stem cells (CSCs) are believed to be a promising target for cancer therapy because these cells are responsible for tumor development, maintenance and chemotherapy resistance. Finding out the critical factors regulating CSC fate is the key for target therapy of CSCs. Just as normal stem cells are regulated by their microenvironment (niche), CSCs are also regulated by cells in the tumor microenvironment. However, whether various tumor microenvironments can induce CSCs to differentiate into different cancer cells is not clear. Here, we show that single-cell-cloned CSCs, accidentally obtained from a human liver cancer microvascular endothelial cells, express classic stem cell markers, genes associated with self-renewal and pluripotent factors and possess colony-forming ability in vitro and the ability of serial transplantation in vivo. The single-cell-cloned CSCs treated with the different tumor cell/tissue-derived conditioned culture medium, which is a mimic of carcinoma microenvironment, could differentiate into corresponding tumor cells and express specific markers of the respective type of tumor cells at the gene, protein and cell levels, respectively. Interestingly, this multilineage differentiation potential of single-cell-cloned liver CSCs sharply declined after the specific knockdown of octamer-binding transcription factor 4 (Oct4) alone, even though they were under the same induction conditions (carcinoma microenvironments). These data support the hypothesis that single-cell-cloned liver CSCs have the potential of differentiating into different types of tumor cells, and the tumor microenvironment does play a crucial role in deciding differentiation directions. Simultaneously, Oct4 in CSCs is indispensable in this process. These factors are promising targets for liver CSC-specific therapy.
癌症干细胞（CSC）被认为是癌症治疗的有前途的靶点，因为这些细胞负责肿瘤的发展、维持和化疗耐药性。找出调节 CSC 命运的关键因素是 CSC 靶向治疗的关键。就像正常干细胞受到其微环境（龛）的调节一样，CSC 也受到肿瘤微环境中细胞的调节。然而，各种肿瘤微环境是否能诱导 CSC 分化为不同的癌细胞尚不清楚。在这里，我们显示从人肝癌微血管内皮细胞中偶然获得的单细胞克隆 CSC 表达经典的干细胞标记物、与自我更新和多能因子相关的基因，并具有体外集落形成能力和体内连续移植能力。用不同的肿瘤细胞/组织衍生的条件培养基处理单细胞克隆 CSC，这是癌微环境的模拟物，可以分别分化为相应的肿瘤细胞，并在基因、蛋白和细胞水平上分别表达各自类型肿瘤细胞的特异性标记物。有趣的是，即使在相同的诱导条件（癌微环境）下，单细胞克隆肝 CSC 中八聚体结合转录因子 4（Oct4）的特异性敲低，会使它们的多谱系分化潜能急剧下降。这些数据支持了这样的假设，即单细胞克隆肝 CSC 具有分化为不同类型肿瘤细胞的潜力，肿瘤微环境在决定分化方向方面起着至关重要的作用。同时，CSC 中的 Oct4 在这个过程中是不可或缺的。这些因素是肝 CSC 特异性治疗的有前途的靶点。
