Department of Cell Biology, Faculty of Biology, University of Bielefeld, Universitätsstrasse 25, 33615 Bielefeld, Germany.
Forschungsverbund BioMedizin Bielefeld/OWL FBMB e.V., 33615 Bielefeld, Germany.
Int J Mol Sci. 2022 Feb 22;23(5):2426. doi: 10.3390/ijms23052426.
Cancer stem cells (CSCs) are a small subpopulation of tumor cells harboring properties that include self-renewal, multi-lineage differentiation, tumor reconstitution, drug resistance and invasiveness, making them key players in tumor relapse. In the present paper, we develop new CSC models and analyze the molecular pathways involved in survival to identify targets for the establishment of novel therapies. Endometrial carcinoma-derived stem-like cells (ECSCs) were isolated from carcinogenic gynecological tissue and analyzed regarding their expression of prominent CSC markers. Further, they were treated with the MYC-signaling inhibitor KJ-Pyr-9, chemotherapeutic agent carboplatin and type II diabetes medication metformin. ECSC populations express common CSC markers, such as Prominin-1 and CD44 antigen as well as epithelial-to-mesenchymal transition markers, Twist, Snail and Slug, and exhibit the ability to form free-floating spheres. The inhibition of MYC signaling and treatment with carboplatin as well as metformin significantly reduced the cell survival of ECSC-like cells. Further, treatment with metformin significantly decreased the mitochondrial membrane potential of ECSC-like cells, while the extracellular lactate concentration was increased. The established ECSC-like populations represent promising in vitro models to further study the contribution of ECSCs to endometrial carcinogenesis. Targeting MYC signaling as well as mitochondrial bioenergetics has shown promising results in the diminishment of ECSCs, although molecular signaling pathways need further investigations.
癌症干细胞（CSCs）是肿瘤细胞中的一小部分亚群，具有自我更新、多谱系分化、肿瘤重建、耐药性和侵袭性等特性，是肿瘤复发的关键因素。在本文中，我们建立了新的 CSC 模型，并分析了涉及存活的分子途径，以确定建立新疗法的靶点。我们从致癌妇科组织中分离出子宫内膜癌衍生的干细胞样细胞（ECSCs），并分析其是否表达突出的 CSC 标志物。此外，还对 ECSC 进行了 MYC 信号抑制剂 KJ-Pyr-9、化疗药物卡铂和 2 型糖尿病药物二甲双胍的处理。ECSC 群体表达常见的 CSC 标志物，如 Prominin-1 和 CD44 抗原以及上皮间质转化标志物 Twist、Snail 和 Slug，并具有形成自由浮动球体的能力。抑制 MYC 信号以及用卡铂和二甲双胍处理可显著降低 ECSC 样细胞的存活率。此外，二甲双胍处理可显著降低 ECSC 样细胞的线粒体膜电位，同时增加细胞外乳酸浓度。建立的 ECSC 样群体代表了进一步研究 ECSC 对子宫内膜癌发生的有前途的体外模型。尽管分子信号通路需要进一步研究，但靶向 MYC 信号和线粒体生物能学已显示出减少 ECSC 的可喜结果。
