Sheta Mona, Hassan Ghmkin, Afify Said M, Monzur Sadia, Kumon Kazuki, Abu Quora Hagar A, Farahat Mahmoud, Zahra Maram H, Fu Xiaoying, Seno Akimasa, Seno Masaharu
Department of Nano-Biotechnology, Graduate School of Interdisciplinary Science and Engineering in Health Systems, Okayama University, Okayama, Japan; Department of Cancer Biology, National Cancer Institute, Cairo University, Cairo, Egypt.
Department of Nano-Biotechnology, Graduate School of Interdisciplinary Science and Engineering in Health Systems, Okayama University, Okayama, Japan; Department of Microbiology and Biochemistry, Faculty of Pharmacy, Damascus University, Damascus, Syria.
Cancer Lett. 2021 Aug 26;521:142-154. doi: 10.1016/j.canlet.2021.08.026.
We previously demonstrated the conversion of normal stem cells, including induced pluripotent stem cells (iPSCs), into cancer stem cells (CSCs) without genetic manipulation. Herein, we designed a meta-analysis to assess gene expression profiles in different breast cancer cell lines focusing on the secretory factors responsible for conversion. As a result, fibroblast growth factor 2 (FGF2) was found to be the best candidate in T47D and BT549 cells, of which conditioned medium was previously successful in inducing CSCs. When treated with 3.1 μg/ml FGF2, mouse iPSCs not only maintained survival without LIF for three weeks but also acquired growth ability independent of FGF2. The resultant cells exhibited expression of stemness and cancer stem cell markers, sphere-forming ability, differentiation, and tumorigenicity with malignancy. The primary cultures of the tumor confirmed the signatures of CSCs with two different phenotypes with or without GFP expression under control of the Nanog promoter. Bioinformatic analysis of gene expression profiles suggested constitutive autocrine activation of the FGF receptor, integrins, focal adhesions, and PI3K/AKT pathways. FGF2 could potently initiate cancer as a component of the inflammatory microenvironment.
我们之前证明了在不进行基因操作的情况下，可将包括诱导多能干细胞（iPSC）在内的正常干细胞转化为癌症干细胞（CSC）。在此，我们设计了一项荟萃分析，以评估不同乳腺癌细胞系中的基因表达谱，重点关注负责转化的分泌因子。结果发现，成纤维细胞生长因子2（FGF2）是T47D和BT549细胞中的最佳候选因子，其条件培养基此前成功诱导出了CSC。用3.1μg/ml FGF2处理时，小鼠iPSC不仅在无白血病抑制因子（LIF）的情况下维持存活三周，还获得了不依赖FGF2的生长能力。所得细胞表现出干性和癌症干细胞标志物的表达、成球能力、分化以及具有恶性的致瘤性。肿瘤的原代培养证实了在Nanog启动子控制下具有两种不同表型（有或无绿色荧光蛋白（GFP）表达）的CSC特征。基因表达谱的生物信息学分析表明，FGF受体、整合素、粘着斑和PI3K/AKT信号通路存在组成性自分泌激活。FGF2作为炎症微环境的一个组成部分，可有力地引发癌症。
