Olmez Inan, Shen Wangzhen, McDonald Hayes, Ozpolat Bulent
Department of Neurology, Vanderbilt University, Nashville, TN, USA.
Department of Biochemistry, Vanderbilt University, Nashville, TN, USA.
J Cell Mol Med. 2015 Jun;19(6):1262-72. doi: 10.1111/jcmm.12479. Epub 2015 Mar 19.
Emerging evidence shows that glioblastoma multiforme (GBM) originates from cancer stem cells (CSCs). Characterization of CSC-specific signalling pathways would help identify new therapeutic targets and perhaps lead to the development of more efficient therapies selectively targeting CSCs. Here; we successfully dedifferentiated two patient-derived GBM cell lines into CSC-like cells (induced glioma stem cells, iGSCs) through expression of Oct4, Sox2 and Nanog transcription factors. Transformed cells exhibited significant suppression of epidermal growth factor receptor and its downstream pathways. Compared with parental GBM cells, iGSCs formed large neurospheres even in the absence of exogenous mitogens; they exhibited significant sensitivity to salinomycin and chemoresistance to temozolomide. Further characterization of iGSCs revealed induction of NOTCH1 and Wnt/β-catenin signalling and expression of CD133, CD44 and ALDH1A1. Our results indicate that iGSCs may help us understand CSC physiology and lead to development of potential therapeutic interventions aimed at differentiating tumour cells to render them more sensitive to chemotherapy or other standard agents.
新出现的证据表明，多形性胶质母细胞瘤（GBM）起源于癌症干细胞（CSCs）。对CSC特异性信号通路的表征将有助于识别新的治疗靶点，并可能导致开发出更有效的选择性靶向CSCs的疗法。在此，我们通过表达Oct4、Sox2和Nanog转录因子，成功地将两种源自患者的GBM细胞系去分化为CSC样细胞（诱导性胶质瘤干细胞，iGSCs）。转化后的细胞表现出表皮生长因子受体及其下游通路的显著抑制。与亲代GBM细胞相比，iGSCs即使在没有外源性促细胞分裂剂的情况下也能形成大的神经球；它们对沙林霉素表现出显著的敏感性，对替莫唑胺具有化学抗性。对iGSCs的进一步表征揭示了NOTCH1和Wnt/β-连环蛋白信号的诱导以及CD133、CD44和ALDH1A1的表达。我们的结果表明，iGSCs可能有助于我们理解CSC生理学，并导致开发旨在使肿瘤细胞分化以使其对化疗或其他标准药物更敏感的潜在治疗干预措施。
