背景:尽管在化疗和放疗方面取得了进步,但胶质瘤对有效治疗提出了重大挑战。胶质瘤干细胞(GSC),肿瘤中的一个子集,有助于抵抗,肿瘤异质性,和可塑性。最近的研究揭示了GSCs在治疗抗性中的作用,由DNA修复机制和细胞状态之间的动态转换驱动。耐药机制可能涉及不同的细胞途径,其中大多数是最近在文献中报道的。尽管取得了进展,由于GSCs的高可塑性,靶向治疗方法缺乏共识。
目的:分析针对GSC介导的神经胶质瘤对放疗和化疗耐药的靶向治疗,关注潜在机制。
方法:在主要医学数据库中进行了系统搜索(PubMed,Embase,和Cochrane图书馆)至2023年9月30日。搜索策略利用相关医学主题标题术语和与包括“神经胶质瘤干细胞”相关的关键词,“放射治疗”,“化疗”,\"阻力\",和“靶向治疗”。这篇综述中包含的研究是针对GSC介导的放疗抵抗(RTR)分子机制的靶向治疗的出版物。
结果:在对66项关于干细胞治疗SCI的研究的全面回顾中,最初确定了452篇论文,选择203进行全文分析。其中,由于各种原因,在排除168之后,201被认为是合格的。研究的时间细分说明了这一趋势:2005-2010年(33.3%),2011-2015年(36.4%),和2016-2022年(30.3%)。主要GSC型号,特别是U87(33.3%),U251(15.2%),和T98G(15.2%),在研究中脱颖而出,反映其代表性的胶质瘤特点。通路分析表明,主要集中在磷酸肌醇3激酶/蛋白激酶B/哺乳动物雷帕霉素靶蛋白(mTOR)(27.3%)和Notch(12.1%)通路,表明它们在抗性发展中的关键作用。具有mTOR的靶向分子(18.2%),CHK1/2(15.2%),和ATP结合盒G2(12.1%)作为常见的靶标强调了它们在克服GSC介导的抗性中的重要性。各种治疗剂,特别是RNA抑制剂/短发夹RNA(27.3%),抑制剂(例如,LY294002,NVP-BEZ235)(24.2%),和单克隆抗体(例如,西妥昔单抗)(9.1%),在靶向治疗中表现出多功能性。在20项研究(60.6%)中,对化疗耐药反应最常见的影响是替莫唑胺耐药减少(51.5%),其次是卡莫司汀耐药性(9.1%)和多柔比星耐药性(3.0%)下降,而对RTR的耐药性在42.4%的研究中降低。
结论:GSCs在介导放射抗性和化学抗性中起着复杂的作用,强调考虑到GSC人群的异质性和动态肿瘤微环境的精确治疗的必要性,以提高胶质母细胞瘤患者的预后。
BACKGROUND: Gliomas pose a significant challenge to effective treatment despite advancements in chemotherapy and radiotherapy. Glioma stem cells (GSCs), a subset within tumors, contribute to resistance, tumor heterogeneity, and plasticity. Recent studies reveal GSCs\' role in therapeutic resistance, driven by DNA repair mechanisms and dynamic transitions between cellular states. Resistance mechanisms can involve different cellular pathways, most of which have been recently reported in the literature. Despite progress, targeted therapeutic approaches lack consensus due to GSCs\' high plasticity.
OBJECTIVE: To analyze targeted therapies against GSC-mediated resistance to radio- and chemotherapy in gliomas, focusing on underlying mechanisms.
METHODS: A systematic search was conducted across major medical databases (PubMed, Embase, and Cochrane Library) up to September 30, 2023. The search strategy utilized relevant Medical Subject Heading terms and keywords related to including \"glioma stem cells\", \"radiotherapy\", \"chemotherapy\", \"resistance\", and \"targeted therapies\". Studies included in this review were publications focusing on targeted therapies against the molecular mechanism of GSC-mediated resistance to radiotherapy resistance (RTR).
RESULTS: In a comprehensive review of 66 studies on stem cell therapies for SCI, 452 papers were initially identified, with 203 chosen for full-text analysis. Among them, 201 were deemed eligible after excluding 168 for various reasons. The temporal breakdown of studies illustrates this trend: 2005-2010 (33.3%), 2011-2015 (36.4%), and 2016-2022 (30.3%). Key GSC models, particularly U87 (33.3%), U251 (15.2%), and T98G (15.2%), emerge as significant in research, reflecting their representativeness of glioma characteristics. Pathway analysis indicates a focus on phosphoinositide 3-kinase/protein kinase B/mammalian target of rapamycin (mTOR) (27.3%) and Notch (12.1%) pathways, suggesting their crucial roles in resistance development. Targeted molecules with mTOR (18.2%), CHK1/2 (15.2%), and ATP binding cassette G2 (12.1%) as frequent targets underscore their importance in overcoming GSC-mediated resistance. Various therapeutic agents, notably RNA inhibitor/short hairpin RNA (27.3%), inhibitors (e.g., LY294002, NVP-BEZ235) (24.2%), and monoclonal antibodies (e.g., cetuximab) (9.1%), demonstrate versatility in targeted therapies. among 20 studies (60.6%), the most common effect on the chemotherapy resistance response is a reduction in temozolomide resistance (51.5%), followed by reductions in carmustine resistance (9.1%) and doxorubicin resistance (3.0%), while resistance to RTR is reduced in 42.4% of studies.
CONCLUSIONS: GSCs play a complex role in mediating radioresistance and chemoresistance, emphasizing the necessity for precision therapies that consider the heterogeneity within the GSC population and the dynamic tumor microenvironment to enhance outcomes for glioblastoma patients.