Neural Tumor-Initiating Cells Have Distinct Telomere Maintenance and Can be Safely Targeted for Telomerase Inhibition
Neural Tumor-Initiating Cells Have Distinct Telomere Maintenance and Can be Safely Targeted for Telomerase Inhibition
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DOI：
10.1158/1078-0432.ccr-10-2075
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发表时间：
2011-01-01
影响因子：
11.5
通讯作者：
Tabori, Uri
中科院分区：
文献类型：
--
作者：
Castelo-Branco, Pedro;Zhang, Cindy;Tabori, Uri
目的：癌症复发是肿瘤学的主要挫折之一。维持端粒对于维持这类癌症的无限复制潜力至关重要。因为端粒酶被认为在所有肿瘤细胞和正常干细胞中是活性的，所以端粒酶抑制可能是非特异性的，并且通过影响正常干细胞的自我更新而对组织维持和发育具有不利影响。我们检测了新鲜切除的胶质瘤、长期原发性胶质瘤、神经肿瘤起始细胞（TIC）和相应的正常干细胞系。然后，我们测试了端粒酶抑制剂Imetelstat对TIC和正常干细胞在体外和体内的繁殖和自我更新能力的疗效。结果：端粒酶是无法检测到的大多数肿瘤细胞和特定的TIC亚群，具有严重短端粒。相反，正常组织干细胞具有较长的端粒和不可检测的端粒酶活性，并且对端粒酶抑制不敏感，这导致神经TIC中的增殖停滞、细胞成熟和DNA损伤。在异种移植模型中观察到神经母细胞瘤TIC的显著存活益处和晚期肿瘤生长停滞（P = 0.02）。此外，神经TIC表现出不可逆转的自我更新和干细胞的能力，即使在体外和体内治疗停止后的损失。结论：TIC耗尽端粒酶抑制和缺乏端粒酶的依赖性在正常干细胞端粒假说增加了新的层面，并建议端粒酶抑制剂，针对TIC可能代表一个特定的和安全的治疗方法，为神经源性肿瘤。临床癌症研究; 17（1）; 111-21。(C)2011年AACR。
Purpose: Cancer recurrence is one of the major setbacks in oncology. Maintaining telomeres is essential for sustaining the limitless replicative potential of such cancers. Because telomerase is thought to be active in all tumor cells and normal stem cells, telomerase inhibition may be nonspecific and have detrimental effects on tissue maintenance and development by affecting normal stem cell self-renewal.Methods: We examined telomerase activity, telomere maintenance, and stem cell maturation in tumor subpopulations from freshly resected gliomas, long-term, primary, neural tumor-initiating cells (TIC) and corresponding normal stem cell lines. We then tested the efficacy of the telomerase inhibitor Imetelstat on propagation and self-renewal capacity of TIC and normal stem cells in vitro and in vivo.Results: Telomerase was undetectable in the majority of tumor cells and specific to the TIC subpopulation that possessed critically short telomeres. In contrast, normal tissue stem cells had longer telomeres and undetectable telomerase activity and were insensitive to telomerase inhibition, which results in proliferation arrest, cell maturation, and DNA damage in neural TIC. Significant survival benefit and late tumor growth arrest of neuroblastoma TIC were observed in a xenograft model (P = 0.02). Furthermore, neural TIC exhibited irreversible loss of self-renewal and stem cell capabilities even after cessation of treatment in vitro and in vivo.Conclusions: TIC exhaustion with telomerase inhibition and lack of telomerase dependency in normal stem cells add new dimensions to the telomere hypothesis and suggest that targeting TIC with telomerase inhibitors may represent a specific and safe therapeutic approach for tumors of neural origin. Clin Cancer Res; 17(1); 111-21. (C) 2011 AACR.