Glioma stem cells promote radioresistance by preferential activation of the DNA damage response
Glioma stem cells promote radioresistance by preferential activation of the DNA damage response
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DOI：
10.1038/nature05236
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发表时间：
2006-12-07
期刊：
影响因子：
64.8
通讯作者：
Rich, Jeremy N.
中科院分区：
文献类型：
--
作者：
Bao, Shideng;Wu, Qiulian;Rich, Jeremy N.
电离辐射是胶质母细胞瘤（世界卫生组织IV级胶质瘤）最有效的治疗方法，胶质母细胞瘤是最致命的人类恶性肿瘤之一（1），但由于放射抵抗性，放射治疗仍然只是姑息治疗（2）。肿瘤放射抗性的机制仍然难以捉摸。在这里，我们表明，癌症干细胞有助于胶质瘤的辐射抗性，通过优先激活DNA损伤检查点反应和DNA修复能力的增加。表达CD 133（Prominin-1）的肿瘤细胞部分，神经干细胞和脑癌干细胞的标志物（3-6），在神经胶质瘤中放射后富集。在细胞培养和免疫功能低下小鼠的大脑中，表达CD 133的神经胶质瘤细胞在电离辐射中存活的比例相对于大多数缺乏CD 133的肿瘤细胞增加。从人胶质瘤异种移植物和原发性胶质母细胞瘤标本中分离的表达CD 133的肿瘤细胞优先激活DNA损伤检查点以响应辐射，并且比CD 133阴性肿瘤细胞更有效地修复辐射诱导的DNA损伤。此外，CD 133阳性胶质瘤干细胞的放射抗性可以用Chk 1和Chk 2检查点激酶的特异性抑制剂逆转。我们的研究结果表明，CD 133阳性肿瘤细胞代表的细胞群，赋予胶质瘤放射抗性，并可能是放射后肿瘤复发的来源。靶向癌症干细胞中的DNA损伤检查点反应可以克服这种辐射抗性，并为恶性脑癌提供治疗模型。
Ionizing radiation represents the most effective therapy for glioblastoma ( World Health Organization grade IV glioma), one of the most lethal human malignancies(1), but radiotherapy remains only palliative(2) because of radioresistance. The mechanisms underlying tumour radioresistance have remained elusive. Here we show that cancer stem cells contribute to glioma radioresistance through preferential activation of the DNA damage checkpoint response and an increase in DNA repair capacity. The fraction of tumour cells expressing CD133 (Prominin-1), a marker for both neural stem cells and brain cancer stem cells(3-6), is enriched after radiation in gliomas. In both cell culture and the brains of immunocompromised mice, CD133-expressing glioma cells survive ionizing radiation in increased proportions relative to most tumour cells, which lack CD133. CD133-expressing tumour cells isolated from both human glioma xenografts and primary patient glioblastoma specimens preferentially activate the DNA damage checkpoint in response to radiation, and repair radiation-induced DNA damage more effectively than CD133-negative tumour cells. In addition, the radioresistance of CD133-positive glioma stem cells can be reversed with a specific inhibitor of the Chk1 and Chk2 checkpoint kinases. Our results suggest that CD133-positive tumour cells represent the cellular population that confers glioma radioresistance and could be the source of tumour recurrence after radiation. Targeting DNA damage checkpoint response in cancer stem cells may overcome this radioresistance and provide a therapeutic model for malignant brain cancers.