CD133+ glioblastoma stem-like cells are radiosensitive with a defective DNA damage response compared with established cell lines.
CD133+ glioblastoma stem-like cells are radiosensitive with a defective DNA damage response compared with established cell lines.
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DOI：
10.1158/1078-0432.ccr-09-0263
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发表时间：
2009-08-15
期刊：
影响因子：
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通讯作者：
Tofilon PJ
中科院分区：
文献类型：
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作者：
McCord AM;Jamal M;Williams ES;Camphausen K;Tofilon PJ
CD133+胶质母细胞瘤（GB）肿瘤干细胞样细胞（TSCs）已被定义为放射耐药。然而，尽管之前与CD133−细胞相对分类，CD133+ TSCs相对于标准GB模型（已建立的胶质瘤细胞系）的放射敏感性尚未确定。因此，为了更好地了解这种癌症干细胞的放射反应，我们使用已建立的细胞系作为定义其体外放射反应的框架。用克隆法测定CD133+ TSC培养物和胶质瘤细胞系的固有放射敏感性。还比较了TSCs和已建立的细胞系在DNA双链断裂（DSB）修复能力和细胞周期检查点激活方面的差异。基于克隆性分析，6种TSC培养物对辐射的敏感性均高于已建立的胶质瘤细胞系。与增加的放射敏感性一致，通过中性彗星试验和γH2AX和Rad51焦点定义的DSB修复能力在tsc中与细胞系相比显着降低。与细胞系不同，G2检查点的激活是完整的，辐照后TSCs中的DNA合成没有受到抑制，这表明没有s期检查点。这些数据表明，CD133+ TSCs对辐射的反应机制与传统GB体外模型建立的胶质瘤细胞系有显著不同。如果tsc在GB治疗反应中起关键作用，那么这种差异可能会对放射增敏剂的开发和测试产生影响。
CD133+ glioblastoma (GB) tumor stem-like cells (TSCs) have been defined as radioresistant. However, whereas previously classified relative to CD133− cells, the radiosensitivity of CD133+ TSCs with respect to the standard GB model, established glioma cell lines, has not been determined. Therefore, to better understand the radioresponse of this cancer stem cell, we have used established cell lines as a framework for defining their in vitro radioresponse. The intrinsic radiosensitivity of CD133+ TSC cultures and established glioma cell lines was determined by clonogenic assay. The TSCs and established cell lines were also compared in terms of DNA double strand break (DSB) repair capacity and cell cycle checkpoint activation. Based on clonogenic analysis, each of the six TSC cultures evaluated was more sensitive to radiation than the established glioma cell lines. Consistent with increased radiosensitivity, the DSB repair capacity as defined by neutral comet assay and γH2AX and Rad51 foci was significantly reduced in TSCs as compared to the cell lines. Whereas G2 checkpoint activation was intact, in contrast to the cell lines, DNA synthesis was not inhibited in TSCs after irradiation indicating the absence of the intra-S phase checkpoint. These data indicate that the mechanisms through which CD133+ TSCs respond to radiation are significantly different from those of the traditional GB in vitro model, established glioma cell lines. If TSCs play a critical role in GB treatment response, then such differences are likely to be of consequence in the development and testing of radiosensitizing agents.