Atm deletion with dual recombinase technology preferentially radiosensitizes tumor endothelium
Atm deletion with dual recombinase technology preferentially radiosensitizes tumor endothelium
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DOI：
10.1172/jci73932
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发表时间：
2014-08-01
影响因子：
15.9
通讯作者：
Kirsch, David G.
中科院分区：
文献类型：
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作者：
Moding, Everett J.;Lee, Chang-Lung;Kirsch, David G.
从共济失调毛细血管扩张患者分离的细胞对电离辐射非常敏感。在共济失调毛细血管扩张症中突变的基因ATM的激酶抑制剂可以使肿瘤细胞对放射治疗敏感，但由于担心在正常组织中抑制ATM也会增加正常组织的放射毒性，限制了它们的临床应用。内皮细胞损伤可能导致放射治疗后长期副作用的发展，但内皮细胞死亡在肿瘤对放射治疗反应中的作用仍然存在争议。在这里，我们开发了双重组酶技术，使用FlpO和Cre重组酶在内皮细胞特异性缺失Atm的小鼠中产生原发性肉瘤，以确定内皮细胞中Atm的缺失是否会使肿瘤和正常组织对辐射敏感。尽管增殖肿瘤内皮细胞中Atm的缺失增强了肉瘤对辐射的反应，但心脏静止内皮细胞中Atm的缺失并没有使小鼠对辐射诱导的心肌坏死敏感。阻断细胞周期进程逆转了Atm丢失对肿瘤内皮细胞放射敏感性的影响。这些结果表明内皮细胞必须经过细胞周期才能被Atm缺失致敏。
Cells isolated from patients with ataxia telangiectasia are exquisitely sensitive to ionizing radiation. Kinase inhibitors of ATM, the gene mutated in ataxia telangiectasia, can sensitize tumor cells to radiation therapy, but concern that inhibiting ATM in normal tissues will also increase normal tissue toxicity from radiation has limited their clinical application. Endothelial cell damage can contribute to the development of long-term side effects after radiation therapy, but the role of endothelial cell death in tumor response to radiation therapy remains controversial. Here, we developed dual recombinase technology using both FlpO and Cre recombinases to generate primary sarcomas in mice with endothelial cell-specific deletion of Atm to determine whether loss of Atm in endothelial cells sensitizes tumors and normal tissues to radiation. Although deletion of Atm in proliferating tumor endothelial cells enhanced the response of sarcomas to radiation, Atm deletion in quiescent endothelial cells of the heart did not sensitize mice to radiation-induced myocardial necrosis. Blocking cell cycle progression reversed the effect of Atm loss on tumor endothelial cell radiosensitivity. These results indicate that endothelial cells must progress through the cell cycle in order to be radiosensitized by Atm deletion.