Contextual synthetic lethality of cancer cell kill based on the tumor microenvironment.
Contextual synthetic lethality of cancer cell kill based on the tumor microenvironment.
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基于肿瘤微环境的癌细胞杀伤的背景综合致死率。
DOI：
10.1158/0008-5472.can-10-2352
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发表时间：
2010-10-15
期刊：
影响因子：
11.2
通讯作者：
Bristow RG
中科院分区：
文献类型：
--
作者：
Chan N;Pires IM;Bencokova Z;Coackley C;Luoto KR;Bhogal N;Lakshman M;Gottipati P;Oliver FJ;Helleday T;Hammond EM;Bristow RG
实体瘤的 3D 微环境内存在急性和慢性缺氧，并导致治疗耐药、遗传不稳定和转移。复制细胞暴露于严重急性缺氧（0.02% O2 16 小时）然后再充氧或中度慢性缺氧（0.2% O2 72 小时）处理后，同源重组 (HR) 蛋白表达和功能降低。由于 HR 缺陷对于聚（ADP-核糖）聚合酶 1 (PARP1) 抑制具有综合致死性，因此我们评估了修复缺陷缺氧细胞对 PARP 抑制的敏感性。尽管 PARP 抑制本身并不影响 HR 表达或功能，但我们观察到化学抑制 PARP1 后 HR 缺陷的缺氧细胞中克隆形成杀伤增加。 RAD51 过度表达可部分逆转这种效应。与 PARP1+/+ MEF 相比，PARP1−/− MEF 在缺氧条件下表现出增殖劣势。由于 S 期特异性细胞杀伤过程中 DNA 复制激发的改变，PARP 抑制的缺氧细胞积累了 γH2AX 和 53BP1 焦点。为了支持这种拟议的作用模式，PARP抑制剂处理的异种移植物在体内RAD51缺陷的缺氧亚区域中显示出γH2AX和裂解的caspase-3表达增加，这与实验放疗后离体克隆存活率降低有关。这是首次报道由于微环境介导的“背景合成致死”导致体内 HR 缺陷缺氧细胞的选择性细胞杀伤。由于所有实体瘤都含有侵袭性缺氧细胞，这可能会扩大 PARP 和 DNA 修复抑制的临床应用，无论是单独使用还是与放疗和化疗联合使用，甚至在缺乏综合致死基因突变的肿瘤细胞中也是如此。
Acute and chronic hypoxia exists within the 3D microenvironment of solid tumors and drives therapy resistance, genetic instability and metastasis. Replicating cells exposed to either severe acute hypoxia (16 h with 0.02% O2) followed by reoxygenation or moderate chronic hypoxia (72 h with 0.2% O2) treatments have decreased homologous recombination (HR) protein expression and function. As HR defects are synthetically lethal with poly(ADP-ribose) polymerase 1 (PARP1) inhibition, we evaluated the sensitivity of repair-defective hypoxic cells to PARP inhibition. Although PARP inhibition itself did not affect HR expression or function, we observed increased clonogenic killing in HR-deficient hypoxic cells following chemical inhibition of PARP1. This effect was partially reversible by RAD51 over-expression. PARP1−/− MEFs showed a proliferative disadvantage under hypoxic gassing when compared to PARP1+/+ MEFs. PARP-inhibited hypoxic cells accumulated γH2AX and 53BP1 foci as a consequence of altered DNA replication firing during S phase-specific cell killing. In support of this proposed mode of action, PARP inhibitor treated xenografts displayed increased γH2AX and cleaved caspase-3 expression in RAD51-deficient hypoxic subregions in vivo which was associated with decreased ex vivo clonogenic survival following experimental radiotherapy. This is the first report of selective cell killing of HR-defective hypoxic cells in vivo as a consequence of microenvironment-mediated “contextual synthetic lethality”. As all solid tumors contain aggressive hypoxic cells, this may broaden the clinical utility of PARP and DNA repair inhibition either alone, or in combination with radiotherapy and chemotherapy, even in tumor cells lacking synthetically lethal, genetic mutations.