Tumor cells can escape DNA-damaging cisplatin through DNA endoreduplication and reversible polyploidy
Tumor cells can escape DNA-damaging cisplatin through DNA endoreduplication and reversible polyploidy
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DOI：
10.1016/j.cellbi.2008.04.021
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发表时间：
2008-09-01
影响因子：
3.9
通讯作者：
Chauffert, Bruno
中科院分区：
文献类型：
--
作者：
Puig, Pierre-Emmanuel;Guilly, Marie-Noelle;Chauffert, Bruno
癌症化疗可以导致肿瘤消退，在许多情况下，随后会长期复发。因此，这项研究使用体内癌症模型和体外方法来评估这种现象的决定因素。当携带已建立的肿瘤的动物接受顺铂治疗时，肿瘤最初经历急剧缩小，其特征是巨大的肿瘤细胞不增殖，但维持DNA合成。在潜伏数周后，肿瘤恢复发展，并由小的增殖细胞组成。同样，当肿瘤细胞在体外暴露于药物浓度的顺铂时，有丝分裂活动最初停止，但细胞保持DNA复制。这种DNA内复制产生巨大的多倍体细胞，然后这些细胞启动流产的有丝分裂，并可能通过有丝分裂灾难而死亡。然而，许多多倍体细胞以不增殖的单核或多核巨细胞的形式存活数周，并获得衰老表型。对这些细胞的长期观察揭示了细胞分选分析所证明的来自多倍体细胞的有限数量的广泛集落的延迟出现。这些克隆是由小的二倍体细胞组成的，这些细胞不同于亲代细胞，因为固定的染色体异常和对细胞毒药物的耐药性增加。这些数据表明，包括DNA内复制、多倍体、去多倍体和克隆性逃逸细胞的产生在内的多步骤途径可以解释最初有效化疗后肿瘤复发的原因。(C)2008年国际细胞生物学联合会。爱思唯尔有限公司出版。保留所有权利。
Cancer chemotherapy can induce tumor regression followed, in many cases, by relapse in the long-term. Thus this study was performed to assess the determinants of such phenomenon using an in vivo cancer model and in vitro approaches. When animals bearing an established tumor are treated by cisplatin, the tumor initially undergoes a dramatic shrinkage and is characterized by giant tumor cells that do not proliferate but maintain DNA synthesis. After several weeks of latency, the tumor resumes its progression and consists of small proliferating cells. Similarly, when tumor cells are exposed in vitro to pharmacological concentrations of cisplatin, mitotic activity stops initially but cells maintain DNA duplication. This DNA endoreduplication generates giant polyploid cells that then initiate abortive mitoses and can die through mitotic catastrophe. However, many polyploid cells survive for weeks as non-proliferating mono- or multi-nucleated giant cells which acquire a senescence phenotype. Prolonged observation of these cells sheds light on the delayed emergence of a limited number of extensive colonies which originate from polyploid cells, as demonstrated by cell sorting analysis. Theses colonies are made of small diploid cells which differ from parental cells by stereotyped chromosomal aberrations and an increased resistance to cytotoxic drugs. These data suggest that a multistep pathway, including DNA endoreduplication, polyploidy, then depolyploidization and generation of clonogenic escape cells can account for tumor relapse after initial efficient chemotherapy. (C) 2008 International Federation for Cell Biology. Published by Elsevier Ltd. All rights reserved.