影响端粒结构和动力学的微演化过程:端粒在癌症中的作用  

Cancer as A Microevolutionary Process Affecting Telomere Structure and Dynamics:The Contribution of Telomeres to Cancer

作　　者：J.Arturo Londoo-Vallejo 

机构地区：[1]UMR7147,Institut Curie-UPMC-CNRS 26,rue d'Ulm,75248 Paris,France

出　　处：《癌症》2008年第7期775-783,共9页Chinese Journal of Cancer

摘　　要：端粒在基因组稳定、细胞核结构以及减数分裂中染色体配对中发挥关键作用。细胞每分裂一次,端粒会缩短,缩短的端粒可能再延长或不延长,这取决于细胞内是否存在一种专用酶-端粒酶。由于人体的多数体细胞并不表达端粒酶,因此发育和衰老过程中端粒必然缩短。在生理条件下,端粒缩短与延长的细胞增殖相矛盾,因此端粒长度决定了细胞的增殖潜能,并作为细胞无限生长的预防机制。相反,在细胞增殖检查点受破坏的细胞中,缩短的端粒可导致染色体融合并启动断裂-融合-桥周期,这极大地促发了基因组不稳定。在体外研究中,转化细胞中由于端粒严重缩短造成的基因组高度不稳定,在这种细胞种蓄积了有害的遗传改变,从而导致细胞最终死亡(危象)。同时,随机的遗传或拟遗传学改变可使细胞获得端粒维持机制(以及其它肿瘤表型),从而成为永生细胞。在体内研究中,尽管在早期肿瘤细胞中发现端粒缩短和其它形式的端粒功能障碍可能使基因组不稳定,但端粒功能障碍对于人类肿瘤表型的直接作用有待进一步研究。Telomeres play fundamental roles in genome stability, nuclear architecture and chromosome pairing during meiosis. They shorten at every cell division and may be re-elongated or not depending on the presence of the dedicated enzyme, telomerase. Since in most human somatic cells telomerase is not expressed, shortening of telomeres during development and aging is the rule. Short telomeres being, under physiological conditions, incompatible with extended cell proliferation, telomere length defines the proliferation potential of a cell and operates as a mechanism to prevent uncontrolled cell growth. Conversely, in cells in which proliferation checkpoints have been abolished, shortening of telomeres causes chromosomes to fuse and to initiate cycles of breakage-fusion-bridge thus becoming a strong driving force for genome instability. In vitro, transformed cells with highly unstable genomes because of severe telomere shortening accumulate deleterious genetic changes and die （crisis）. At the same time, random genetic or epigenetic changes may allow cells to acquire a telomere maintenance mechanism （as well as other tumor phenotypes） and to become immortal. Although telomere shortening and other types of telomere dysfunction probably contribute to the genome instability detected in early tumors in vivo, the direct contributions of dysfunctional telomeres to the acquisition of tumor phenotypes in humans remain largely unspecified.

关 键 词：端粒缩短 端粒酶 危象 基因组不稳定 永生化 肿瘤发生 核型演化 断裂-融合-桥 突变基因表型 染色体不稳定表型 微卫星不稳定 

分 类 号：R730.2[医药卫生—肿瘤]