Harvard (Dana Farber) Cancer Institute, Boston, Mass; VA Boston Healthcare System, Boston, Mass.
Transl Res. 2013 Dec;162(6):364-70. doi: 10.1016/j.trsl.2013.09.003. Epub 2013 Oct 1.
The purpose of this review is to highlight the importance of telomeres, the mechanisms implicated in their maintenance, and their role in the etiology as well as the treatment of human esophageal cancer. We will also discuss the role of telomeres in the maintenance and preservation of genomic integrity, the consequences of telomere dysfunction, and the various factors that may affect telomere health in esophageal tissue predisposing it to oncogenesis. There has been growing evidence that telomeres, which can be affected by various intrinsic and extrinsic factors, contribute to genomic instability, oncogenesis, as well as proliferation of cancer cells. Telomeres are the protective DNA-protein complexes at chromosome ends. Telomeric DNA undergoes progressive shortening with age leading to cellular senescence and/or apoptosis. If senescence/apoptosis is prevented as a consequence of specific genomic changes, continued proliferation leads to very short (ie, dysfunctional) telomeres that can potentially cause genomic instability, thus, increasing the risk for activation of telomere maintenance mechanisms and oncogenesis. Like many other cancers, esophageal cancer cells have short telomeres and elevated telomerase, the enzyme that maintains telomeres in most cancer cells. Homologous recombination, which is implicated in the alternate pathway of telomere elongation, is also elevated in Barrett's-associated esophageal adenocarcinoma. Evidence from our laboratory indicates that both telomerase and homologous recombination contribute to telomere maintenance, DNA repair, and the ongoing survival of esophageal cancer cells. This indicates that telomere maintenance mechanisms may potentially be targeted to make esophageal cancer cells static. The rate at which telomeres in healthy cells shorten is determined by a number of intrinsic and extrinsic factors, including those associated with lifestyle. Avoidance of factors that may directly or indirectly injure esophageal tissue including its telomeric and other genomic DNA can not only reduce the risk of development of esophageal cancer but may also have positive impact on overall health and lifespan.
本综述旨在强调端粒的重要性、涉及端粒维持的机制，以及它们在人类食管癌的病因学和治疗中的作用。我们还将讨论端粒在维持和保护基因组完整性、端粒功能障碍的后果，以及可能影响易发生癌变的食管组织中端粒健康的各种因素。越来越多的证据表明，端粒可以受到各种内在和外在因素的影响，导致基因组不稳定、癌变和癌细胞增殖。端粒是染色体末端的保护性 DNA-蛋白质复合物。端粒 DNA 随着年龄的增长逐渐缩短，导致细胞衰老和/或凋亡。如果由于特定的基因组变化而阻止了衰老/凋亡，持续的增殖会导致非常短的（即功能失调的）端粒，这可能导致基因组不稳定，从而增加激活端粒维持机制和癌变的风险。与许多其他癌症一样，食管癌细胞的端粒较短，端粒酶活性升高，端粒酶是大多数癌细胞中维持端粒的酶。同源重组，它涉及端粒延长的替代途径，也在 Barrett 相关的食管腺癌中升高。我们实验室的证据表明，端粒酶和同源重组都有助于端粒维持、DNA 修复和食管癌细胞的持续存活。这表明端粒维持机制可能成为使食管癌细胞静止的潜在靶点。健康细胞中端粒缩短的速度取决于许多内在和外在因素，包括与生活方式相关的因素。避免可能直接或间接损伤食管组织（包括其端粒和其他基因组 DNA）的因素，不仅可以降低食管癌的发病风险，而且可能对整体健康和寿命产生积极影响。
