柳叶刀肿瘤特刊8.docx

Delayed Activation of Telomerase May Both Limitand Foster（养育、培）养Neoplastic Progression延迟激活的端粒酶可能会在促进肿瘤发生、阻碍肿瘤发生中起到双向作用There is now evidence that clones of incipient cancer cells oftenexperience telomere loss-induced crisis relatively early duringthe course ofmultistep tumor progression due to their inability toexpress signi?cant levels of telomerase. Thus, extensivelyeroded telomeres have been documented in premalignantgrowths through the use of ?uorescence in situ hybridization(FISH), which has also revealed the end-to-end chromosomalfusions that signal telomere failure and crisis (Kawai et al.,2007; Hansel et al., 2006). These results also suggest that suchcells have passed through a substantial number of successivetelomere-shortening cell divisions during their evolution fromfully normal cells-of-origin. Accordingly, the development ofsome human neoplasias may be aborted by telomere-inducedcrisis long before they succeed in becoming macroscopic,frankly neoplastic growths. In contrast, the absence of TP53-mediated surveillance ofgenomic integrity may permit other incipient neoplasias tosurvive initial telomere erosion and attendant chromosomalbreakage-fusion-bridge (BFB) cycles. The genomic alterationsresulting from these BFB cycles, including deletions and ampli?cations of chromosomal segments, evidently serve to increasethe mutability of the genome, thereby accelerating the acquisition ofmutant oncogenes and tumor suppressor genes. The realization that impaired telomere function can actually foster tumorprogression has come from the study of mutant mice that lackboth p53 and telomerase function (Artandi and DePinho, 2010,2000). The proposition that these two defects can cooperativelyenhance human tumorigenesis has not yet been directly documented. 目前已经有证据证明，早期肿瘤细胞在复制过程中会经历由于端粒缩短导致的细胞崩盘，当然，这个情况只在肿瘤发生的极早期才会有，而导致这一情况产生的原因就是早期的肿瘤细胞并不能够完全诱导高表达端粒酶。（编者按：可见，及时发现肿瘤及时治疗是相当有意义的）使用原位荧光杂交方法（FISH）证实，在肿瘤早期，由于需要正常细胞到恶变细胞转化，会出现由于端粒缩短，会出现细胞的过度复制，端粒的长度会持续不断的缩短，因此，最终会出现染色体的端-端融合，这标