柳叶刀肿瘤特刊8.docx

Delayed Activation of Telomerase May Both Limit and 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 often experience telomere loss-induced crisis relatively early during the course of multistep tumor progression due to their inability to express signicant levels of telomerase. Thus, extensively eroded telomeres have been documented in premalignant growths through the use of uorescence in situ hybridization(FISH), which has also revealed the end-to-end chromosomal fusions that signal telomere failure and crisis (Kawai et al.,2007; Hansel et al., 2006). These results also suggest that such cells have passed through a substantial number of successive telomere-shortening cell divisions during their evolution from fully normal cells-of-origin. Accordingly, the development of some human neoplasias may be aborted by telomere-induced crisis long before they succeed in becoming macroscopic, frankly neoplastic growths. In contrast, the absence of TP53-mediated surveillance of genomic integrity may permit other incipient neoplasias to survive initial telomere erosion and attendant chromosomal breakage-fusion-bridge (BFB) cycles. The genomic alterations resulting from these BFB cycles, including deletions and amplications of chromosomal segments, evidently serve to increase the mutability of the genome, thereby accelerating the acquisition of mutant oncogenes and tumor suppressor genes. The realization that impaired telomere function can actually foster tumor progression has come from the study of mutant mice that lack both p53 and telomerase function (Artandi and DePinho, 2010, 2000). The proposition that these two defects can cooperatively enhance 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，这标志着端粒功能不复存在。因此，一些肿瘤在发生过程中，会因为端粒酶高表达出现的较晚而出现一种细胞凋亡、崩盘的现象，这种情况严重阻碍了肿瘤的形成。相反，TP53缺失会引起基因组完整性不足，这会允许早期的肿瘤避免端粒缩短、避免染色体断裂、相互融合（BFB）。但是，一个值得注意的事情就是，在BFB出现的时候，也就是染色体某一段被删除或被过度表达的时候，基因组的不稳定性就会增加，增加的基因组的不稳定性最终会加速原癌基因和抑癌基因的突变（编者按：从这一点可以看出来，如果机体会在岁月的发展过程中出现染色体的紊乱，早晚会患得肿瘤）。使用缺乏p53和端粒的老鼠做实验，实验结果证实，如果缺乏端粒，那么机体很有可能会有癌症出现。目前，这两种自相矛盾的现象还没有被放在一起研究。Circumstantial support for the importance of transient telomere deciency in facilitating malignant progression has come, in addition, from comparative analyses of premalignant and malignant lesions in the human breast (Raynaud et al., 2010;Chin et al., 2004). The premalignant lesions did not express signicant levels of telomerase and were marked by telomere shortening and nonclonal chromosomal aberrations. In contrast, overt（明显的） carcinomas exhibited telomerase expression concordantly with the reconstruction of longer telomeres and the xation (via clonal outgrowth) of the aberrant karyotypes（染色体组型、核型） that would seem to have been acquired after telomere failure but before the acquisition of telomerase activity. When portrayed（表述、表达） in this way, the delayed acquisition of telomerase function serves to generate tumor-promoting mutations, whereas its subsequent activation stabilizes the mutant genome and confers the unlimited replicative capacity that cancer cells require in order to generate clinically apparent tumors.通过对比研究人类早期乳腺癌和晚期乳腺癌损害、其他研究已经证实，端粒的一过性缩短可以加速肿瘤的恶变。早期的肿瘤没有高表达端粒酶，他们的端粒不断缩短，他们的染色体会出现非克隆性的异常。然而，恶性肿瘤却会在染色体端粒缺失后高表达端粒酶，因此，他们的端粒会增加，他们的染色体异常也会变得恒定。从这一层面上看，随后出现的端粒酶其实是有助于肿瘤的发生的，因为它能够保证后续出现的基因突变不被机体修复，保证肿瘤细胞的不断复制。 New Functions of Telomerase 端粒酶的新功能Telomerase was discovered because of its ability to elongate and maintain telomeric DNA, and almost all telomerase research has been posited on the notion that its functions are conned to this crucial function. However, in recent years it has become apparent that telomerase exerts functions that are relevant to cell proliferation but unrelated to telomere maintenance. The noncanonical roles of telomerase, and in particular its protein subunit TERT, have been revealed by functional studies in mice and cultured cells; in some cases novel functions have been demonstrated in conditions where the telomerase enzymatic activity has been eliminated (Cong and Shay, 2008).Among the growing list of telomere-independent functions of TERT/telomerase is the ability of TERT to amplify signaling by the Wnt pathway, by serving as a cofactor of the b-catenin/LEF transcription factor complex (Park et al., 2009). Other ascribed telomere-independent effects include demonstrable enhancement of cell proliferation and/or resistance to apoptosis (Kang et al., 2004), involvement in DNA-damage repair (Masutomiet al., 2005), and RNA-dependent RNA polymerase function(Maida et al., 2009). Consistent with these broader roles, TERT can be found associated with chromatin at multiple sites along the chromosomes, not just at the telomeres (Park et al., 2009; Masutomi et al., 2005). Hence, telomere maintenance is proving to be the most prominent of a diverse series of functions to which TERT contributes. The contributions of these additional functions of telomerase to tumorigenesis remain to be fully elucidated. 端粒酶在刚刚被发现的时候，其定位是帮助延长和维持端粒DNA的长度。几乎所有的研究都定位于研究端粒酶的这个功能，并且证实，端粒酶的确有这个能耐。但是，最近几年的研究却慢慢开始研究端粒酶的其他方面。最近研究证实，端粒和细胞增生相关，但是并不和端粒维持相关。端粒酶的这个非经典的功能学特点和他的特殊亚基-TERT在老鼠的功能性研究和细胞培养性研究中已经被证实：当端粒酶被移除的时候，细胞仍