Recagni Marta, Bidzinska Joanna, Zaffaroni Nadia, Folini Marco
Molecular Pharmacology Unit, Department of Applied Research and Technological Development, Fondazione IRCCS Istituto Nazionale dei Tumori di Milano, 20133 Milano, Italy.
2nd Department of Radiology, Medical University of Gdańsk, 80-214 Gdańsk, Poland.
Cancers (Basel). 2020 Apr 11;12(4):949. doi: 10.3390/cancers12040949.
Telomere maintenance mechanisms (i.e., telomerase activity (TA) and the alternative lengthening of telomere (ALT) mechanism) contribute to tumorigenesis by providing unlimited proliferative capacity to cancer cells. Although the role of either telomere maintenance mechanisms seems to be equivalent in providing a limitless proliferative ability to tumor cells, the contribution of TA and ALT to the clinical outcome of patients may differ prominently. In addition, several strategies have been developed to interfere with TA in cancer, including Imetelstat that has been the first telomerase inhibitor tested in clinical trials. Conversely, the limited information available on the molecular underpinnings of ALT has hindered thus far the development of genuine ALT-targeting agents. Moreover, whether anti-telomerase therapies may be hampered or not by possible adaptive responses is still debatable. Nonetheless, it is plausible hypothesizing that treatment with telomerase inhibitors may exert selective pressure for the emergence of cancer cells that become resistant to treatment by activating the ALT mechanism. This notion, together with the evidence that both telomere maintenance mechanisms may coexist within the same tumor and may distinctly impinge on patients' outcomes, suggests that ALT may exert an unexpected role in tumor biology that still needs to be fully elucidated.
端粒维持机制（即端粒酶活性（TA）和端粒的替代延长（ALT）机制）通过赋予癌细胞无限增殖能力而促进肿瘤发生。尽管这两种端粒维持机制在赋予肿瘤细胞无限增殖能力方面的作用似乎相当，但TA和ALT对患者临床结局的影响可能显著不同。此外，已经开发了几种干扰癌症中TA的策略，包括在临床试验中进行测试的首个端粒酶抑制剂伊美司他。相反，目前关于ALT分子基础的信息有限，这阻碍了真正针对ALT的药物的开发。此外，抗端粒酶疗法是否会受到可能的适应性反应的阻碍仍存在争议。尽管如此，可以合理推测，用端粒酶抑制剂治疗可能会对通过激活ALT机制而对治疗产生抗性的癌细胞的出现施加选择性压力。这一观点，连同两种端粒维持机制可能在同一肿瘤中共存并可能对患者结局产生明显影响的证据，表明ALT可能在肿瘤生物学中发挥意想不到的作用，仍有待充分阐明。
