The Molecular Mechanisms and Therapeutic Prospects of Alternative Lengthening of Telomeres (ALT).
The Molecular Mechanisms and Therapeutic Prospects of Alternative Lengthening of Telomeres (ALT).
复制标题
作者：
本文综述了端粒的替代性延长机制（ALT）的端粒维持机制。本文综述了ALT通路在维持癌细胞生存中的作用、可识别的指标和可能的机制。提出了未来治疗发展的潜在分子靶点，目标是综合目前对ALT途径的理解，这将是ALT癌症治疗未来进展所必需的。正如末端复制问题所详述的那样，细胞染色体的线性末端（称为端粒）随着每一轮连续的复制而缩短，直到细胞进入称为衰老的生长停滞状态。为了维持其不朽的增殖能力，癌细胞必须采用端粒维持机制，例如端粒酶激活或端粒替代延长途径（ALT）。只有10-15%的癌症利用ALT机制，直到最近才在了解其分子组成和相关标志方面取得进展。本文综述了ALT通路的研究进展，包括：（1）详细阐述了与ALT通路相关的机制，以及（2）确定可能导致新型癌症治疗的ALT潜在治疗靶点。总的来说，这些研究表明，ALT的分子机制涉及至少两个不同的途径诱导的复制应激和端粒损伤。我们认为，利用肿瘤对ALT的依赖性是一个很有前途的研究领域，因为它为预后较差的癌症提供了ALT特异性治疗的新方法。虽然ALT研究领域已经取得了实质性进展，但要将这些进展实现到临床实践中以治疗ALT癌症并改善患者病情，还需要取得更多进展。
This review summarizes the current understanding of the telomere maintenance mechanism known as the Alternative Lengthening of Telomeres (ALT). The role, recognizable indicators, and proposed mechanism of the ALT pathway in sustaining cancer cells are reviewed. Potential molecular targets for future therapeutic development are proposed with the goal of synthesizing the current understanding of the ALT pathway that will be required to make future advances in ALT cancer treatments. As detailed by the end replication problem, the linear ends of a cell’s chromosomes, known as telomeres, shorten with each successive round of replication until a cell enters into a state of growth arrest referred to as senescence. To maintain their immortal proliferation capacity, cancer cells must employ a telomere maintenance mechanism, such as telomerase activation or the Alternative Lengthening of Telomeres pathway (ALT). With only 10–15% of cancers utilizing the ALT mechanism, progress towards understanding its molecular components and associated hallmarks has only recently been made. This review analyzes the advances towards understanding the ALT pathway by: (1) detailing the mechanisms associated with engaging the ALT pathway as well as (2) identifying potential therapeutic targets of ALT that may lead to novel cancer therapeutic treatments. Collectively, these studies indicate that the ALT molecular mechanisms involve at least two distinct pathways induced by replication stress and damage at telomeres. We suggest exploiting tumor dependency on ALT is a promising field of study because it suggests new approaches to ALT-specific therapies for cancers with poorer prognosis. While substantial progress has been made in the ALT research field, additional progress will be required to realize these advances into clinical practices to treat ALT cancers and improve patient prognoses.
登录
查看更多内容
影响因子：
14.9
作者：
Bakr A;Oing C;Köcher S;Borgmann K;Dornreiter I;Petersen C;Dikomey E;Mansour WY
通讯作者：
Mansour WY
31种癌症类型的端粒长度和躯体改变的系统分析。
影响因子：
30.8
作者：
Barthel FP;Wei W;Tang M;Martinez-Ledesma E;Hu X;Amin SB;Akdemir KC;Seth S;Song X;Wang Q;Lichtenberg T;Hu J;Zhang J;Zheng S;Verhaak RG
通讯作者：
Verhaak RG
影响因子：
16.6
作者：
Arora, Rajika;Lee, Yongwoo;Wischnewski, Harry;Brun, Catherine M.;Schwarz, Tobias;Azzalin, Claus M.
通讯作者：
Azzalin, Claus M.
DOI：
10.15252/embj.201488663
发表时间：
2014-11-03
期刊：
The EMBO journal
影响因子：
--
作者：
Castillo Bosch P;Segura-Bayona S;Koole W;van Heteren JT;Dewar JM;Tijsterman M;Knipscheer P
通讯作者：
Knipscheer P
影响因子：
64.8
作者：
Chen, Liuh-Yow;Redon, Sophie;Lingner, Joachim
通讯作者：
Lingner, Joachim