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端粒与端粒酶在前列腺癌发生发展及治疗中的作用

Telomeres and telomerase in prostate cancer development and therapy.

机构信息

Johns Hopkins University School of Medicine, Pathology, Oncology, Urology, 1503 Jefferson Street, Bond Street Annex, Room B300, Baltimore, Maryland 21231, USA.

出版信息

Nat Rev Urol. 2017 Oct;14(10):607-619. doi: 10.1038/nrurol.2017.104. Epub 2017 Jul 4.

Abstract

Aberrations in telomere biology are among the earliest events in prostate cancer tumorigenesis and continue during tumour progression. Substantial telomere shortening occurs in prostate cancer cells and high-grade prostatic intraepithelial neoplasia. Not all mechanisms of telomere shortening are understood, but oxidative stress from local inflammation might accelerate prostatic telomere loss. Critically short telomeres can drive the accumulation of tumour-promoting genomic alterations; however, continued telomere erosion is unsustainable and must be mitigated to ensure cancer cell survival and unlimited replication potential. Prostate cancers predominantly maintain telomeres by activating telomerase, but alternative mechanisms of telomere extension can occur in metastatic disease. Telomerase activity and telomere length assessment might be useful in prostate cancer diagnosis and prognosis. Telomere shortening in normal stromal cells has been associated with prostate cancer, whereas variable telomere lengths in prostate cancer cells and telomere shortening in cancer-associated stromal cells correlated with lethal disease. Single-agent telomerase-targeted treatments for solid cancers were ineffective in clinical trials but have not been investigated in prostate cancer and might be useful in combination with established regimens. Telomere-directed strategies have not been explored as extensively. Telomere deprotection strategies have the advantage of being effective in both telomerase-dependent and telomerase-independent cancers. Disruption of androgen receptor function in prostate cancer cells results in telomere dysfunction, indicating telomeres and telomerase as potential therapeutic targets in prostate cancer.

摘要

端粒生物学异常是前列腺癌肿瘤发生的最早事件之一,并在肿瘤进展过程中持续存在。前列腺癌细胞和高级别前列腺上皮内瘤变中存在大量端粒缩短。并非所有端粒缩短的机制都被理解,但局部炎症引起的氧化应激可能会加速前列腺端粒丢失。临界短端粒会导致促进肿瘤的基因组改变积累;然而,持续的端粒侵蚀是不可持续的,必须加以缓解,以确保癌细胞的存活和无限复制潜力。前列腺癌主要通过激活端粒酶来维持端粒,但在转移性疾病中可能会发生端粒延长的替代机制。端粒酶活性和端粒长度评估可能对前列腺癌的诊断和预后有用。正常基质细胞中端粒缩短与前列腺癌有关,而前列腺癌细胞中端粒长度可变和癌相关基质细胞中端粒缩短与致命疾病相关。单一制剂的端粒酶靶向治疗在临床试验中无效,但尚未在前列腺癌中进行研究,并且可能与既定方案联合使用有用。端粒定向策略尚未得到广泛探索。端粒保护策略具有在端粒酶依赖性和非依赖性癌症中都有效的优势。前列腺癌细胞中雄激素受体功能的破坏会导致端粒功能障碍,这表明端粒和端粒酶是前列腺癌的潜在治疗靶点。

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