端粒酶的起源、调控及与肿瘤关系的研究进展

端粒酶的激活与恶性肿瘤发生发展之间存在着密切的关系。有效地抑制端粒酶活性有可能导致肿瘤治疗方面的重大突破。有关端粒酶自身起源及结构的深入研究有助于这一问题的解决。本文对端粒酶的起源、组分、功能调控研究方面的最新进展进行了综述，并将端凿酶与肿瘤的关系予以总结和展望。     

人端粒酶RNA基因与肿瘤的相关研究进展

目的:总结国内外关于人端粒酶RNA基因与肿瘤的相关研究进展.方法:应用Medline和CNKI期刊全文数据库检索系统,以"人端粒酶RNA基因"和"肿瘤"为关键词,检索1995-01-2008-12相关人端粒酶RNA基因的文献,其中英文文献326篇,中文文献4篇.纳入标准:1)人端粒酶RNA基因的结构和功能;2)人端粒酶RNA基因在恶性肿瘤中的扩增和表达情况;3)人端粒酶RNA基因与致肿瘤性作用;4)人端粒酶RNA基因与肿瘤的靶向治疗研究.根据纳入标准,精选80篇文献,最后纳入分析28篇文献.结果:人端粒酶RNA基因作为人端粒酶RNA组分的编码基因,在多种恶性肿瘤中有扩增及表达增加,且它的扩增和表达水平与肿瘤的诊断和预后是相关的.结论:深入研究人端粒酶RNA基因在恶性肿瘤中的扩增、表达及致肿瘤性作用,有助于进一步理解肿瘤的发生机制,有望在肿瘤的靶向治疗上取得新的突破.     

乳腺癌化疗耐药中肿瘤干细胞的作用及其机制

目的:了解肿瘤干细胞在乳腺癌化疗耐药中的作用及其相关机制的研究进展。方法:应用检索Pubmed及CNKI数据库检索系统,以肿瘤、干细胞、乳腺癌、化疗和耐药等为关键词,检索1999-01-2011-05的相关文献,纳入标准:肿瘤干细胞与乳腺癌化疗耐药。根据纳入标准分析42篇文献。结果:肿瘤干细胞是导致乳腺癌化疗耐药和治疗失败的主要细胞,其耐药的机制包括ATP结合盒转运子的过度表达、细胞解毒酶的过度活化、细胞存活和凋亡相关信号转导通路的异常激活、肿瘤壁龛对肿瘤干细胞的保护作用以及大部分肿瘤干细胞处于静止期。通过对这些耐药机制的干预,可以逆转肿瘤干细胞的耐药性。结论:肿瘤干细胞是导致乳腺癌化疗耐药的关键细胞,对其耐药机制的研究有助于展开针对肿瘤干细胞的靶向治疗,改善患者的预后。     

肿瘤干细胞研究进展

目的:了解近年来肿瘤千细胞的研究进展.方法:应用检索Pubmed数据库检索系统,以"肿瘤"、"干细胞"、"肿瘤干细胞"为关键词,检索1979-01-2008-12的相关文献,共检索到英文文献2 760条.纳入标准:1)肿瘤干细胞的表面标志、耐药机制、信号传导通路;2)肿瘤干细胞来源;3)肿瘤干细胞与肿瘤临床诊治的联系.根据纳入标准,最后精选33篇文献进行分析综述.结果:肿瘤干细胞能够自我更新和分化,具有特异的表面分子标志,对放化疗不敏感.肿瘤干细胞存在Wnt、Notch、Hedgehog、Bmi-1等调节细胞自我更新信号通路异常.肿瘤干细胞是维持肿瘤生长、复发和转移的根源,已经成为抗肿瘤研究的靶细胞.结论:肿瘤干细胞研究进展迅速,深入研究肿瘤干细胞的特性,对恶性肿瘤的诊断,治疗和预后评估具有重要意义.肿瘤干细胞理论将改变目前肿瘤的诊治模式.     

天然产物诱导肿瘤细胞凋亡作用机制的研究进展

目的:总结天然产物诱导肿瘤细胞凋亡主要的作用机制。方法:应用PubMed、SpringerLink和万方全文数据库检索系统,以"细胞凋亡、肿瘤和天然产物"为关键词,检索2006-2010年的相关文献857篇。纳入标准:1)细胞凋亡机制;2)肿瘤细胞凋亡;3)天然产物作用;4)天然产物性状。根据纳入标准,符合分析的文献28篇。结果:天然产物诱导肿瘤细胞凋亡的主要作用机制包括下调或上调细胞增殖/凋亡相关基因的表达、调节细胞周期和调节端粒酶基因表达或端粒酶活性等。结论:许多天然产物可经过多种机制诱导肿瘤细胞凋亡。     

端粒酶与肿瘤的研究现状

 端粒酶 -维持端粒功能的酶 ,已成为对肿瘤药物研究及开发极有吸引力的靶。人的大多数体细胞端粒酶活性被抑制 ,且随着细胞的分裂端粒进行性缩短。大多数人的肿瘤细胞表达端粒酶且它们的端粒相对稳定 ,导致肿瘤细胞的永生化。理论上如果肿瘤细胞的端粒酶活性被抑制 ,那么这种细胞将停止增殖。尽管过去的几年里对端粒酶进行了密集性的研究 ,仍几乎没有强有力的端粒酶抑制剂被确认 ,也没有进入临床试验。端粒酶是否愧对于早期人们对它的期望呢 ?回答是否定的 ,Ｂｌａｃｋｂｕｒｎ[1] 这位 195 8年从原生动物中发现端粒酶的学者 ,明确指出在过去的几年里端粒酶的研究取得了很大的进步 ,在细胞内搞清楚了端粒酶的作用机制和功能、端粒酶催化亚单位ＴＥＲＴ的克隆、新的端粒酶抑制研究和开发、端粒酶疫苗的发现、端粒酶活性在肿瘤临床诊断和预后的应用等 ,显示了端粒酶与肿瘤的研究以及运用的广泛前景。1　端粒、端粒酶与肿瘤的发生和发展　　“端粒 端粒酶假说”认为端粒酶的再激活与细胞的永生化和恶性肿瘤的发生和发展密切相关。染色体末端的端粒ＤＮＡ进行性的缩短是限制人细胞寿命的先决条件。相对的 ,端粒酶的激活 ,合成端粒的ＤＮＡ被认为是细胞永生化和癌症...     

侧群细胞与肿瘤干细胞研究进展

目的:总结国内外采用侧群细胞分析法(side populations analysis)研究肿瘤干细胞的现状。方法:应用检索PubMed数据库检索系统,以“侧群细胞“和“肿瘤干细胞“等为关键词,检索1996-01-2008-12侧群细胞法研究肿瘤干细胞的文献。资料选择:选择所有侧群细胞法研究肿瘤干细胞的文献。纳入标准:1)侧群细胞法分离肿瘤干细胞;2)侧群细胞法鉴定肿瘤干细胞。根据纳入标准,精选80篇文献,最后纳入分析36篇文献。结果:采用SP法可以有效的分离和富集大部分类型的肿瘤干细胞,但是某些肿瘤SP细胞不具有肿瘤干细胞特性,此外,SP法还存在细胞毒性的问题。结论:采用SP分析法研究肿瘤干细胞存在许多问题,但是当无法确认到某种类型的肿瘤干细胞的表面标志时,它仍然是分离和富集肿瘤干细胞的有效方法之一。     

大肠癌端粒长度变化与端粒酶活性的研究

近年来对端粒、端粒酶的研究证实,端粒酶的激活和端粒的稳定是维持人类肿瘤无限增殖的重要因素.为了探讨大肠癌端粒长度变化与端粒酶活性的关系,我们采用Southern blot及端粒重复扩增(TRAP)法对30例大肠癌组织及相应的癌旁组织和正常大肠黏膜组织的端粒长度和端粒酶活性进行检测和分析.     

乳腺癌干细胞的研究进展

目的:总结国内外关于乳腺癌干细胞在乳腺癌中的作用及对其进行靶向调控的研究进展.方法:应用Medline及CNKI期刊全文数据库系统,以"乳腺癌干细胞、信号通路、表皮生长因子受体(EGFR)"为关键词,检索1997-01-2008-12的相关文献,共检索到英文文献4 191篇和中文文献25篇.纳入标准:1)乳腺癌干细胞的起源及其特点;2)乳腺癌干细胞的分选及富集方法;3)调控乳腺癌干细胞自我更新的信号通路;4)EGFR信号通路在乳腺癌干细胞中的作用.根据纳入标准,精选60篇文献,最后纳入分析29篇文献.结果:乳腺癌干细胞在乳腺癌的发生发展以及复发转移中发挥重要作用.因其具有较高的耐药性,故传统的化疗药物很难对其杀伤,通过阻断癌干细胞中激活的信号通路,如EGFR信号通路可以有效抑制干细胞的生长.结论:根据乳腺癌干细胞的自身特点,靶向于其中激活的信号通路对其进行抑制为乳腺癌的治疗提供了一个新的思路.     

端粒酶抑制剂研究进展

端粒酶是存在于干细胞、精原细胞和绝大多数恶性肿瘤细胞中的一种能延长端粒ＤＮＡ的逆转录酶 ,研究表明它与细胞的永生化直接相关。根据目前已经检测出的肿瘤组织标本的统计学分析 ,恶性肿瘤组织端粒酶活性的阳性率达到 84%～ 95 % ,而良性肿瘤和正常组织的端粒酶活性检出率仅为 4%左右。端粒酶活性与恶性肿瘤之间的高度相关性使端粒酶成为近年来肿瘤治疗研究的新热点 ,对于端粒酶抑制剂的研究和开发为肿瘤治疗提供了新的思路。纵观近年的研究成果可以发现 ,围绕端粒酶抑制剂的研究主要集中在反义核酸、核酶、逆转录酶抑制剂、细胞分化剂等…     

Telomerase as a useful target in cancer fighting—the breast cancer case

Telomerase was initially considered as a relevant factor distinguishing cancer from normal cells. During detailed studies, it appeared that its expression and activity is not only limited to cancer cells however, but in this particular cells, the telomerase is much more abundant. Thus, it has become a very promising target for an anticancer therapy. It was revealed in many studies that regulation of telomerase is a multifactorial process in mammalian cells, involving regulation of expression of telomerase subunits coding genes, post-translational protein–protein interactions, and protein phosphorylation. Numerous proto-oncogenes and tumor suppressor genes are engaged in this mechanism, and the complexity of telomerase control is studied in the context of tumor development as well as aging. Additionally, since numerous studies reveal a correlation between short telomeres and increased genome instability or cell mortality, the telomerase control appears to be one of the crucial factors to study in order to improve the cancer diagnostics and therapy or prevention. Interestingly, almost 100 % of adenocarcinoma, including breast cancer cells, expresses telomerase which makes it a good target for telomerase-related therapy. Additionally, telomerase is also supposed to be associated with drug resistance. Thus, targeting the enzyme might result in attenuation of this phenomenon. Moreover, since stem cells existence was reported, it must be considered whether targeting telomerase can bring some serious side effects and result in stem cells viability or their regenerative potential decrease. Thus, we review some molecular mechanisms engaged in therapy based on targeting telomerase in breast cancer cells.     

Telomeres and telomerase in the clinical management of colorectal cancer

Colorectal cancer (CRC) is the third most common cancer worldwide. Our aim is to describe the state of the art about the role of telomeres and telomerase in the clinical management of CRC and its potential utility as prognostic and diagnostic biomarkers and targets of new treatments. Telomere length could be a new diagnostic marker as an anomalous behavior is observed in peripheral blood cells when CRC patients and healthy people are compared. Moreover, telomeres and telomerase may be used as diagnostic markers considering that universal changes appear along the CRC process. Currently, new therapeutic cancer approaches are focused on inhibiting the maintenance of telomere length, choosing as targets telomerase -or its subunits- or the Shelterin complex. The goal of these therapies is the shortening of telomeres and the induction of cell senescence. Telomeres and telomerase emerge as useful molecular tools in the clinical management of CRC.     

The telomeric PARP, tankyrases, as targets for cancer therapy

The requirement for the maintenance of telomeres by telomerase by most cancer cells for continued proliferation is a target in anticancer strategies. Tankyrases are poly(ADP-ribose) polymerases that enhance telomerase access to telomeres. Tankyrase 1 modulates telomerase inhibition in human cancer cells and is reviewed in this report as a potential telomere-directed anticancer target.     

Dysfunctional telomeres promote genomic instability and metastasis in the absence of telomerase activity in oncogene induced mammary cancer

Telomerase is a ribonucleoprotein that maintains the ends of chromosomes (telomeres). In normal cells lacking telomerase activity, telomeres shorten with each cell division because of the inability to completely synthesize the lagging strand. Critically shortened telomeres elicit DNA damage responses and limit cellular division and lifespan, providing an important tumor suppressor function. Most human cancer cells express telomerase which contributes significantly to the tumor phenotype. In human breast cancer, telomerase expression is predictive of clinical outcomes such as lymph node metastasis and survival. In mouse models of mammary cancer, telomerase expression is also upregulated. Telomerase overexpression resulted in spontaneous mammary tumor development in aged female mice. Increased mammary cancer also was observed when telomerase deficient mice were crossed with p53 null mutant animals. However, the effects of telomerase and telomere length on oncogene driven mammary cancer have not been completely characterized. To address these issues we characterized neu proto‐oncogene driven mammary tumor formation in G1 Terc?/? (telomerase deficient with long telomeres), G3 Terc?/? (telomerase deficient with short telomeres), and Terc+/+ mice. Telomerase deficiency reduced the number of mammary tumors and increased tumor latency regardless of telomere length. Decreased tumor formation correlated with increased apoptosis in Terc deficient tumors. Short telomeres dramatically increased lung metastasis which correlated with increased genomic instability, and specific alterations in DNA copy number and gene expression. We concluded that short telomeres promote metastasis in the absence of telomerase activity in neu oncogene driven mammary tumors. © 2011 Wiley Periodicals, Inc.     

KML001 cytotoxic activity is associated with its binding to telomeric sequences and telomere erosion in prostate cancer cells.

PURPOSE: KML001 (sodium metaarsenite) is an orally bioavailable arsenic compound that has entered phase I/II clinical trials in prostate cancer. In this study, we elucidated the mode of action of KML001 and investigated its effects on telomerase and telomeres. EXPERIMENTAL DESIGN: We compared telomere length to KML001 cytotoxic activity in a panel of human solid tumor cell lines. Duration of exposure and concentrations of KML001 that affect telomerase and telomeres were evaluated in relation to established mechanisms of arsenite action such as reactive oxygen species-related DNA damage induction. Binding of KML001 to telomeres was assessed by matrix-assisted laser desorption/ionization mass spectrometry. RESULTS: We established a significant inverse correlation (r(2) = 0.9) between telomere length and cytotoxicity. KML001 exhibited activity in tumor cells with short telomeres at concentrations that can be achieved in serum of patients. We found that telomerase is not directly inhibited by KML001. Instead, KML001 specifically binds to telomeric sequences at a ratio of one molecule per three TTAGGG repeats leading to translocation of the telomerase catalytic subunit into the cytoplasm. In prostate cancer cells with short telomeres, KML001 caused telomere-associated DNA damage signaling as shown by gamma-H2AX induction and chromatin immunoprecipitation assays as well as a rapid telomere erosion shown by metaphase fluorescence in situ hybridization. These effects were not seen in a lung cancer cell line with long telomeres. Importantly, arsenification of telomeres preceded DNA lesions caused by reactive oxygen species production. CONCLUSIONS: Sodium metaarsenite is a telomere targeting agent and should be explored for the treatment of tumors with short telomeres.     

Organ- and tissue-specific stem cells and carcinogenesis

Tissue-specific cancers originate in organ- or tissue-specific cells with the potential to proliferate. Recent reports have shown that every adult tissue may have its own stem cells. Cancer cells and organ- and tissue-specific stem cells and other progenitor cells are strikingly similar: both types self-renew, proliferate indefinitely, migrate, differentiate and express telomerase. Telomerase is a ribonucleoprotein that adds on nucleotides to the telomeres of chromosomes and so protects them from degradation, recombination and fusion at double-stranded DNA breaks. Cancer cells differ from normal tissue-specific stem cells only in their uncontrolled growth and altered genotypes. Based on the many similarities between cancer cells and stem cells, I propose that cancers (both solid and hematopoietic) arise from tissue-specific stem cells. Some such stem cells are always present among the stem cells in the peripheral blood of cancer patients and some of their asymptomatic first-degree relatives. It may therefore be possible to diagnose cancer predisposition early by identifying these circulating stem cells by their genetic defects. I, therefore, suggest that drug development for cancer treatment be directed towards tissue-specific stem cells.