Telomerase And Homologous Recombination As Targets In Barrett's Adenocarcinoma

端粒酶和同源重组作为巴雷特腺癌的靶标

• 批准号: 7692236
• 负责人: MASOOD A SHAMMAS
• 金额: $ 35.81万
• 依托单位: DANA-FARBER CANCER INST
• 依托单位国家: 美国
• 财政年份: 2008
• 资助国家: 美国
• 起止时间: 2008-09-24 至 2013-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7692236
• 关键词: Abnormal Cell; Adenocarcinoma; Adenocarcinoma Cell; Apoptosis; Barrett Esophagus; Barrett' s Adenocarcinoma; Behavior; Biological; Cancer Cell Growth; Cancer cell line; Cell Line; Cell Survival; Cells; Characteristics; Chemicals; Chromosomes; Columnar Metaplasia; DNA Damage; DNA Repair; DNA Sequence Rearrangement; Disease; Dysplasia; Epithelial Cells; Esophageal; Esophageal Adenocarcinoma; Esophagus; Exposure to; Gene Expression; Genes; Genetic Recombination; Genomics; Growth; Human; In Vitro; Incidence; Intestinal Metaplasia; Laboratory Research; Lasers; Lead; Length; Lesion; Life; Malignant Neoplasms; Malignant neoplasm of esophagus; Microscopy; Modeling; Molecular; Molecular Profiling; Normal Cell; Nuclear Structure; Oncogene Activation; Oncogenic; Phenotype; Play; Premalignant; Prevention; Proteins; Public Health; Regulation; Relative (related person); Reporting; Role; SCID Mice; Sampling; Squamous Epithelium; Staging; Telomerase; Telomerase Inhibitor; Telomerase inhibition; Telomere Maintenance; Telomere Shortening; Therapeutic; Transgenic Organisms; Up-Regulation; Xenograft Model; base; cancer cell; cancer prevention; carcinogenesis; cell growth; homologous recombination; human tissue; in vivo; inhibitor/antagonist; novel; outcome forecast; prevent; progression marker; recombinase; subcutaneous; telomere; therapeutic target; tumor; tumor xenograft

DESCRIPTION (provided by applicant): Telomere maintenance, by telomerase and/or homologous recombination (HR), plays a key role in providing unlimited growth potential to cancer cells. We have shown that telomerase activity is markedly elevated and telomeres are shorter in Barrett's adenocarcinoma cells relative to normal cells, and inhibitors of telomerase cause suppression of cancer cell growth in vitro and in xenograft model of human BEAC in SCID mice. The mechanisms of telomere maintenance and their activation during carcinogenesis are not known. However we have found that HR activity and recombinase expression are markedly elevated and ALT associated PML bodies are highly expressed in BEAC cells, providing an evidence of HR based telomere elongation in BEAC. Moreover elevated HR causes genomic rearrangements and may also lead to activation of oncogenes, including the induction of telomerase. We have also shown that key HR proteins, including recombinase, physically interact with telomerase in BEAC cells and suppression of these proteins suppresses telomerase activity and induces apoptosis. These observations indicate that elevated HR in BEAC may be involved in both the telomerase regulation and telomerase-independent maintenance of telomeres. Concomitant suppression of both telomerase and HR may enhance telomere shortening and apoptosis in BEAC by acting at multiple levels. The specific aims of this proposal are: 1) To study telomere function and expression of related genes in well defined human tissues in different histological stages of BEAC. Defined abnormal cells will be obtained using laser capture microscopy. 2) To determine the roles of HR in telomere function and cell survival in BEAC cultures by transgenic suppression or upregulation of HR genes. The influence of these manipulations on telomerase activity, telomere length, and cell survival will be determined. 3) To examine the therapeutic potential of telomerase and HR inhibitors alone and in combination on additional BEAC cell lines in vitro and in a xenograft model of human BEAC in SCID mice. Relevance to Public Health: In this proposal we will study the mechanisms by which esophageal cancer cells prevent shortening of their chromosomes ends and hence attain unlimited growth potential. We will also identify the agents which would re-activate shortening of chromosome ends in these cells and inhibit the growth of this cancer.

描述（由申请人提供）：端粒维持，端粒酶和/或同源重组（HR）在为癌细胞提供无限的生长潜力方面起着关键作用。我们已经表明，相对于正常细胞，端粒酶活性显着升高，端粒的端粒较短，而端粒酶抑制剂在SCID小鼠中会导致体外和人类BEAC的异种移植模型抑制癌细胞生长。端粒维持的机制及其在致癌过程中的激活尚不清楚。但是，我们发现HR活性和重组酶表达显着升高，ALT相关的PML体在BEAC细胞中高度表达，提供了BEAC中基于HR的端粒伸长的证据。此外，HR升高会导致基因组重排，还可能导致癌基因的激活，包括诱导端粒酶。我们还表明，包括重组酶在内的关键HR蛋白在BEAC细胞中与端粒酶物理相互作用并抑制这些蛋白质会抑制端粒酶活性并诱导凋亡。这些观察结果表明，BEAC中的HR升高可能与端粒的端粒酶调节和端粒酶无关的维护有关。端粒酶和HR的同时抑制可能通过多种水平作用来增强BEAC中的端粒缩短和凋亡。该提案的具体目的是：1）研究BEAC不同组织学阶段中定义明确的人体组织中相关基因的端粒功能和表达。使用激光捕获显微镜将获得定义的异常细胞。 2）通过转基因抑制或上调人力资源基因，确定人力资源在BEAC培养中的端粒功能和细胞存活的作用。这些操纵对端粒酶活性，端粒长度和细胞存活的影响将得到确定。 3）单独检查端粒酶和HR抑制剂的治疗潜力，并在SCID小鼠中人类BEAC的其他BEAC细胞系与其他BEAC细胞系组合使用。 与公共卫生的相关性：在此提案中，我们将研究食道癌细胞防止其染色体末端缩短的机制，从而获得无限的生长潜力。我们还将确定将重新激活这些细胞中染色体终止并抑制该癌症生长的药物。