Impact of aging on prostate cancer with TMPRSS2-ETS gene fusion

TMPRSS2-ETS 基因融合衰老对前列腺癌的影响

• 批准号: 9203369
• 负责人: Zhe Li
• 金额: $ 6万
• 依托单位: BRIGHAM AND WOMEN'S HOSPITAL
• 依托单位国家: 美国
• 财政年份: 2016
• 资助国家: 美国
• 起止时间: 2016-09-16 至 2018-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9203369
• 关键词: Advanced Development; Affect; Age; Age-Months; Aging; Alleles; Androgens; Animal Model; Breeding; Cells; Chromosomal Rearrangement; Chromosomes, Human, Pair 21; Chronic; Clinical; Code; Collagen; Cre-LoxP; Development; Disease; ERG gene; ETS2 gene; ETV1 gene; Ectopic Expression; Elderly; Epithelial Cells; Estrogens; Event; Excision; Experimental Designs; Family; Gene Fusion; Genes; Genetic Recombination; Genomics; Hormones; Human; Human Chromosomes; Incidence; Inflammation; Kinetics; Knock-in; Knock-in Mouse; Knock-out; Lead; Lesion; LoxP-flanked allele; Malignant Neoplasms; Malignant neoplasm of prostate; Mediating; Metabolism; Modeling; Molecular; Mus; Mutation; Oncogenes; Oncogenic; Organism; Outcome; Oxidative Stress; Pathology; Patients; Phase; Prostate; Prostatic Intraepithelial Neoplasias; Reporter; Research; Risk Factors; Sampling; Smooth Muscle Myocytes; Somatic Mutation; Study models; TMPRSS2 gene; Tamoxifen; Testing; Tumor Suppressor Proteins; age related; aged; androgenic; anticancer research; base; cancer initiation; cancer type; carcinogenesis; cohort; design; human disease; interstitial; male; men; mouse model; overexpression; prostate cancer cell; prostate carcinogenesis; research study; transcription factor; tumor progression

This proposed project will test a central hypothesis that aged milieu of the organism has an impact on the pathobiology of prostate cancer. Prostate cancer is one of the human cancer types most notably associated with advanced age. In fact, old age is thought as the most significant risk factor for developing prostate cancer in men. Several aging-associated molecular and cellular changes, such as changes in the prostatic microenvironment (e.g., chronic inflammation, changes in collagen and smooth muscle cells in the stroma), oxidative stress, genomic damage due to androgenic stimulation, changes in the hormone milieu (e.g., estrogen/androgen ratio), and changes in metabolism, etc., may contribute to prostate tumorigenesis. Among somatic mutations in prostate cancers, gene fusions involving ETS family transcription factors (mainly ERG, followed by ETV1) have been found in ~50% of human prostate cancer cases. The majority of these gene fusions are formed by joining the control region of an androgen (and estrogen)-responsive gene, TMPRSS2, to the coding region of ERG or ETV1. Collectively, these ETS fusions represent an early event in prostate tumorigenesis. Several Cre/loxP-based inducible knockin mouse models were generated by us to recapitulate the three major types of TMPRSS2-ETS fusions found in patients, including TMPRSS2-ERG fusion with an interstitial deletion between TMPRSS2 and ERG loci (both genes are located on human chromosome 21 and are ~3Mb apart), TMPRSS2-ERG fusion without deletion, and TMPRSS2-ETV1 fusion. Previous studies using these models showed that while neither of the Tmprss2-ETS fusions alone was sufficient to initiate prostate tumorigenesis, they could all cooperate with Pten-loss to drive prostate cancer progression, suggesting these fusions sensitize prostate cells for cooperation with additional oncogenic events during prostate tumorigenesis. As these findings were made in young mice, it is hypothesized that in aged mice, aging-associated molecular and cellular changes may cooperate with TMPRSS2-ETS fusions, leading to prostate cancer initiation and/or progression. To test this hypothesis, a CreER knockin (to the constitutive Rosa26 locus) mouse model (R26-CreER) will be used to control activation of Tmprss2-ETS knockin alleles, either alone or together with inactivation of one copy of Pten, in prostate cells, by administration of tamoxifen to either aged (24 months) or matched young (4 months) male mice. The induced mice will be followed for up to one year to determine the incidence, kinetics, grade and pathology [e.g., prostatic intraepithelial neoplasia (PIN) or invasive cancer] of prostate lesions. A comparison of these in the aged versus young cohorts would reveal aging-associated changes and whether such changes cooperate with Tmprss2-ETS fusions, or with Tmprss2-ETS fusions plus Pten-loss to drive prostate cancer development, and whether old mice represent a better model for studying prostate cancer.

这个拟议的项目将检验一个中心假设，即该生物体的陈年环境对 前列腺癌病理生物学。前列腺癌是最显着相关的人类癌类型之一 与高龄。实际上，老年被认为是发展前列腺的最重要危险因素 男性的癌症。几种与衰老相关的分子和细胞变化，例如前列腺的变化 微环境（例如，慢性炎症，基质中胶原蛋白和平滑肌细胞的变化）， 氧化应激，雄激素刺激引起的基因组损伤，激素环境的变化（例如， 雌激素/雄激素比）以及代谢等的变化可能导致前列腺肿瘤发生。 在前列腺癌中的体细胞突变中，涉及ETS家族转录因子的基因融合 （主要是ERG，其次是ETV1）在约50％的人前列腺癌病例中发现。大多数 这些基因融合是通过连接雄激素（和雌激素）响应基因的控制区而形成的。 TMPRSS2，到ERG或ETV1的编码区域。总的来说，这些ETS融合代表了早期事件 在前列腺肿瘤发生中。我们生成了几种基于CRE/LOXP的诱导型敲蛋白模型 概述患者中发现的三种主要类型的TMPRSS2-ETS融合，包括TMPRSS2-ERG TMPRSS2和ERG基因座之间具有间质缺失的融合（这两个基因都位于人 21染色体，分开约3MB），无删除的TMPRSS2-GERT融合以及TMPRSS2-ETV1融合。 先前使用这些模型的研究表明，虽然TMPRSS2-ETS融合都不是 足以启动前列腺肿瘤发生，它们都可以与PTEN损失合作以驱动前列腺癌 进展，表明这些融合使前列腺细胞敏感以与其他致癌性合作 前列腺肿瘤发生期间的事件。由于这些发现是在年轻小鼠中做出的，因此假设 老化的小鼠，与衰老相关的分子和细胞变化可能与TMPRSS2-ETS融合合作， 导致前列腺癌的启动和/或进展。为了检验这一假设，cr敲蛋白（到 组成型ROSA26小鼠模型（R26-CREER）将用于控制TMPRSS2-ETS的激活 单独或与一个单独的敲击等位基因一起，或者与PTEN副本灭活，在前列腺细胞中，通过 对他莫昔芬的给药对年龄（24个月）或匹配的年轻（4个月）雄性小鼠。这 诱导的小鼠将遵循长达一年的时间，以确定发病率，动力学，等级和病理学 [这些比较 在老年人和年轻队列中，将揭示与衰老相关的变化以及这种变化是否 与TMPRSS2-ETS融合或与TMPRSS2-ETS融合以及PTEN-LOSS合作，以驱动前列腺癌 发育以及旧小鼠是否代表了研究前列腺癌的更好模型。