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: 10007618
• 负责人: Zhe Li
• 金额: $ 15万
• 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 2022-02-28
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10007618
• 关键词: Advanced Development; Affect; Age; Aging; Alleles; Androgens; Animal Model; Cells; Chromosomal Rearrangement; Chromosome 21; Chronic; Clinical; Code; Collagen; Cre-LoxP; DNA cassette; 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; Lead; LoxP-flanked allele; Malignant Neoplasms; Malignant neoplasm of prostate; Mediating; Metabolism; Modeling; Molecular; Mus; Mutation; Oncogenic; Organism; Outcome; Oxidative Stress; Pathology; Patients; Phase; Prostate; Prostatic; Prostatic Intraepithelial Neoplasias; Reporter; Research; Risk Factors; Sampling; Smooth Muscle Myocytes; Somatic Mutation; Study models; TMPRSS2 gene; Tamoxifen; Testing; Tumor Suppressor Proteins; advanced prostate cancer; aged; androgenic; anticancer research; base; cancer initiation; cancer invasiveness; cancer type; carcinogenesis; cohort; conditional knockout; design; experimental study; human disease; interstitial; male; men; mouse model; overexpression; prostate cancer cell; prostate cancer progression; prostate carcinogenesis; prostate lesions; transcription factor

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.

这项拟议的项目将测试一个中心假设，即生物体的老化环境对生物体的生长有影响。 前列腺癌的病理生物学前列腺癌是人类癌症类型之一， 年纪大了事实上，老年被认为是前列腺最重要的危险因素 男性癌症一些与衰老相关的分子和细胞变化，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，由于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/雄激素比率），以及代谢的变化等，可能导致前列腺肿瘤的发生。 在前列腺癌的体细胞突变中，涉及ETS家族转录因子的基因融合 在约50%的人前列腺癌病例中发现了视网膜电图（主要是ERG，其次是ETV 1）。大多数 这些基因融合体是通过连接雄激素（和雌激素）反应基因的控制区而形成的， TMPRSS 2与ERG或ETV 1的编码区连接。总的来说，这些ETS融合代表了早期事件 前列腺肿瘤的发生。我们建立了几种基于Cre/loxP的诱导型敲入小鼠模型 为了概括在患者中发现的三种主要类型的TMPRSS 2-ETS融合，包括TMPRSS 2-ERG 在TMPRSS 2和ERG基因座之间具有间质缺失的融合（两种基因都位于人 21号染色体并且相距约3 Mb）、TMPRSS 2-ERG融合而无缺失和TMPRSS 2-ETV 1融合。 先前使用这些模型的研究表明，虽然Tmprss 2-ETS融合体单独 足以启动前列腺肿瘤发生，它们都可以与Pten丢失合作，以驱动前列腺癌 进展，表明这些融合使前列腺细胞与其他致癌因子合作敏感。 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进行的，因此假设在 在老年小鼠中，与衰老相关的分子和细胞变化可能与TMPRSS 2-ETS融合物协同作用， 导致前列腺癌的发生和/或进展。为了验证这一假设，一个CreER敲入（到 组成型Rosa 26基因座）小鼠模型（R26-CreER）将用于控制Tmprss 2-ETS的激活 敲入等位基因，单独或与Pten的一个拷贝的失活一起，在前列腺细胞中， 向老年（24个月）或匹配的年轻（4个月）雄性小鼠施用他莫昔芬。的 将对诱导小鼠进行长达一年的随访，以确定发病率、动力学、分级和病理学 [e.g.,前列腺上皮内瘤（PIN）或浸润性癌]。比较这些 将揭示与衰老相关的变化，以及这些变化是否 与Tmprss 2-ETS融合体或与Tmprss 2-ETS融合体加上Pten-丢失协同作用以驱动前列腺癌 以及老年小鼠是否是研究前列腺癌的更好模型。