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.

这个拟议的项目将测试一个中心假设，即生物体的老化环境对 前列腺癌的病理学。前列腺癌是最显着相关的人类癌症类型之一 随着年龄的增长。事实上，老年被认为是患前列腺的最重要的危险因素 男性癌症。一些与衰老相关的分子和细胞变化，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/雄激素比例）、新陈代谢的改变等可能促进前列腺肿瘤的发生。 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 （主要是 ERG，其次是 ETV1）已在约 50% 的人类前列腺癌病例中发现。大部分 这些基因融合体是通过连接雄激素（和雌激素）反应基因的控制区域而形成的， TMPRSS2，连接到 ERG 或 ETV1 的编码区。总的来说，这些 ETS 融合代表了一个早期事件 在前列腺肿瘤发生中。我们构建了多个基于 Cre/loxP 的诱导敲入小鼠模型 概括在患者中发现的三种主要类型的 TMPRSS2-ETS 融合，包括 TMPRSS2-ERG TMPRSS2 和 ERG 基因座之间存在间质性缺失的融合（这两个基因均位于人类基因座上） 21 号染色体，相距约 3Mb）、无删除的 TMPRSS2-ERG 融合以及 TMPRSS2-ETV1 融合。 先前使用这些模型的研究表明，虽然单独的 Tmprss2-ETS 融合都不能 足以引发前列腺肿瘤发生，它们都可以与 Pten 缺失合作驱动前列腺癌 进展，表明这些融合使前列腺细胞与其他致癌物质合作变得敏感 前列腺肿瘤发生过程中的事件。由于这些发现是在年轻小鼠身上进行的，因此推测 老年小鼠，衰老相关的分子和细胞变化可能与 TMPRSS2-ETS 融合相配合， 导致前列腺癌的发生和/或进展。为了检验这一假设，CreER 基因敲入（对 组成型 Rosa26 位点）小鼠模型 (R26-CreER) 将用于控制 Tmprss2-ETS 的激活 敲入等位基因，单独或与前列腺细胞中 Pten 一个拷贝的失活一起，通过 将他莫昔芬给予老年（24 个月）或匹配的年轻（4 个月）雄性小鼠。这 诱导小鼠将被跟踪长达一年以确定发病率、动力学、等级和病理学 [例如，前列腺上皮内瘤变 (PIN) 或浸润性癌症] 前列腺病变。这些的比较 老年人与年轻人的比较将揭示与衰老相关的变化，以及这些变化是否 与Tmprss2-ETS融合配合，或与Tmprss2-ETS融合加上Pten缺失来驱动前列腺癌 发育，以及老年小鼠是否代表研究前列腺癌的更好模型。