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

这项拟议的项目将检验一个中心假设，即有机体的老化环境对 前列腺癌的病理生物学。前列腺癌是人类最显著的癌症类型之一。 年纪大了。事实上，老年被认为是发展前列腺癌的最重要的风险因素。 男性患癌症。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、间质中胶原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/雄激素比值)以及新陈代谢的改变等，都可能导致前列腺癌的发生。 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。大多数人 这些基因融合是通过连接雄激素(和雌激素)反应基因的控制区而形成的， TMPRSS2至ERG或ETV1的编码区。总体而言，这些ETS融合代表着一个早期事件 在前列腺癌发生中的作用。我们建立了几种基于Cre/loxP的可诱导敲击小鼠模型 总结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基因座之间存在间隙缺失的融合(这两个基因都位于人类 21号染色体，相距约3MB)，TMPRSS2-ERG融合无缺失，TMPRSS2-ETV1融合。 之前使用这些模型的研究表明，虽然TMPRSS2-ETS的融合都不是单独的 足以启动前列腺癌的形成，它们都可以与Pten-Lost协同驱动前列腺癌 进展，表明这些融合使前列腺细胞与其他致癌细胞合作敏感 前列腺癌发生过程中的事件。由于这些发现是在幼鼠身上发现的，因此假设在 衰老小鼠，衰老相关的分子和细胞变化可能与TMPRSS2-ETS融合协同作用， 导致前列腺癌的发生和/或进展。为了检验这一假设，克里尔敲门(对 R26-Creer)小鼠模型将用于控制TMPRSS2-ETS的激活 Knockin等位基因，单独或与一个拷贝的Pten一起失活，在前列腺细胞中，通过 给老年(24个月)或匹配的年轻(4个月)雄性小鼠注射他莫昔芬。这个 将对诱导的小鼠进行长达一年的跟踪，以确定发病率、动力学、分级和病理学。 [例如，前列腺上皮内瘤变(PIN)或浸润性癌]的前列腺病变。这两种产品的比较 将揭示与衰老相关的变化，以及这种变化 联合TMPRSS2-ETS融合或TMPRSS2-ETS融合加Pten-Lost促前列腺癌 发展，以及老年小鼠是否代表了研究前列腺癌的更好模型。

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.