Effects of Arsenic on Human Prostate Stem Cells and Prostate Cancer Risk

砷对人类前列腺干细胞和前列腺癌风险的影响

• 批准号: 9058540
• 负责人: Shuk-Mei Ho
• 金额: $ 40.55万
• 依托单位: UNIVERSITY OF ILLINOIS AT CHICAGO
• 依托单位国家: 美国
• 财政年份: 2012
• 资助国家: 美国
• 起止时间: 2012-08-23 至 2018-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9058540
• 关键词: Address; Adult; Adverse effects; Arsenic; Arsenites; Biological Assay; Cancer Patient; Candidate Disease Gene; Carcinogens; Cell Line; Cell Lineage; Cell model; DNA; DNA Methylation; Defect; Development; Disease; Dose; Embryo; Epigenetic Process; Epithelial; Epithelial Cells; Epithelium; Evaluation; Event; Exposure to; Gene Expression; Gene Expression Profile; Genes; Goals; Growth; Growth and Development function; Health; Hormonal Carcinogenesis; Human; In Vitro; Incidence; Kidney; Knowledge; Laboratory Study; Life; Link; Malignant Neoplasms; Malignant neoplasm of prostate; Measures; Mesenchyme; Modeling; Modification; Molecular; Monitor; Nude Mice; Organ; Population; Predisposition; Prostate; Prostatic Diseases; Rattus; Role; Seeds; Skin; Source; Specimen; Staging; Stem cells; Steroids; System; Technology; Tissue Microarray; Tissues; Work; cancer risk; cancer stem cell; carcinogenesis; cell transformation; drinking water; embryonic stem cell; epidemiology study; epigenome; epigenomics; exposed human population; genome wide methylation; genome-wide; human embryonic stem cell; human stem cells; in vivo; in vivo Model; innovation; men; methylome; mortality; novel; pluripotency; progenitor; prostate cancer cell line; relating to nervous system; self-renewal; transcriptome; transcriptome sequencing; tumor growth; tumor progression

DESCRIPTION (provided by applicant): The overall goal of the proposed work is to determine whether developmental or adult exposures to inorganic arsenic (iAs) increase prostate cancer (PCa) risk by reprogramming human prostate stem cells. Prior studies have revealed that environmental iAs exposure from natural sources (e.g. drinking water) increases PCa incidence. Recent findings also indicate that iAs directly alters stem cells and augments transformation and studies with PCa cell lines support that this may occur in the prostate gland. To further delineate iAs action(s) in normal human prostate stem cells, determine windows of sensitivity for human exposures and link iAs stem cell exposures to PCa development, novel human prostate stem cell models have been established using primary epithelial cells from disease-free human prostates and human embryonic stem cells (hESC). Importantly, in vivo models using either hESC or adult prostate stem cells mixed with rat inductive mesenchyme have been produced to generate chimeric prostate tissues with normal human prostate epithelium. These original approaches are in place to directly address several unresolved issues regarding iAs exposures and stem cell reprogramming events and to potentially link iAs to growth of human PCa. To accomplish this three specific aims are proposed. Specific Aim 1: Delineate the effects of iAs in modulating normal human prostate and embryonic stem cell self-renewal and differentiation to epithelial cell lineages. To accomplish this, FACS and prostasphere assay of adult human prostate stem cells and directed differentiation of hESC in vitro will be utilized to interrogate te actions of a range of iAs doses in perturbing normal prostate development and growth. Specific Aim 2: Elucidate the molecular underpinnings of As reprogramming of prostate stem cells by identifying DNA methylation modifications and resultant changes in gene expression. In parallel with Specific Aim 1, analysis of prostasphere DNA methylome, DNA hydroxymethylome and transcriptome will be undertaken to identify genome-wide marks in stem cells with resultant As gene expression signatures. Specific Aim 3: Determine whether As exposure initiates carcinogenesis, acts as a co-carcinogen or promotes PCa progression in human prostate epithelium using novel in vivo chimeric prostate models. Adult prostate stem cells from normal men, PCa patients or hESC will be used to generate chimeric tissues grown as renal grafts in nude mice. Carcinogenesis in normal epithelium will be monitored after iAs exposures alone or with steroids as co-carcinogens. PCa progression will be examined in PCa stem cell-derived grafts exposed to iAs. Finally, aberrant expression of iAs-reprogrammed genes will be evaluated in tissue microarrays constructed from PCa patients for translational relevance. The present approaches using fresh human specimens with in vivo models combined with state-of-the-art epigenomic technologies are a marked advance over current approaches that will undoubtedly provide significant new and useful information pertaining to human prostate health. Together, these studies will generate novel information on how iAs increases PCa risk and provide a rationale framework for iAs exposure assessment.

描述（由申请人提供）：拟议工作的总体目标是通过重新编程人类前列腺干细胞来确定发育期或成人接触无机砷（iAs）是否会增加前列腺癌（PCa）风险。先前的研究表明，来自自然资源（例如饮用水）的环境 iAs 暴露会增加前列腺癌的发病率。最近的研究结果还表明，iAs 直接改变干细胞并增强转化，并且对 PCa 细胞系的研究支持这可能发生在前列腺中。为进一步划定 iAs 在正常人类前列腺干细胞中的作用，确定人类暴露的敏感性窗口并将 iAs 干细胞暴露与 PCa 发育联系起来，使用来自无病人类前列腺和人类的原代上皮细胞建立了新型人类前列腺干细胞模型胚胎干细胞（hESC）。重要的是，使用 hESC 或成体前列腺干细胞与大鼠诱导间充质混合的体内模型已经产生，以产生与正常人前列腺上皮嵌合的前列腺组织。这些原始方法旨在直接解决有关 iAs 暴露和干细胞重编程事件的几个未解决的问题，并可能将 iAs 与人类 PCa 的生长联系起来。为了实现这一目标，提出了三个具体目标。具体目标 1：描述 iAs 在调节正常人前列腺和胚胎干细胞自我更新和分化为上皮细胞谱系方面的作用。为了实现这一目标，将利用成人前列腺干细胞的 FACS 和前列腺球测定以及体外 hESC 的定向分化来探究一系列 iAs 剂量在扰乱正常前列腺发育和生长中的作用。具体目标 2：通过鉴定 DNA 甲基化修饰和由此产生的基因表达变化，阐明前列腺干细胞 As 重编程的分子基础。与具体目标 1 并行，将对前球 DNA 甲基化组、DNA 羟甲基化组和转录组进行分析，以鉴定干细胞中的全基因组标记以及由此产生的 As 基因表达特征。具体目标 3：使用新型体内嵌合前列腺模型确定 As 暴露是否会引发致癌、作为共致癌物或促进人前列腺上皮中 PCa 进展。来自正常男性、PCa 患者或 hESC 的成年前列腺干细胞将用于生成嵌合组织，在裸鼠中作为肾移植物生长。在单独接触 iAs 或与类固醇作为共致癌物接触后，将监测正常上皮的致癌作用。将在暴露于 iAs 的 PCa 干细胞衍生移植物中检查 PCa 进展。最后，将在 PCa 患者构建的组织微阵列中评估 iAs 重编程基因的异常表达的翻译相关性。目前的方法使用新鲜的人类标本和体内模型，结合最先进的表观基因组技术，是目前方法的显着进步，无疑将提供有关人类前列腺健康的重要的新的和有用的信息。这些研究将共同​​产生有关 iAs 如何增加 PCa 风险的新信息，并为 iAs 暴露评估提供基本框架。

项目成果

The miR-183 family cluster alters zinc homeostasis in benign prostate cells, organoids and prostate cancer xenografts.

miR-183 家族簇改变良性前列腺细胞、类器官和前列腺癌异种移植物中的锌稳态。

• 发表时间: 2017
• 影响因子: 4.6
• 作者: Dambal, Shweta;Baumann, Bethany;McCray, Tara;Williams, LaTanya;Richards, Zachary;Deaton, Ryan;Prins, Gail S;Nonn, Larisa
• 通讯作者: Nonn, Larisa

Keratin Profiling by Single-Cell RNA-Sequencing Identifies Human Prostate Stem Cell Lineage Hierarchy and Cancer Stem-Like Cells.

通过单细胞 RNA 测序进行角蛋白分析可鉴定人类前列腺干细胞谱系层次和癌症干细胞样细胞。

• 发表时间: 2021-07-28
• 影响因子: 5.6
• 作者: Hu, Wen;Hu, Dan;Xie, Lishi;Nonn, Larisa;Lu, Ranli;Abern, Michael;Shioda, Toshihiro;Prins, Gail S
• 通讯作者: Prins, Gail S