Estrogen Receptors in Human Prostate Stem-Progenitor Cells

人前列腺干祖细胞中的雌激素受体

• 批准号: 8419827
• 负责人: Gail S Prins
• 金额: $ 34.53万
• 依托单位: UNIVERSITY OF ILLINOIS AT CHICAGO
• 依托单位国家: 美国
• 财政年份: 2013
• 资助国家: 美国
• 起止时间: 2013-01-01 至 2017-12-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8419827
• 关键词: Adult; Agonist; Androgens; Apoptosis; Benign; Benign Prostatic Hypertrophy; Biological Assay; Biology; Cancer Patient; Cancerous; Cell Line; Cells; Chimera organism; Coculture Techniques; Data; Development; Differentiation and Growth; Disease; Embryo; Epithelial; Epithelial Cells; Epithelium; Estradiol; Estrogen Receptors; Estrogens; Exhibits; Female; Fibroblasts; Future; Genetic Recombination; Goals; Grant; Growth; Health; Homeostasis; Hormonal Carcinogenesis; Hormones; Human; In Vitro; Kidney; Laboratories; Life; Malignant Neoplasms; Malignant neoplasm of prostate; Mediating; Mesenchyme; Minor; Modeling; Molecular; Organ; Organ Donor; Patients; Play; Population; Prostate; Prostate Cancer therapy; Prostatic Diseases; Rattus; Receptor Cell; Recombinants; Research; Resistance; Role; Selective Estrogen Receptor Modulators; Source; Specimen; Stem cells; Stromal Cells; System; Testing; Therapeutic; Tissues; Urogenital Sinus; cancer stem cell; carcinogenesis; drug discovery; in vivo; in vivo Model; men; neoplastic cell; new therapeutic target; novel; prevent; prostate cancer cell; prostate carcinogenesis; public health relevance; receptor; receptor expression; response; self-renewal; small hairpin RNA; small molecule; stem; stem cell niche; therapeutic target; treatment strategy; tumor; tumor progression

DESCRIPTION (provided by applicant): The prostate gland is a hormone dependent tissue regulated throughout life by androgen action. It is also known that estrogens play key roles in prostate development and homeostasis and contribute to prostate carcinogenesis and progression. While estrogen actions through multiple receptors have been studied in detail in female organs, the mechanisms of estrogenic effects in the prostate gland are not well understood. Recently, our laboratory demonstrated that human prostate epithelial stem and progenitor cells from normal adult prostates express robust levels of estrogen receptors - ER¿, ER¿ and GPR30 - and exhibit increased proliferative responses to estradiol-17¿. Further, preliminary data indicate heightened ER expression in human prostate cancer (PCa) stem-like cells suggesting that this minor tumor cell population may be a direct estrogen target. The overall goal of the proposed studies is to delineate the roles of estrogen receptors (ER¿, ER¿ and GPR30) in epithelial stem and progenitor cells of the normal and cancerous human prostate gland and to elucidate their specific roles in promoting or preventing carcinogenesis and progression. Three Specific Aims are proposed to accomplish these goals. AIM 1: Define the specific roles for ER¿, ER¿ and GPR30 in regulating self-renewal, amplification, apoptosis and/or differentiation in human prostate stem- progenitor cells from normal adult tissues. To accomplish this, we will utilize a fully characterized prostasphere system to interrogate stem and progenitor cells from primary prostate epithelial cultures of disease-free organ donors. AIM 2: Elucidate the expression and roles of specific ERs in human prostate cancer stem-like cells. Primary epithelial cultures of benign and PCa cells from patient specimens will be utilized to enrich for stem/progenitor cells by prostasphere assay. Results will be supported by interrogating ER actions in two immortalized human PCa stem-like cell lines, HPET and HuSLC. Co-culture studies with normal and cancer- associated fibroblasts will be used to define the estrogen-responsive stem cell niche in normal and cancerous human prostates. AIM 3: Delineate the actions of specific ERs in mediating hormonal carcinogenesis in vivo and regulating PCa growth and progression. An in vivo cell recombination graft model has been established using normal human prostate stem/progenitor cells or human PCa stem-like cells mixed with embryonic mesenchyme to generate chimeric prostate-like tissues with normal human prostate epithelium or prostate cancer. Targeted ER knockdown and selective estrogen receptor modulators (SERMs) will be tested to delineate estrogen actions and regulate PCa growth in vivo. Together, the present approaches will provide the first direct evidence for ER-specific actions in human prostate stem and progenitor cells. Importantly, use of fresh human prostate specimens from organ donors and PCa patients will grant translational relevance to the findings. The detailed molecular results supported by in vivo responses of prostate cancer growth to SERMs have potential to identify new therapeutic targets for management of PCa and inform future drug discovery strategies using novel small molecules that target stem cell ER actions.

描述（由申请人提供）：前列腺是一种激素依赖性组织，终生受雄激素作用调节。众所周知，雌激素在前列腺发育和体内平衡中发挥着关键作用，并有助于前列腺癌的发生和进展。虽然雌激素通过多种受体在女性器官中的作用已被详细研究，但雌激素在前列腺中作用的机制尚不清楚。最近，我们的实验室证明，来自正常成人前列腺的人类前列腺上皮干细胞和祖细胞表达高水平的雌激素受体 - ER¿、ER¿ 和 GPR30 - 并表现出对 estradiol-17¿ 的增殖反应增加。此外，初步数据表明，人前列腺癌（PCa）干细胞样细胞中 ER 表达升高，表明这种小肿瘤细胞群可能是雌激素的直接靶点。拟议研究的总体目标是描绘雌激素受体（ER¿、ER¿和GPR30）在正常和癌性人类前列腺的上皮干细胞和祖细胞中的作用，并阐明它们在促进或预防癌发生和进展中的具体作用。为了实现这些目标，提出了三个具体目标。目标 1：定义 ER¿、ER¿和 GPR30 在调节来自正常成体组织的人前列腺干祖细胞的自我更新、扩增、凋亡和/或分化中的具体作用。为了实现这一目标，我们将利用完全表征的前列腺球系统来询问来自无病器官捐献者的原代前列腺上皮培养物的干细胞和祖细胞。目标 2：阐明特定 ER 在人类前列腺癌干细胞样细胞中的表达和作用。来自患者标本的良性细胞和 PCa 细胞的原代上皮培养物将用于通过前列腺球测定富集干细胞/祖细胞。结果将通过研究两种永生化人 PCa 干细胞样细胞系 HPET 和 HuSLC 中的 ER 作用来支持。正常和癌症相关成纤维细胞的共培养研究将用于定义正常和癌性人类前列腺中的雌激素反应性干细胞生态位。目标 3：描述特定 ER 在介导体内激素致癌作用以及调节 PCa 生长和进展中的作用。使用正常人前列腺干/祖细胞或人PCa干样细胞与胚胎间充质混合以产生与正常人前列腺上皮或前列腺癌嵌合的前列腺样组织，建立了体内细胞重组移植模型。将测试靶向 ER 敲低和选择性雌激素受体调节剂 (SERM)，以描述雌激素作用并调节体内 PCa 生长。总之，目前的方法将为人类前列腺干细胞和祖细胞中 ER 特异性作用提供第一个直接证据。重要的是，使用来自器官捐献者和前列腺癌患者的新鲜人类前列腺标本将为研究结果提供转化相关性。前列腺癌生长对 SERM 的体内反应所支持的详细分子结果有可能确定治疗 PCa 的新治疗靶点，并为未来使用针对干细胞 ER 作用的新型小分子的药物发现策略提供信息。