Estrogen Receptors in Human Prostate Stem-Progenitor Cells

人前列腺干祖细胞中的雌激素受体

基本信息

批准号：
9193620
负责人：
Gail S Prins
金额：
$ 33.05万
依托单位：
UNIVERSITY OF ILLINOIS AT CHICAGO
依托单位国家：
美国
项目类别：
财政年份：
2013
资助国家：
美国
起止时间：
2013-01-01 至 2019-08-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9193620
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 GPER gene 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 Primary Cell Cultures 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 Tumor Initiators Urogenital Sinus cancer stem cell carcinogenesis drug discovery estrogenic in vivo in vivo Model knock-down 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 stem-like cell therapeutic target treatment strategy tumor progression

项目摘要

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）：前列腺是终生受雄激素作用调节的激素依赖性组织，众所周知，雌激素在前列腺发育和稳态中发挥关键作用，并有助于前列腺癌的发生和进展。尽管已经在女性器官中进行了详细研究，但前列腺中雌激素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出高水平的雌激素。受体 - ER�、ER� 和 GPR30 – 并对雌二醇-17�表现出增加的增殖反应。此外，初步数据表明，人类前列腺癌 (PCa) 干细胞样细胞中存在丰富的 ER 表达，表明该肿瘤细胞群可能是直接的。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。为实现这些目标，提出了三个具体目标：确定 ER�、ER�和 GPR30 在调节自我更新、扩增、细胞凋亡和增殖中的具体作用。为了实现这一点，我们将利用完全表征的前列腺球系统来研究来自原代前列腺上皮培养物的干细胞和祖细胞。目的 2：阐明人类前列腺癌干细胞样细胞中特定 ER 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富集干细胞/祖细胞。结果将通过对两种永生化人类 PCa 干细胞系、HPET 和 HuSLC 与正常和癌症相关成纤维细胞的共培养研究中的 ER 作用进行支持。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 在介导体内激素癌变和调节 PCa 生长和进展中的作用已经建立了体内细胞重组移植模型。使用正常人前列腺干/祖细胞或人PCa干细胞样细胞与胚胎间充质混合，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。靶向 ER 敲低和选择性雌激素受体调节剂 (SERM) 将被测试，以描述雌激素作用并调节体内 PCa 生长，重要的是，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。，使用来自器官捐献者和 PCa 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，由前列腺癌生长对 SERM 的体内反应支持的详细分子结果有可能确定用于治疗 PCa 和前列腺癌的新治疗靶点。使用针对干细胞 ER 作用的新型小分子为未来的药物发现策略提供信息。

项目成果

期刊论文数量（4）

专著数量（0）

科研奖励数量（0）

会议论文数量（0）

专利数量（0）

Isolation of Stem-like Cells from 3-Dimensional Spheroid Cultures.

从 3 维球体培养物中分离干细胞。

DOI：
10.3791/60357
发表时间：
2019
期刊：
Journal of visualized experiments : JoVE
影响因子：
0
作者：
Hu,Wen-Yang;Hu,Dan-Ping;Xie,Lishi;Birch,LynnA;Prins,GailS
通讯作者：
Prins,GailS

Magnetic kyphoplasty: A novel drug delivery system for the spinal column.

DOI：
10.1371/journal.pone.0201402
发表时间：
2018
期刊：
PloS one
影响因子：
3.7
作者：
Denyer S;Bhimani AD;Papastefan S;Kheirkhah P;Aguilar T;Zakrzewski J;Rosinski CL;Patel AS;Patel S;Zakrzewski V;Seksenyan A;Prins GS;Mehta AI
通讯作者：
Mehta AI

The Development of Prostate Adenocarcinoma in a Transgender Male to Female Patient: Could Estrogen Therapy Have Played a Role?

跨性别男性变女性患者前列腺腺癌的发展：雌激素治疗是否发挥了作用？

DOI：
10.1002/pros.23322
发表时间：
2017
期刊：
The Prostate
影响因子：
0
作者：
Sharif,Asma;Malhotra,NehaR;Acosta,AndresM;Kajdacsy-Balla,AndreA;Bosland,Maarten;Guzman,Grace;Prins,GailS;Abern,MichaelR
通讯作者：
Abern,MichaelR