Molecular mechanisms of initiation of benign prostatic hyperplasia

良性前列腺增生起始的分子机制

• 批准号: 10625982
• 负责人: Li Xin
• 金额: $ 57.77万
• 依托单位: UNIVERSITY OF WASHINGTON
• 依托单位国家: 美国
• 财政年份: 2016
• 资助国家: 美国
• 起止时间: 2016-07-01 至 2025-04-30
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10625982
• 关键词: AXIN2 gene; Acute; Affect; Age; Aging; Anatomy; Attenuated; Bacterial Infections; Benign Prostatic Hypertrophy; Biological; Cells; Development; Disease; Embryo; Epithelial Cell Proliferation; Epithelial Cells; Epithelial-Stromal Communication; Epithelium; Etiology; Fibroblast Growth Factor; Gene Expression; Genetically Engineered Mouse; Goals; Growth; Heterogeneity; Histologic; Homeostasis; Human; In Situ; In Vitro; Inflammation; Left; Life; Ligands; Mesenchymal; Mitotic; Molecular; Mus; Muscle; Nodule; Non-Malignant; Pathogenesis; Peptide Initiation Factors; Phenotype; Play; Process; Proliferating; Prostate; Prostatic; Prostatic Epithelium; Prostatic duct; Quantitative Reverse Transcriptase PCR; RNA; Regional Anatomy; Role; Signal Transduction; Specimen; Stromal Cells; Stromal Hyperplasia; Techniques; Tissues; Transforming Growth Factor beta; Urethra; Urinary Retention; WNT Signaling Pathway; Work; autocrine; beta catenin; cohort; epithelial stem cell; fetal; improved; in vitro Assay; in vivo; insight; laser capture microdissection; lower urinary tract symptoms; men; mouse model; novel; novel therapeutics; paracrine; single-cell RNA sequencing; stem cells; theories; transcriptome sequencing

Project Summary/Abstract Benign prostatic hyperplasia (BPH) is a progressive condition in aging men that is characterized by the enlargement of the periurethral regions of the prostate gland. An estimated 50% of men have histologic evidence of BPH by age 50 years and 75% by age 80 years. BPH is often accompanied by lower urinary tract symptoms (LUTS). BPH is rarely fatal, but may cause serious life-threatening complications such as acute urinary retention if left untreated. However, molecular mechanisms of BPH initiation and progression remain incompletely understood. The lack of understanding of these mechanisms is a barrier to improved treatment. BPH is a heterogeneous disease that results from nonmalignant proliferations of both the prostate epithelial and stromal compartments. The stromal nodules and the epithelial glandular nodules are the two typical nodules in BPH. Histological comparison of the stromal nodules with human fetal prostate stroma revealed that the ontogenetic processes of fetal prostate stroma (a transition from immature mesenchymal phenotype to fibroblastic, fibromuscular, and ultimately smooth-muscular phenotype) are recapitulated in the development of the BPH stromal nodules. This observation supports a theory of embryonic “reawakening”, which proposes that improper reactivation of embryonic signaling like FGFs attributes to initiation and progression of these stromal nodules. Formation of glandular nodules is suggested to develop as a result of stromal hyperplasia and deregulated stromal-epithelial interaction. But the underlying molecular mechanisms for glandular nodules have not been defined definitively. Our preliminary study shows that the Wnt signaling is active in prostate stromal cells and is capable of regulating the prostate epithelial stem cell activity. The goal of this application is to use a combination of molecular and cellular biological approaches, genetically engineered mouse models, and human BPH specimens to investigate how the Wnt signaling in prostate stromal cells is altered in BPH and how it affects BPH pathogenesis.

项目概要/摘要 良性前列腺增生（BPH）是老年男性的一种进行性疾病，其特征是 前列腺尿道周围区域增大估计 50% 的男性有组织学证据。 50 岁的 BPH 和 80 岁的 75% 的 BPH 常伴有下尿路症状。 (LUTS) 很少致命，但可能导致严重危及生命的并发症，例如急性尿潴留。 然而，如果不及时治疗，BPH 发生和进展的分子机制仍然不完整。 缺乏对这些机制的了解是改善 BPH 治疗的一个障碍。 由前列腺上皮和间质非恶性增殖引起的异质性疾病 间质结节和上皮腺结节是 BPH 中的两个典型结节。 基质结节与人胎儿前列腺基质的组织学比较表明，个体发生 胎儿前列腺基质的过程（从不成熟的间充质表型到成纤维细胞的转变， 纤维肌肉表型，最终是平滑肌表型）在 BPH 的发展过程中得到了重演 这一观察结果支持了胚胎“重新觉醒”的理论，该理论提出了不适当的做法。 FGF 等胚胎信号的重新激活归因于这些基质结节的起始和进展。 腺结节的形成被认为是由于基质增生和失调而形成的 但腺结节的基质-上皮相互作用的潜在分子机制尚未阐明。 我们的初步研究表明 Wnt 信号在前列腺基质细胞中活跃并且是 该应用的目标是使用能够调节前列腺上皮干细胞活性的组合。 分子和细胞生物学方法、基因工程小鼠模型和人类 BPH 样本以研究前列腺基质细胞中的 Wnt 信号如何在 BPH 中发生改变及其影响 前列腺增生症发病机制。

项目成果

Stromal FOXF2 suppresses prostate cancer progression and metastasis by enhancing antitumor immunity.

• DOI: 10.1038/s41467-022-34665-z
• 发表时间: 2022-11-11
• 期刊: NATURE COMMUNICATIONS
• 影响因子: 16.6
• 作者: Jia, Deyong;Zhou, Zhicheng;Kwon, Oh-Joon;Zhang, Li;Wei, Xing;Zhang, Yiqun;Yi, Mingyang;Roudier, Martine P.;Regier, Mary C.;Dumpit, Ruth;Nelson, Peter S.;Headley, Mark;True, Lawrence;Lin, Daniel W.;Morrissey, Colm;Creighton, Chad J.;Xin, Li
• 通讯作者: Xin, Li

De novo induction of lineage plasticity from human prostate luminal epithelial cells by activated AKT1 and c-Myc.

• DOI: 10.1038/s41388-020-01487-6
• 发表时间: 2020-11
• 期刊: Oncogene
• 影响因子: 8
• 作者: Kwon OJ;Zhang L;Jia D;Zhou Z;Li Z;Haffner M;Lee JK;True L;Morrissey C;Xin L
• 通讯作者: Xin L

Ablating Lgr5-expressing prostatic stromal cells activates the ERK-mediated mechanosensory signaling and disrupts prostate tissue homeostasis.

• DOI: 10.1016/j.celrep.2022.111313
• 发表时间: 2022-09-06
• 期刊: CELL REPORTS
• 影响因子: 8.8
• 作者: Wei, Xing;Zhang, Li;Zhang, Yiqun;Cooper, Cody;Brewer, Chris;Tsai, Chia-Feng;Wang, Yi-Ting;Glaz, Micah;Wessells, Hunter B.;Que, Jianwe;Titus, Mark A.;Cirulli, Vincenzino;Glaser, Adam;Liu, Tao;Reder, Nicholas P.;Creighton, Chad J.;Xin, Li
• 通讯作者: Xin, Li

Elevated expression of the colony-stimulating factor 1 (CSF1) induces prostatic intraepithelial neoplasia dependent of epithelial-Gp130.

• DOI: 10.1038/s41388-021-02169-7
• 发表时间: 2022-03
• 期刊: Oncogene
• 影响因子: 8
• 作者: Kwon OJ;Zhang B;Jia D;Zhang L;Wei X;Zhou Z;Liu D;Huynh KT;Zhang K;Zhang Y;Labhart P;Sboner A;Barbieri C;Haffner MC;Creighton CJ;Xin L
• 通讯作者: Xin L