The Notch Signaling in Prostate Homeostasis and Carcinogenesis

前列腺稳态和癌发生中的Notch信号传导

基本信息

批准号：
8958462
负责人：
Li Xin
金额：
$ 36.26万
依托单位：
BAYLOR COLLEGE OF MEDICINE
依托单位国家：
美国
项目类别：
财政年份：
2015
资助国家：
美国
起止时间：
2015-07-07 至 2020-06-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8958462
关键词：
Anoikis Biological Breeding Cellular biology Cessation of life Clinic Clinical Trials Collaborations Consensus Data Data Set Disease Disease Progression Disseminated Malignant Neoplasm Distal Epithelial Cell Proliferation Epithelial Cells Goals Homeostasis Human In Vitro Knockout Mice Knowledge Lead Lesion Ligands Link Malignant Neoplasms Malignant neoplasm of prostate Mediating Metastatic Prostate Cancer Metastatic/Recurrent Modeling Molecular Molecular Genetics Mus Neoplasm Metastasis Oncogenes Oncogenic Pathway interactions Patients Penetrance Play Prostate Prostatic Neoplasms Publishing Resistance Role Signal Transduction Solid Specimen Texas Therapeutic Therapeutic Agents Tissue Microarray Up-Regulation base cancer cell cancer recurrence cancer therapy carcinogenesis cell motility established cell line high throughput screening in vivo mouse model neoplastic cell new therapeutic target notch protein novel novel therapeutics preclinical study prostate cancer cell prostate cancer model prostate carcinogenesis public health relevance receptor screening small molecule therapeutic target tool tumor tumor microenvironment tumor progression

项目摘要

DESCRIPTION (provided by applicant): Notch signaling plays a critical role in the initiation and progression of various malignancies, and has been targeted therapeutically for several malignancies in clinical trials. Despite the consensus that Notch signaling is deregulated during prostate carcinogenesis, Notch has not yet been employed as a therapeutic target for prostate cancer due to the inadequately defined role of Notch signaling during prostate cancer progression. Our preliminary studies showed that increased expression of the active Notch1 intracellular domain (NICD) in the prostate (the PB-NICD model) promotes prostate luminal epithelial cell proliferation, supporting Notch as a pro-oncogenic pathway in the prostate in vivo. In addition, most Notch signaling components are upregulated in prostate tumor specimens of patients that developed recurrent metastatic diseases. Consistent with this observation, our preliminary studies show that increased Notch activity induces anoikis resistance of prostate epithelial cells and enhances the in vitro and in vivo metastatic potential of prostate cancer cell. Based on these preliminary studies, Notch signaling may promote prostate cancer metastasis. The goals of this application are to determine how Notch signaling alters prostate epithelial cell biology, and to determine whether and how Notch promotes prostate cancer metastasis. To achieve our goals, we will increase Notch activity by manipulating either Notch ligand or receptor in mouse models for human prostate cancer to directly determine whether Notch signaling promotes prostate cancer metastasis. In addition, a combination of genetic, molecular, and cellular biological approaches will be utilized to investigate the molecular mechanisms through which Notch promotes anoikis resistance. Finally, we will perform high-throughput screenings to identify small- molecule compounds that suppress Notch induced anoikis resistance.

描述（由申请人提供）：Notch 信号传导在各种恶性肿瘤的发生和进展中发挥着关键作用，并且在临床试验中已用于治疗多种恶性肿瘤，尽管人们一致认为 Notch 信号传导在前列腺癌发生过程中失调，但 Notch 尚未实现这一点。由于Notch信号在前列腺癌进展过程中的作用尚未明确，因此被用作前列腺癌的治疗靶点。我们的初步研究表明，前列腺中活性Notch1细胞内结构域（NICD）的表达增加。 PB-NICD 模型）促进前列腺管腔上皮细胞增殖，支持 Notch 作为前列腺体内的促癌途径。此外，在患有复发性转移性疾病的患者的前列腺肿瘤标本中，大多数Notch信号成分上调，与这一观察结果一致，我们的初步研究表明，Notch活性的增加会诱导前列腺上皮细胞的失巢凋亡抵抗，并增强体外和体内的转移。基于这些初步研究，Notch 信号传导可能促进前列腺癌转移，本申请的目标是确定 Notch 信号传导如何改变前列腺上皮细胞生物学，并确定是否和改变。 Notch如何促进前列腺癌转移为了实现我们的目标，我们将通过操纵人类前列腺癌小鼠模型中的Notch配体或受体来增加Notch活性，以直接确定Notch信号传导是否促进前列腺癌转移。我们将利用分子和细胞生物学方法来研究Notch促进失巢凋亡抗性的分子机制，最后，我们将进行高通量筛选来鉴定抑制Notch诱导的失巢凋亡抗性的小分子化合物。