The Notch Signaling in Prostate Homeostasis and Carcinogenesis

前列腺稳态和癌发生中的Notch信号传导

• 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
• 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

 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起着关键作用，并且在临床试验中已成为几种恶性肿瘤的治疗靶点。尽管Notch信号传导在前列腺癌发生过程中失调是共识，但由于Notch信号传导在前列腺癌进展过程中的作用定义不充分，Notch尚未被用作前列腺癌的治疗靶点。我们的初步研究表明，在前列腺（PB-NICD模型）中增加的活性Notch 1胞内结构域（NICD）的表达促进前列腺腔上皮细胞增殖，支持Notch作为体内前列腺中的促癌途径。 此外，大多数Notch信号传导组分在发生复发性转移性疾病的患者的前列腺肿瘤标本中上调。与这一观察结果一致，我们的初步研究表明，增加的Notch活性诱导前列腺上皮细胞的失巢凋亡抗性，并增强前列腺癌细胞的体外和体内转移潜力。基于这些初步研究，Notch信号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Notch是否以及如何促进前列腺癌转移。为了实现我们的目标，我们将通过在人类前列腺癌小鼠模型中操纵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。此外，将利用遗传学、分子生物学和细胞生物学方法的组合来研究Notch促进抗失巢凋亡的分子机制。最后，我们将进行高通量筛选以鉴定抑制Notch诱导的失巢凋亡抗性的小分子化合物。