The Notch Signaling in Prostate Homeostasis and Carcinogenesis

 描述(申请人提供)：Noch信号在各种恶性肿瘤的发生和发展中起着关键作用，在临床试验中已成为几种恶性肿瘤的靶向治疗药物。尽管人们一致认为Notch信号在前列腺癌发生过程中被解除调控，但由于Notch信号在前列腺癌进展过程中的作用还不够明确，Notch尚未被用作前列腺癌的治疗靶点。我们的初步研究表明，活跃的Notch1胞内域(NICD)在前列腺中的表达增加(PB-NICD模型)促进了前列腺腔上皮细胞的增殖，支持Notch作为体内前列腺癌的致癌途径。 此外，大多数Notch信号成分在复发转移性疾病患者的前列腺癌标本中上调。与此一致，我们的初步研究表明，Notch活性增加诱导了前列腺上皮细胞对失巢凋亡的抵抗，并增强了前列腺癌细胞的体外和体内转移潜能。基于这些初步研究，Notch信号可能促进前列腺癌的转移。这项应用的目标是确定Notch信号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的活性，以直接确定Notch信号是否促进前列腺癌转移。此外，还将结合遗传、分子和细胞生物学方法来研究Notch促进失巢抵抗的分子机制。最后，我们将进行高通量筛选，以确定能够抑制Notch诱导的失巢抵抗的小分子化合物。

 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.