Neuroendocrine Cell Signaling in Prostate Cancer

前列腺癌中的神经内分泌细胞信号转导

• 批准号: 6563900
• 负责人: SARAH J PARSONS
• 金额: $ 19.9万
• 依托单位: UNIVERSITY OF VIRGINIA
• 依托单位国家: 美国
• 财政年份: 2002
• 资助国家: 美国
• 起止时间: 2002-02-01 至 2003-01-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6563900
• 关键词: SCID mouse; athymic mouse; biological signal transduction; cell differentiation; cell line; cell population study; cyclic AMP; hormone regulation /control mechanism; male; neoplastic cell; neoplastic process; neuroendocrine system; paracrine; prostate neoplasms; secretion; tissue /cell culture

This proposal focuses on neuroendocrine (NE) cells of the prostate and the role they play in promoting androgen-interdependent growth of prostate tumors. Neuroendocrine (NE) cells are fully differentiated, post- mitotic secretory cells that populate both normal and malignant prostate tissue. Morphologically, NE cells can be identified by their characteristic neuronal appearance, which includes the presence of long neuritic processes and dense secretory vesicles in the cell body. In prostate tumors the proliferative index of neoplastic epithelial cells surrounding the NE cells is also frequently elevated, suggesting that the NE cells act in a paracrine fashion by secreting growth-inducing factors and contributing toe the progression of the disease. Several of these factors have been identified and include serotonin, thyroid stimulating hormone (TSH), calcitonin, bombesin, and somatostatin. Increases in the number of NE cells occur as part of tumor progression, presumably. Increases in the number of NE cells occur as part of tumor progression, presumably due to the influence of both genetic and epigenetic factors. The origin of these increased number sin later stage prostatic carcinomas is uncertain, but several studies suggest that NE cells arise from within the tumor, either from a hyperplastic basal epithelial cell or from a transformed exocrine epithelial c4ll by de-differentiation or trans-differentiation, respectively. Bang have in fact shown that the prostate tumor cells, LNCaP and PC3M, can be induced to differentiate into post-mitotic NE-like cells upon addition for agents that increase intracellular cyclic AMP. These experiments provide evidence for the transdifferentiation model of NE cell derivation and suggest that physiological factors that elevate internal cAMP levels may play a role in the differentiation process. The goal of the studies described in this proposal is to identify physiological factors and critical signaling pathways that contribute to the differentiation of NE cells and to determine whether NE cells secrete paracrine signals which potential the growth of prostate carcinomas. To accomplish these aims, a panel of hormones and peptide factors that cause elevations in intracellular cAMP in LNCaP cells will be tested, and signaling pathways emanating from the most potent differentiating agents will be analyzed. In addition, a LacSwitch will be generated that directs the regulated expression of a constitutively active form of the catalytic subunit of protein kinase I and used to differentiated prostate tumor cell lines to NE cells. These differentiated cells will then be tested both in culture and in the animal for their ability to enhance proliferation of non-differentiated tumor cells. Finally, the signaling mechanisms regulating secretion will also be examined. The goals of the project are to elucidate signaling pathways that regulate differentiation and secretion of cell cells and to identify critical components of these pathways that could serve as molecular targets for the development of novel therapies for late stage, androgen-independent prostate tumors.

该提案的重点是前列腺的神经内分泌（NE）细胞及其在促进前列腺肿瘤的雄激素间依赖性生长中所起的作用。神经内分泌（NE）细胞是完全分化的有丝分泌物分泌细胞，这些细胞既有正常和恶性前列腺组织。 从形态上讲，NE细胞可以通过其特征性神经元外观来识别，其中包括长长的神经过程和细胞体内密集的分泌囊泡。在前列腺肿瘤中，NE细胞周围的肿瘤上皮细胞的增殖指数也经常升高，这表明NE细胞通过分泌诱导生长的因素并促进该疾病的进展，以旁分泌方式起作用。这些因素中的几个已被鉴定出来，包括5-羟色胺，甲状腺刺激激素（TSH），降钙素，轰炸蛋白和生长抑素。 NE细胞数量的增加大概是肿瘤进展的一部分。 NE细胞数量的增加是作为肿瘤进展的一部分，可能是由于遗传和表观遗传因子的影响。这些增加的数量罪的起源后期前列腺癌的起源尚不确定，但是几项研究表明，NE细胞是由肿瘤内部产生的，要么是由增生的基底上皮细胞或分别通过去分化或反式差异的转化的外分泌上皮C4LL。实际上，BANG表明，对于增加细胞内环状AMP的药物的添加，前列腺肿瘤细胞，LNCAP和PC3M可被诱导地分化为有丝分裂后的NE样细胞。这些实验为NE细胞推导的转分化模型提供了证据，并表明升高内部营地水平的生理因素可能在分化过程中起作用。该提案中描述的研究的目的是确定有助于分化NE细胞的生理因素和关键信号通路，并确定NE细胞是否分泌旁分泌信号，从而潜在前列腺癌的生长。为了实现这些目标，将测试一系列激素和肽因子，这些激素和肽因子将测试LNCAP细胞中细胞内cAMP的升高，并将分析与最有效的分化剂产生的信号通路。此外，将生成一个lacswitch，该lacswitch将蛋白激酶I催化亚基的组成型活性形式的调节表达引入，并用于将前列腺肿瘤细胞系分化为NE细胞。然后，这些分化的细胞将在培养物和动物中进行测试，以增强非差异肿瘤细胞增殖的能力。 最后，还将检查调节分泌的信号传导机制。该项目的目标是阐明调节细胞细胞分化和分泌的信号通路，并鉴定这些途径的关键成分，这些途径可以用作为晚期开发新型疗法的分子靶标，雄激素与雄激素独立的前列腺肿瘤。