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依赖性生长中的作用。神经内分泌（NE）细胞是完全分化的、有丝分裂后的分泌细胞，其存在于正常和恶性前列腺组织中。 在形态学上，NE细胞可以通过其特征性的神经元外观来识别，其包括在细胞体中存在长的神经炎性突起和致密的分泌囊泡。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细胞通过分泌生长诱导因子以旁分泌方式起作用并促进疾病的进展。这些因子中有几个已经被确定，包括血清素、促甲状腺激素（TSH）、降钙素、蛙皮素和生长抑素。据推测，NE细胞数量的增加是肿瘤进展的一部分。NE细胞数量的增加是肿瘤进展的一部分，可能是由于遗传和表观遗传因素的影响。晚期前列腺癌中这些增加的数量的起源是不确定的，但是一些研究表明NE细胞来自肿瘤内，或者来自增生的基底上皮细胞，或者来自分别通过去分化或转分化转化的外分泌上皮c4II。Bang等人事实上已经表明，在加入增加细胞内环AMP的试剂后，前列腺肿瘤细胞LNCaP和PC3M可以被诱导分化成有丝分裂后NE样细胞。这些实验为NE细胞衍生的转分化模型提供了证据，并表明提高内部cAMP水平的生理因素可能在分化过程中发挥作用。本研究的目的是确定有助于NE细胞分化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，从而促进前列腺癌的生长。为了实现这些目标，将测试一组导致LNCaP细胞内cAMP升高的激素和肽因子，并分析来自最有效分化剂的信号传导途径。此外，将产生LacSwitch，其指导蛋白激酶I的催化亚基的组成型活性形式的调节表达，并用于将前列腺肿瘤细胞系分化为NE细胞。然后在培养物和动物中测试这些分化的细胞增强未分化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分化和分泌的信号通路，并确定这些通路的关键组分，这些组分可作为开发晚期雄激素非依赖性前列腺肿瘤新疗法的分子靶点。