NEUROENDOCRINE CELL SIGNALING IN PROSTATE CANCER

这项建议侧重于前列腺和神经内分泌(NE)细胞 它们在促进雄激素非依赖性前列腺生长中的作用 肿瘤。神经内分泌(NE)细胞完全分化，有丝分裂后 存在于正常和恶性前列腺组织中的分泌细胞。 在形态上，NE细胞可以通过它们的特征来识别 神经元的外观，包括长神经炎的存在 体内有突起和致密的分泌小泡。在前列腺癌中 癌旁上皮细胞的增殖指数 NE细胞经常升高，这表明NE细胞在 分泌生长诱导因子和贡献的旁分泌方式 与疾病的发展密切相关。其中几个因素已经被 包括5-羟色胺、促甲状腺激素(TSH)、 降钙素、蛙皮素和生长抑素。网元数量的增加 细胞也作为肿瘤进展的一部分出现，推测是由于 遗传因素和表观遗传因素的共同影响。这些东西的起源 晚期前列腺癌患者人数增加尚不确定，但 几项研究表明，NE细胞来自肿瘤内部， 要么来自增生性基底上皮细胞，要么来自转化的 外分泌上皮细胞通过去分化或转分化， 分别进行了分析。Bang等人。(9)事实上已经表明，前列腺 肿瘤细胞系LNCaP和PC3M可以被诱导分化为 有丝分裂后去甲肾上腺素样细胞 细胞内环磷酸腺苷。这些实验提供了证据证明 NE细胞来源的转分化模型，并提示 升高内源性cAMP水平的生理因素可能起到一定作用 在分化过程中。中描述的研究的目标 这项建议是为了确定生理因素和关键 促进NE细胞分化的信号通路 并确定NE细胞是否分泌旁分泌信号 促进前列腺癌的生长。为了实现这些目标， 一组荷尔蒙和多肽因子会导致血压升高 将检测LNCaP细胞内cAMP，以及信号通路 从最有效的差异化试剂中散发出来的物质将会被分析。 此外，还将生成一个LacSwitch系统，用于引导 一种结构性活性形式的催化蛋白的调控表达 蛋白激酶A亚基，用于前列腺癌的鉴别 细胞系向NE细胞转化。从这些分化出的条件培养液 然后将对细胞进行测试，以确定其是否有能力促进 未分化的肿瘤细胞。最后，信令机制 调节分泌也将被研究。该项目的目标 阐明调节分化和细胞分化的信号通路 去甲肾上腺素细胞的分泌及其重要成分的鉴定 可作为发展的分子靶点的途径 晚期雄激素非依赖性前列腺癌的新疗法。

This proposal focuses on neuroendocrine (NE) cells of the prostate and role they play in promoting androgen-independent growth of prostate tumors. Neuroendocrine (NE) cells are fully differentiated, postmitotic 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 body. In prostate tumors the proliferative index of neoplastic epithelial cells surrounding the NE cells is frequently elevated, suggesting that the NE cells act in a paracrine fashion by secreting growth-inducing factors and contributing to 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 also occur as part of tumor progression, presumably due to the influence of both genetic and epigenetic factors. The origin of these increased numbers in 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 cell by de-differentiation or trans-differentiation, respectively. Bang et al. (9) have in fact shown that the prostate tumor cell lines, LNCaP and PC3M, can be induced to differentiate into post-mitotic NE-like cells upon addition of 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 potentiate 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 system will be generated that directs the regulated expression of a constitutively active form of the catalytic subunit of protein kinase A and used to differentiate prostate tumor cells lines to NE cells. Conditioned medium from these differentiated cells will then be tested for its 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 NE cells and to identify critcal components of these pathways that could serve as molecular targets for the development of novel therapies for late stage, androgen-independent prostate tumors.