Neuroendocrine cells in Prostate Cancer

前列腺癌中的神经内分泌细胞

• 批准号: 6868873
• 负责人: SARAH J PARSONS
• 金额: $ 31.12万
• 依托单位: UNIVERSITY OF VIRGINIA
• 依托单位国家: 美国
• 财政年份: 2004
• 资助国家: 美国
• 起止时间: 2004-03-10 至 2005-08-23
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6868873
• 关键词: apoptosis; athymic mouse; biological signal transduction; cell proliferation; cell surface receptors; epidermal growth factor; growth factor receptors; immunofluorescence technique; metastasis; neoplastic process; neuroendocrine system; neuropeptides; paracrine; phosphorylation; prostate neoplasms; terminal nick end labeling; tissue /cell culture; western blottings

DESCRIPTION (provided by applicant): Cells with neuroendocrine (NE)-Iike properties have been implicated in progression of prostate cancer to hormone independence and increased aggressiveness. NE-like cells are postulated to promote the survival, growth, and metastatic capabilities of surrounding tumor cells by secreting factors that promote these processes, particularly in an androgen-depleted environment. In a nude mouse xenograft model, we tested this paracrine hypothesis and showed that artificially engineered NE-like LNCaP cells provide a growth advantage to non-engineered LNCaP tumor cells following castration (androgen ablation), as compared to LNCaP tumor cells lacking such NE cells upon inoculation. However, the mechanism of action of the NE-like cells in this assay is unknown, i.e., whether they promote mitogenesis or survival, or whether they enhance selection of already existing genetic variants within a population of tumor cells that exhibit a more aggressive and androgen-independent phenotype. It has also not been tested in vivo whether these cells secrete factors that promote metastases. We propose to study these various possibilities in the nude mouse model we have established by examining tumors that arise following castration from various combinations of NE-like cells and parental LNCaP cells for markers of apoptosis (caspase activation, TUNEL, annexin V, etc.), proliferation (Ki67, MAP kinase activation, STAT tyrosine phosphorylation, etc.), metastases, or ability to exhibit enhanced growth following re-implantation either with or without castration. In addition, we will investigate the signaling pathways stimulated by the secreted products of NE-like cells. Most of the known secretory products of NE-like cells are agonists for G protein coupled receptors (GPCRs). A growing literature indicates that many GPCRs transactivate and require the EGF receptor (EGFR) (specifically phosphorylation of Tyr 845 on the EGFR by c-Src) for their action. Based on these findings and the fact that the EGFR has been implicated as an etiological agent in prostate cancer, we will test the dependence on the EGFR of GPCR agonists secreted by NE-like cells for inducing survival, growth and/or metastatsis of prostate cancer cells. We also propose strategies to identify downstream effectors of EGFR and Tyr 845 and to determine effects of Tyr 845-containing inhibitory peptides on prostate cancer growth. This approach of targeting a widely used and critical EGFR phosphorylation site (Tyr 845) is hypothesized to provide a novel means of counteracting the action of NE-like cells in promoting aggressive growth of androgen-independent prostate cancers.

描述（由申请人提供）：具有神经内分泌（NE）样特性的细胞与前列腺癌向激素独立性和侵袭性增加的进展有关。假定 NE 样细胞通过分泌促进这些过程的因子来促进周围肿瘤细胞的存活、生长和转移能力，特别是在雄激素耗尽的环境中。在裸鼠异种移植模型中，我们测试了这种旁分泌假设，结果表明，与缺乏此类 NE 细胞的 LNCaP 肿瘤细胞相比，人工改造的 NE 样 LNCaP 细胞在去势（雄激素消除）后为非工程 LNCaP 肿瘤细胞提供了生长优势接种后。然而，该测定中 NE 样细胞的作用机制尚不清楚，即它们是否促进有丝分裂或存活，或者它们是否增强对表现出更具攻击性和雄激素的肿瘤细胞群中现有遗传变异的选择。 -独立表型。这些细胞是否分泌促进转移的因子也尚未在体内进行测试。我们建议在我们建立的裸鼠模型中研究这些不同的可能性，方法是检查 NE 样细胞和亲本 LNCaP 细胞的各种组合去势后产生的肿瘤的凋亡标志物（半胱天冬酶激活、TUNEL、膜联蛋白 V 等）。 、增殖（Ki67、MAP 激酶激活、STAT 酪氨酸磷酸化等）、转移或在有或没有去势的情况下重新植入后表现出增强生长的能力。此外，我们还将研究NE样细胞分泌产物刺激的信号通路。大多数已知的 NE 样细胞分泌产物都是 G 蛋白偶联受体 (GPCR) 的激动剂。越来越多的文献表明，许多 GPCR 反式激活并需要 EGF 受体 (EGFR)（特别是 c-Src 对 EGFR 上的 Tyr 845 进行磷酸化）才能发挥作用。基于这些发现以及 EGFR 被认为是前列腺癌的病因这一事实，我们将测试 NE 样细胞分泌的 GPCR 激动剂对 EGFR 的依赖性，以诱导前列腺癌的存活、生长和/或转移细胞。我们还提出了识别 EGFR 和 Tyr 845 下游效应子并确定含有 Tyr 845 的抑制肽对前列腺癌生长的影响的策略。这种靶向广泛使用且关键的 EGFR 磷酸化位点 (Tyr 845) 的方法被认为提供了一种新的方法来抵消 NE 样细胞促进雄激素非依赖性前列腺癌侵袭性生长的作用。