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; 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）特性的细胞与前列腺癌的进展有关激素独立性和攻击性提高。假设NE样细胞通过分泌促进这些过程的因素，尤其是在雄激素耗尽的环境中，促进周围肿瘤细胞的生存，生长和转移能力。在裸小鼠异种移植模型中，我们测试了这种旁分泌假说，并表明与缺乏这种接种后缺乏此类NE细胞的LNCAP肿瘤细胞相比，castration（雄激素消融）在castration（雄激素消融）上进行了人工设计的LNCAP肿瘤细胞提供了生长优势。然而，该测定中NE样细胞的作用机理尚不清楚，即它们是促进有丝分裂的还是生存的，还是它们是否增强了在肿瘤细胞中的选择，表现出更具侵略性和雄激素不依赖的表型。还没有在体内测试这些细胞是否分泌促进转移的因素。我们建议在裸鼠模型中研究这些各种可能性，我们通过检查肿瘤从凋亡标记（caspase激活，TUNEL，ANNXIN V等）cast割后出现的肿瘤（caspase-like细胞和父母LNCAP细胞）的各种组合，MAP KI67，MAP KINASE ASTICE，CONTAIME，COMPASTIC ENTRITASIT cORTITION cORTITATION，CLOSITAINS，CLOSITAINS，CLOSITAINS，CLOSSITION，CLOSITAINS，磷酸化的效果，磷酸化的效果。在有或没有cast割的情况下重新植入。此外，我们将研究由NE样细胞的分泌产物刺激的信号传导途径。 NE样细胞的大多数已知分泌产物是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）（特别是通过C-SRC在EGFR上对Tyr 845的磷酸化）才能作用。基于这些发现以及EGFR已被与前列腺癌的病因学有关的事实，我们将测试由NE类细胞分泌的GPCR激动剂对EGFR的依赖性，用于诱导前列腺癌细胞的生存，生长和/或转移。我们还提出了识别EGFR和Tyr 845的下游效应子的策略，并确定含Tyr 845的抑制性肽对前列腺癌生长的影响。假设这种靶向广泛使用和关键的EGFR磷酸化位点（Tyr 845）的方法提供了一种新颖的方法来抵消NE样细胞在促进与雄激素独立前列腺癌的攻击性生长中的作用。