Neuroendocrine Cells in Prostate Cancer

前列腺癌中的神经内分泌细胞

• 批准号: 7728880
• 负责人: SARAH J PARSONS
• 金额: $ 19.96万
• 依托单位: UNIVERSITY OF VIRGINIA
• 依托单位国家: 美国
• 财政年份: 2008
• 资助国家: 美国
• 起止时间: 2008-08-01 至 2010-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7728880
• 关键词: Ablation; Adhesions; Agonist; Androgen Receptor; Androgens; Animals; Apoptosis; Apoptotic; Biological Assay; Bioluminescence; Bombesin; Calcitonin; Cardiac; Caspase; Castration; Catalytic Domain; Cell Line; Cells; Chronic; Clinical Treatment; Clinical Trials; Conditioned Culture Media; Data; Dependence; Diagnostic radiologic examination; Disease; EGF gene; Engineering; Environment; Epidermal Growth Factor Receptor; Exhibits; Family member; Frequencies; G-Protein-Coupled Receptors; Goals; Growth; Hormones; Human; Image; Immunohistochemistry; In Situ Nick-End Labeling; Invasive; Knowledge; LNCaP; Left; Link; Literature; Luciferases; Malignant Epithelial Cell; Malignant Neoplasms; Malignant neoplasm of prostate; Mediating; Mitogen-Activated Protein Kinases; Mitotic; Modality; Modeling; Neoplasm Metastasis; Neuroendocrine Cell; Neuropeptides; Neurosecretory Systems; Neurotensin; Nude Mice; Patients; Peptides; Phenotype; Phosphorylation; Phosphotransferases; Physicians; Physiology; Process; Proliferating; Property; Prostate; Prostatic Neoplasms; Rate; Reporting; Role; Route; SRC gene; Sampling; Serotonin; Signal Pathway; Signal Transduction; Site; Source; Staging; Staining method; Stains; Stimulation of Cell Proliferation; Testing; Therapeutic; Time; Tumor-Derived; Tyrosine Phosphorylation; Western Blotting; Wound Healing; Xenograft Model; Xenograft procedure; androgen independent prostate cancer; annexin A5; autocrine; base; cancer cell; cell growth; human disease; implantation; in vivo; inhibitor/antagonist; insight; leukemia; malignant breast neoplasm; migration; mouse model; mutant; neoplastic cell; novel; novel therapeutics; outcome forecast; paracrine; parathyroid hormone-related protein; receptor; response; size; success; therapeutic target; tissue culture; tumor; tumor progression

Cells with neuroendocrine (NE)-like 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, survival, or 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. The relevance of these findings will be assessed in human tumors by immunohistochemical staining of each marker in samples from patients of various treatment and clinical modalities. 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 is hypothesized to provide a novel means of counteracting the action of NE-like cells in promoting aggressive growth of androgen-independent prostate cancers.

具有神经内分泌（NE）的特性的细胞已与前列腺癌的进展有关 独立和提高侵略性。假定NE样细胞以促进生存，生长和 通过分泌促进这些过程的因素，特别是在 贫血的环境。在裸小鼠异种移植模型中，我们测试了这种旁分泌假设和 表明人为设计的NE样LNCAP细胞为非工程LNCAP提供了增长优势 与缺乏此类NE细胞的LNCAP肿瘤细胞相比，去势后肿瘤细胞（雄激素消融） 接种后。但是，该测定中NE样细胞的作用机理尚不清楚，即是否 它们促进有丝分裂，生存或转移酶。我们建议在裸体中研究这些各种可能性 我们通过检查从各种组合cast割后出现的肿瘤来建立的小鼠模型 用于细胞凋亡的标记（caspase激活，TUNEL，ANNEXIN V等）的NE样细胞和亲本LNCAP细胞 增殖（KI67，MAP激酶激活，Stat酪氨酸磷酸化等），转移或表现的能力 随着或没有cast割的重新植入后，增长了生长。这些发现的相关性将 通过在人类肿瘤中通过免疫组织化学染色在人类肿瘤中进行评估。 各种治疗和临床方式。此外，我们将研究由 Ne样细胞的分泌产物。 NE样细胞的大多数已知分泌产物都是G的激动剂 蛋白偶联受体（GPCR）。越来越多的文献表明许多GPCR反式激活并需要 EGF受体（EGFR）（EGFR）（特异性通过C-SRC在EGFR上磷酸化）的作用。基于 在这些发现以及EGFR被认为是前列腺癌的病因学剂的事实中，我们 将测试对NE类细胞分泌的GPCR激动剂EGFR的依赖性，以诱导生长，生长 和/或前列腺癌细胞的转移。我们还提出了识别EGFR下游效应子的策略 和Tyr 845，并确定含Tyr 845的抑制性肽对前列腺癌生长的影响。这 假设方法可以提供一种新颖的方法来抵消Ne样细胞在促进中的作用 雄激素独立的前列腺癌的积极生长。