Neuroendocrine Cells in Prostate Cancer

前列腺癌中的神经内分泌细胞

基本信息

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
项目类别：
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

项目摘要

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）样特性的细胞与前列腺癌向激素的进展有关独立性和攻击性增强。假定 NE 样细胞能够促进存活、生长和通过分泌促进这些过程的因子来增强周围肿瘤细胞的转移能力，特别是在雄激素耗尽的环境。在裸鼠异种移植模型中，我们测试了这种旁分泌假设并研究表明，人工改造的 NE 样 LNCaP 细胞比非改造的 LNCaP 细胞具有生长优势与缺乏此类 NE 细胞的 LNCaP 肿瘤细胞相比，去势（雄激素消除）后的肿瘤细胞接种后。然而，NE 样细胞在该测定中的作用机制尚不清楚，即是否它们促进有丝分裂、存活或转移。我们建议裸体研究这些不同的可能性我们通过检查不同组合的去势后产生的肿瘤来建立小鼠模型 NE 样细胞和亲本 LNCaP 细胞的细胞凋亡标记物（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）、转移或表现能力无论是否进行去势，再植入后生长均得到增强。这些发现的相关性将通过对来自以下患者的样本中的每个标记物进行免疫组织化学染色来评估人类肿瘤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。大多数已知的 NE 样细胞分泌产物都是 G 的激动剂蛋白质偶联受体（GPCR）。越来越多的文献表明，许多 GPCR 反式激活并需要 EGF 受体 (EGFR)（特别是 c-Src 对 EGFR 上的 Tyr 845 进行磷酸化）的作用。基于根据这些发现以及 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，以诱导生存、生长和/或前列腺癌细胞的转移。我们还提出了识别 EGFR 下游效应器的策略和 Tyr 845 并确定含有 Tyr 845 的抑制肽对前列腺癌生长的影响。这假设该方法提供了一种抵消 NE 样细胞促进不依赖雄激素的前列腺癌的侵袭性生长。