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）样特性的细胞与前列腺癌向激素的进展有关