Neuroendocrine Cells in Prostate Cancer

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 独立性和侵略性。NE样细胞被假定促进存活、生长和 通过分泌促进这些过程的因子，特别是在 一个雄性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说， 表明人工工程化的NE样LNCaP细胞提供了非工程化LNCaP的生长优势， 与缺乏这种NE细胞的LNCaP肿瘤细胞相比，去势（雄激素消融）后的肿瘤细胞 在接种后。然而，NE样细胞在该测定中的作用机制是未知的，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 我们已经建立了小鼠模型，通过检查各种组合去势后产生的肿瘤， NE样细胞和亲本LNCaP细胞的细胞凋亡标志物（半胱天冬酶活化、TUNEL、膜联蛋白V等）， 增殖（Ki 67、MAP激酶活化、STAT酪氨酸磷酸化等），转移，或表现出 在有或没有去势的情况下再植入后生长增强。这些发现的相关性将 通过对来自以下患者的样品中的每种标记物进行免疫组织化学染色， 各种治疗和临床模式。此外，我们还将研究由蛋白质刺激的信号通路。 NE样细胞的分泌产物。已知NE样细胞的分泌产物大多数是G 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）（特别是c-Src对EGFR上Tyr 845的磷酸化）。基于 基于这些发现以及EGFR被认为是前列腺癌的病因，我们 将测试NE样细胞分泌的GPCR激动剂对EGFR的依赖性，以诱导存活、生长 和/或前列腺癌细胞的转移。我们还提出了识别EGFR下游效应物的策略 和Tyr 845，并测定含Tyr 845的抑制肽对前列腺癌生长的作用。这 假设这种方法提供了一种新的方法，可以抵消NE样细胞在促进细胞增殖中的作用。 雄激素非依赖性前列腺癌的侵袭性生长。

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.