Neuroendocrine mechanisms of prostate cancer progression

 描述（由申请人提供）：晚期前列腺癌经常表现出异常的神经内分泌信号传导，例如具有神经内分泌分化的细胞过度积聚和/或神经肽过度产生。也就是说，对正常前列腺发育，再生和癌变过程中神经内分泌信号的作用知之甚少，从而使前列腺癌进展关键机制的识别和解释复杂化。我们最近已经产生了几种小鼠品系，其中神经内分泌细胞可以被耗尽，特别是在前列腺上皮细胞。我们在这些模型中的初步结果表明，神经内分泌细胞的耗竭导致前列腺萎缩，可能是由于前列腺干细胞池的大小减少。在另一系列初步实验中，我们观察到神经肽加工酶膜金属内肽酶（MME）的缺乏可能会加速小鼠模型中的前列腺癌发生，其中Pten基因在前列腺上皮中特异性失活。有趣的是，缺乏MME和Pten的小鼠优先在前列腺导管的近端区域发展肿瘤，该区域高度富集前列腺干细胞。我们的初步研究结果表明，MME可以控制胃泌素释放肽（GRP）依赖性前列腺干细胞龛的维持，GRP受体拮抗剂的管理可能会导致癌症传播细胞（CPC，又名癌症干细胞）的耗尽。基于我们的初步研究结果，我们假设神经内分泌信号是必不可少的前列腺上皮干细胞龛的维护，这种信号的失调促进雄激素戒断抗性细胞与干细胞特性的扩展。为了解决这一假设，我们建议（1）建立神经内分泌细胞在前列腺正常发育和再生过程中的作用，（2）测试神经内分泌细胞在与Pten，p53/mir-34和Rb肿瘤抑制基因缺陷相关的前列腺癌原位小鼠模型中的作用，以及（3）研究神经肽失调对前列腺癌进展的影响。

 DESCRIPTION (provided by applicant): Advanced prostate cancers frequently manifest aberrant neuroendocrine signaling, such as excessive accumulation of cells with neuroendocrine differentiation and/or overproduction of neuropeptides. That said, little is known about roles of neuroendocrine signaling during the normal prostate development, regeneration and carcinogenesis, thereby complicating the identification and interpretation of mechanisms critical for prostate cancer progression. We have recently generated several mouse strains in which neuroendocrine cells can be depleted specifically in the prostate epithelium. Our preliminary results in these models suggest that the depletion of neuroendocrine cells leads to prostate hypotrophy, likely due to decreased size of the prostate stem cell pool. In another series of preliminary experiments, we have observed that deficiency for the neuropeptide processing enzyme membrane metallo-endopeptidase (MME) may accelerate prostate carcinogenesis in a mouse model, in which Pten gene is specifically inactivated in the prostate epithelium. Interestingly, mice deficient for both MME and Pten preferentially developed neoplasms in the proximal regions of prostatic ducts, the areas highly enriched with prostate stem cells. Our preliminary results show that MME may control gastrin-releasing peptide (GRP)-dependent maintenance of the prostate stem cell niche, and administration of a GRP receptor antagonist may lead to depletion of cancer propagating cells (CPC, aka cancer stem cells). Based on our preliminary results we hypothesize that the neuroendocrine signaling is essential for the maintenance of the prostate epithelium stem cell niche, and that dysregulation of such signaling promotes expansion of androgen withdrawal-resistant cells with stem cell properties. To address this hypothesis we propose to (1) establish the role of neuroendocrine cells during the normal development and regeneration of the prostate, (2) test the role of neuroendocrine cells in autochthonous mouse models of prostate cancer associated with deficiency of Pten, p53/mir-34 and Rb tumor suppressor genes, and (3) study the effects of neuropeptide dysregulation on prostate cancer progression.