Neuroendocrine mechanisms of prostate cancer progression

 描述(申请人提供)：晚期前列腺癌通常表现为神经内分泌信号的异常，例如神经内分泌分化的细胞过度聚集和/或神经肽的过度产生。尽管如此，人们对神经内分泌信号在正常前列腺发育、再生和癌变过程中的作用知之甚少，从而使前列腺癌进展的关键机制的识别和解释变得复杂。我们最近培育了几个小鼠品系，在这些品系中，神经内分泌细胞可以被耗尽，特别是在前列腺上皮中。我们在这些模型中的初步结果表明，神经内分泌细胞的枯竭导致前列腺萎缩，这可能是由于前列腺干细胞池的大小减小所致。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)的缺失可能会加速小鼠前列腺癌的发生，在该模型中，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管的近端区域发生肿瘤，这些区域高度富含前列腺干细胞。我们的初步结果表明，MME可能控制依赖胃泌素释放肽(GRP)的前列腺干细胞生态位的维持，GRP受体拮抗剂的应用可能导致肿瘤增殖细胞(CPC，又名癌症干细胞)的耗竭。根据我们的初步结果，我们假设神经内分泌信号对维持前列腺上皮干细胞生态位是必不可少的，并且这种信号的失调促进了具有干细胞特性的雄激素戒断抵抗细胞的扩张。为了解决这一假说，我们建议(1)确定神经内分泌细胞在前列腺正常发育和再生中的作用，(2)在Pten、P53/mir-34和Rb肿瘤抑制基因缺失的固有小鼠模型中测试神经内分泌细胞的作用，以及(3)研究神经肽失调在前列腺癌进展中的作用。

 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.