Neuroendocrine mechanisms of prostate cancer progression

前列腺癌进展的神经内分泌机制

• 批准号: 10245737
• 负责人: Alexander Y Nikitin
• 金额: $ 5万
• 依托单位: CORNELL UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2015
• 资助国家: 美国
• 起止时间: 2015-07-07 至 2021-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10245737
• 关键词: Ablation; Address; Affect; Androgens; Area; Bombesin Receptor; Cancer Etiology; Castration; Cell Culture Techniques; Cell Differentiation process; Cells; Cessation of life; Development; Down-Regulation; Environment; Enzymes; Epithelial; Epithelium; Gastrin releasing peptide; Heterogeneity; Human; Immunocompetent; Immunocompromised Host; Laboratories; Lead; Maintenance; Malignant Neoplasms; Malignant neoplasm of prostate; Metastatic Prostate Cancer; Modeling; Molecular; Mouse Strains; Mus; Natural regeneration; Neoplasms; Neprilysin; Neuroendocrine Cell; Neuropeptides; Neurosecretory Systems; PTEN gene; Pathogenesis; Patients; Peptide Signal Sequences; Property; Prostate; Prostatic duct; Regulation; Resistance; Role; Sampling; Series; Signal Transduction; TP53 gene; Testing; Text; Therapeutic; Tissue Transplantation; Tumor Suppressor Genes; Tumorigenicity; United States; Withdrawal; Work; Xenograft procedure; advanced prostate cancer; base; cancer cell; cancer diagnosis; cancer stem cell; cancer therapy; carcinogenesis; combinatorial; deprivation; epithelial stem cell; experimental study; high risk; in vivo; men; mouse model; neuroendocrine differentiation; prostate cancer model; prostate cancer progression; prostate carcinogenesis; public health relevance; relapse patients; self-renewal; stem; stem cell niche; stem cells; stem-like cell; tumor

 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.

 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，例如神经内分泌分化的细胞过度积累和/或神经肽的过度产生。也就是说，对于神经内分泌信号传导在正常前列腺发育、再生过程中的作用知之甚少。和致癌作用，从而使对前列腺癌进展至关重要的机制的识别和解释变得复杂化。我们最近培育了几种小鼠品系，其中前列腺中的神经内分泌细胞可以被特异性地耗尽。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肥大，这可能是由于前列腺干细胞库的大小减少所致。在另一系列初步实验中，我们观察到神经肽加工酶膜的缺陷。金属内肽酶 (MME) 可能会加速小鼠模型中前列腺癌的发生，其中 Pten 基因在前列腺上皮中特异性失活，提示同时缺乏 MME 和 Pten 的小鼠优先发育。我们的初步结果表明，MME 可以控制前列腺干细胞生态位的胃泌素释放肽 (GRP) 依赖性维持，以及 GRP 受体拮抗剂的施用。可能会导致癌症增殖细胞（CPC，又名癌症干细胞）的消耗。根据我们的初步结果，我们发现神经内分泌信号对于维持前列腺上皮干细胞生态位至关重要，并且这种信号传导的失调会促进具有干细胞特性的雄激素撤退抵抗细胞的扩增。为了解决这一假设，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本土小鼠模型中的作用，以及 (3) 研究神经肽失调对前列腺癌进展的影响。

项目成果

CAMKK2 Promotes Prostate Cancer Independently of AMPK via Increased Lipogenesis.

• DOI: 10.1158/0008-5472.can-18-0585
• 发表时间: 2018-12-15
• 期刊: Cancer research
• 影响因子: 11.2
• 作者: Penfold L;Woods A;Muckett P;Nikitin AY;Kent TR;Zhang S;Graham R;Pollard A;Carling D
• 通讯作者: Carling D

AMPK activation protects against prostate cancer by inducing a catabolic cellular state.

• DOI: 10.1016/j.celrep.2023.112396
• 发表时间: 2023-04-25
• 期刊: Cell reports
• 影响因子: 8.8

Cells expressing PAX8 are the main source of homeostatic regeneration of adult mouse endometrial epithelium and give rise to serous endometrial carcinoma.

• DOI: 10.1242/dmm.047035
• 发表时间: 2020-10-30
• 期刊: Disease models & mechanisms
• 影响因子: 4.3
• 作者: Fu DJ;De Micheli AJ;Bidarimath M;Ellenson LH;Cosgrove BD;Flesken-Nikitin A;Nikitin AY
• 通讯作者: Nikitin AY