Vitamin D3 alters stromal-epithelial inflammatory crosstalk in human prostate

维生素 D3 改变人前列腺基质-上皮炎症串扰

• 批准号: 8600662
• 负责人: LARISA NONN
• 金额: $ 7.74万
• 依托单位: UNIVERSITY OF ILLINOIS AT CHICAGO
• 依托单位国家: 美国
• 财政年份: 2013
• 资助国家: 美国
• 起止时间: 2013-01-01 至 2014-12-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8600662
• 关键词: Adverse effects; Affect; Anti-Inflammatory Agents; Anti-inflammatory; Area; Calcium; Cell Culture Techniques; Cells; Chemoprevention; Cholecalciferol; Clinical Research; Clinical Trials; Coculture Techniques; Complement; Data; Diet; Environment; Epidemiology; Epithelial; Epithelial Cells; Epithelium; Feedback; Fibroblasts; Funding; Future; Genes; Gland; Grant; Homeostasis; Hormones; Human; Immune; In Vitro; Inflammation; Inflammation Mediators; Inflammatory; Inflammatory Response; Lasers; Malignant neoplasm of prostate; Measures; Mediating; Mediator of activation protein; MicroRNAs; Modeling; Myofibroblast; Non-Steroidal Anti-Inflammatory Agents; PTGS2 gene; Population; Prevention; Property; Prostate; Prostatic; Prostatic Epithelium; Prostatic Stroma; Publishing; Radical Prostatectomy; Recruitment Activity; Risk Factors; Role; Running; Signal Transduction; Smooth Muscle Myocytes; Specimen; Stimulus; Stromal Cells; Time; Tissues; Universities; Vitamin D; Vitamins; Work; base; bench to bedside; cancer prevention; cancer therapy; carcinogenesis; cell type; cytokine; in vitro Model; in vivo Model; inhibitor/antagonist; men; preclinical study; prevent; prostate cancer prevention; prostatitis; public health relevance; randomized trial; research study; response

DESCRIPTION (provided by applicant): Vitamin D is a pleiotropic dietary hormone that protects against carcinogenesis. Epidemiologic and pre-clinical studies show that vitamin D is involved in prostate cancer prevention and may have a role in prostate cancer treatment. There is mounting evidence that inflammation is a risk factor for prostate cancer. Our overall hypothesis is that vitamin D3 is an anti-inflammatory agent in the prostate and this activity contributes to prostate cancer prevention by vitamin D3. The concept that anti-inflammatory agents may prevent prostate cancer is not new. However, long term prevention clinical studies with COX-2- selective inhibitors are not practical due to severe side effects and studies with non-prescription NSAIDS are difficult to run over long periods of time. Therefore, it is appealing to reduce prostatic inflammation, and likely systemic inflammation, by maintaining adequate vitamin D status. This new proposal is based on our previous published studies on the anti-inflammatory actions of vitamin D in prostate epithelial cells and preliminary results of the PI's funded K22 grant "Significance of Vitamin D-Regulated MicroRNAs in Prostate Cancer Prevention". MicroRNAs are also crucial to inflammatory signaling and feedback loops. Global and specific changes in miR expression have been demonstrated in prostate cancer. We identified several inflammatory miRs that were regulated by vitamin D3 in prostate epithelial cells and clinical trial tissue. Men in this trial (N=60, completed at the University of Toronto) wre given 400IU, 10,000IU or 40,000IU of vitamin D3 (cholecalciferol) for 4-6 weeks prior to radical prostatectomy. Our preliminary work focused on prostatic epithelium, however, prostatic epithelial glands are surrounded by prostate stroma. It is well established the prostate stroma is involved in prostate cancer as the stroma has regulatory control over epithelial proliferation, differentiation and is a necessary mediator of the prostatic inflammatory response. In response to inflammatory stimulus, epithelial and stromal cells rapidly release cytokines that propagate the inflammatory response and recruit immune cells to the area. To interrogate the interplay between cell types, we have developed a three-dimensional co-culture in vitro model of inflammation using primary prostatic stromal and epithelial cells. Using this model, our preliminary data show that not only do prostate stromal cells produce different cytokines and microRNAs than epithelial cells, but that vitamin D3 abrogates different specific cytokines and microRNAs in each cell type. The experiments in this proposal will examine the hypothesis that the interplay between prostate stroma and epithelium is altered by vitamin D3; creating a micro-environment of decreased proliferation, increased differentiation and decreased inflammation. We propose a bedside-to-bench approach to first quantify the key genes and microRNAs in stromal tissue then assess these inflammatory mediators in a relevant in vitro model.

说明(申请人提供)：维生素D是一种多效性的饮食荷尔蒙，可预防癌症发生。流行病学和临床前研究表明，维生素D参与前列腺癌预防，并可能在前列腺癌治疗中发挥作用。越来越多的证据表明，炎症是前列腺癌的风险因素。我们的总体假设是，维生素D3是前列腺中的一种抗炎剂，这种活性有助于通过维生素D3预防前列腺癌。抗炎药可以预防前列腺癌的概念并不新鲜。然而，使用COX-2选择性抑制剂的长期预防临床研究由于严重的副作用而不实用，而使用非处方药NSAIDs的研究很难长期进行。因此，通过保持足够的维生素D状态来减少前列腺炎症，以及可能的全身性炎症是很有吸引力的。这项新的建议是基于我们之前发表的关于维生素D在前列腺上皮细胞中的抗炎作用的研究，以及PI资助的K22基金的初步结果：维生素D调节的MicroRNAs在前列腺癌预防中的意义。MicroRNAs对炎症信号和反馈环也是至关重要的。前列腺癌中miR表达的全局性和特异性变化已被证明。我们在前列腺上皮细胞和临床试验组织中发现了几个受维生素D3调节的炎性微核受体。在多伦多大学完成的这项试验中，60名男性在前列腺癌根治术前给予400IU、10000IU或40000IU的维生素D3(胆钙化醇)，为期4-6周。我们的初步工作集中在前列腺上皮，然而，前列腺上皮腺被前列腺间质所包围。前列腺间质参与前列腺癌的发生是公认的，因为间质对上皮细胞的增殖、分化具有调控作用，是前列腺炎性反应的必要介质。作为对炎症刺激的反应，上皮和间质细胞迅速释放细胞因子，传播炎症反应，并向该区域招募免疫细胞。为了探讨细胞类型之间的相互作用，我们建立了一种三维共培养的炎症模型，该模型使用原代前列腺基质细胞和上皮细胞。使用这个模型，我们的初步数据显示，前列腺基质细胞不仅产生不同于上皮细胞的细胞因子和microRNAs，而且维生素D3消除了每种细胞类型中不同的特定细胞因子和microRNAs。这项提案中的实验将检验这样一种假设，即维生素D3改变了前列腺间质和上皮之间的相互作用；创造了一个减少增殖、增加分化和减少炎症的微环境。我们提出了一种床边到工作台的方法，首先量化间质组织中的关键基因和microRNAs，然后在相关的体外模型中评估这些炎症介质。