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: 8426306
• 负责人: LARISA NONN
• 金额: $ 7.98万
• 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/8426306
• 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.

描述（由申请人提供）：维生素D是一种可预防癌变的多效性饮食激素。流行病学和临床前研究表明，维生素D参与了前列腺癌的预防，并且可能在前列腺癌治疗中起作用。有越来越多的证据表明炎症是前列腺癌的危险因素。我们的总体假设是，维生素D3是前列腺中的抗炎药，这种活性有助于预防维生素D3的前列腺癌。抗炎剂可能预防前列腺癌并不是什么新鲜事物的概念。但是，由于严重的副作用，对COX-2-2-选择性抑制剂的长期预防临床研究是不切实际的，并且对非处方NSAID的研究很难在长时间内进行。因此，通过保持足够的维生素D状态来减少前列腺炎症和可能的全身性炎症非常有吸引力。 这项新提案基于我们先前发表的关于维生素D在前列腺上皮细胞中抗炎作用的研究，以及PI资助的K22 Grant的初步结果“维生素D调节的Microtara在前列腺癌预防中的重要性”。 microRNA对炎症信号传导和反馈回路也至关重要。在前列腺癌中已经证明了miR表达的全球和特定变化。我们确定了几种炎症性miR，这些miR受到前列腺上皮细胞和临床试验组织中维生素D3的调节。在这项试验中的男性（n = 60，在多伦多大学完成）WRE 400IU，10,000IU或40,000IU的维生素D3（胆固醇）（胆固醇酚）进行了4-6周，前4-6周。 我们的初步工作以前列腺上皮为重点，但是，前列腺上皮腺被前列腺基质所包围。它已经确定了前列腺基质参与前列腺癌，因为基质对上皮增殖，分化具有调节性控制，并且是前列腺炎症反应的必要介体。为了响应炎症刺激，上皮细胞和基质细胞迅速释放细胞因子，从而传播炎症反应并募集免疫细胞到该区域。为了询问细胞类型之间的相互作用，我们使用原发性前列腺基质和上皮细胞开发了三维共培养炎症模型。使用此模型，我们的初步数据表明，前列腺基质细胞不仅会产生与上皮细胞不同的细胞因子和microRNA，而且维生素D3消除了每种细胞类型中不同特定的细胞因子和microRNA。 该提案中的实验将研究以下假设：前列腺基质和上皮之间的相互作用会因维生素D3改变。创造了降低增殖，增加分​​化和减少炎症的微环境。我们提出了一种首先量化基质组织中的关键基因和microRNA的床头到基础方法，然后在相关的体外模型中评估这些炎症介质。