Inflammation and Prostate Cancer Development and Progression

炎症与前列腺癌的发生和进展

• 批准号: 8009233
• 负责人: Timothy L. Ratliff
• 金额: $ 20.47万
• 依托单位: PURDUE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2010
• 资助国家: 美国
• 起止时间: 2010-07-01 至 2012-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8009233
• 关键词: Anti-Inflammatory Agents; Anti-inflammatory; Antigens; Atrophic; Benign; Binding; Cells; Code; Data; Development; Disease Progression; Elements; Environment; Epithelial Cell Proliferation; Epithelial Cells; Evaluation; Foundations; Glutamate Carboxypeptidase II; Glutathione S-Transferase; Growth; Immune response; Incidence; Individual; Induced Mutation; Infiltration; Inflammation; Inflammatory; Interferons; Interleukin-6; Knock-out; Leukocytes; Link; Luciferases; Malignant neoplasm of prostate; Membrane; Modeling; Mus; Oncogenes; Ovalbumin; PTEN gene; Pharmaceutical Preparations; Positioning Attribute; Predisposition; Production; Prostate; Prostatic; Proteins; Reactive Oxygen Species; Ribonucleases; Risk; Role; Staging; System; Time; Transgenic Organisms; base; cellular imaging; cytokine; epidemiology study; intraepithelial; macrophage scavenger receptors; mouse model; neoplastic; novel; prostatitis; public health relevance; tumor; tumor progression

DESCRIPTION (provided by applicant): Data forming the foundation for a role for inflammation in prostate cancer comes from a variety of fields. Epidemiology studies show an increased incidence of prostate cancer associated with prostatitis and a decreased risk for individuals taking anti-inflammatory drugs. Notably, two-candidate familial prostate cancer genes code for proteins associated with the innate immune response, interferon inducible ribonuclease (RNASEL) and macrophage scavenger receptor-1 (MSR1). Also, the loss of glutathione S-transferase (GST) expression, which has been described in most prostate cancers, increases the susceptibility to mutations induced by oxygen radicals produced by inflammation. Further, inflammation induced prostatic intraepithelial atrophy (PIA) is hypothesized to be a precursor to the development of prostate cancer. Finally, IL-6 has been linked to prostate cancer growth. The multiplicity of associations between inflammation and prostate cancer are correlative but strongly implicate a relationship. Thus, establishment of models that will provide a system for defining mechanisms associated with inflammation-induced modulation of prostate cancer development and progression are needed. We have developed a genetically modified mouse model expressing a prostate specific model antigen,membrane bound ovalbumin (mOVA), prostate specific PTEN knockout generated by Cre/Loxp, and luciferase expression in prostate epithelial cells for imaging purposes (POETPTEN). The model was generated by crossing a prostate specific mOVA transgenic (POET-3) with the genetically modified PTEN knockout expressing luciferase (PTENfl/fl-luc). Preliminary data demonstrate in both POET-3 and POETPTEN demonstrate that inflammation is induced in both models. Studies in POET-3 show inflammation remains 84 days after initiation. Notably, significantly elevated prostate epithelial cell proliferation was observed in the inflamed prostate as late as the 84 day time point. Likewise, cytokine production remains elevated in the inflamed prostate 45 days after initiation, which is the latest evaluation time point. Because the prostate- specific PTEN null model represents various stages of prostate cancer progression, we are in a unique position to evaluate the impact of inflammation on disease progression in the combined POET-PTEN model. These data provide a basis for the hypothesis that prostate inflammation modulates tumor development and progression. Studies outlined in this application propose to characterize prostate inflammation in both a pre- neoplastic and a tumor environment and identify potential immunoregulatory elements present during inflammation. To this end the following specific aims are proposed: Aim 1. Characterize prostate cancer development and progression in the inflamed prostate; and Aim 2. Characterization of inflammatory cell infiltration during prostate inflammation in a pre-neoplastic (PTEN+/fl), tumor (PTENfllfl) and benign (PTEN+/+) mice. PUBLIC HEALTH RELEVANCE: The proposed studies introduce a novel model for evaluating the impact of inflammation on prostate cancer development. The studies proposed will determine the impact of inflammation on prostate cancer development and progression.

描述（由申请人提供）：构成炎症在前列腺癌中作用的基础的数据来自各个领域。流行病学研究表明，与前列腺炎相关的前列腺癌发病率增加，服用抗炎药物的个体风险降低。值得注意的是，两个候选家族性前列腺癌基因编码与先天免疫反应、干扰素诱导核糖核酸酶 (RNASEL) 和巨噬细胞清道夫受体 1 (MSR1) 相关的蛋白质。此外，大多数前列腺癌中谷胱甘肽 S-转移酶 (GST) 表达的丧失增加了对炎症产生的氧自由基诱导突变的易感性。此外，炎症诱导的前列腺上皮内萎缩（PIA）被假设为前列腺癌发展的先兆。最后，IL-6 与前列腺癌的生长有关。炎症与前列腺癌之间的多重关联是相关的，但强烈暗示了一种关系。因此，需要建立模型来提供一个系统来定义与炎症诱导的前列腺癌发生和进展调节相关的机制。我们开发了一种转基因小鼠模型，表达前列腺特异性模型抗原、膜结合卵清蛋白 (mOVA)、Cre/Loxp 产生的前列腺特异性 PTEN 敲除以及用于成像目的的前列腺上皮细胞中的荧光素酶表达 (POETPTEN)。该模型是通过将前列腺特异性 mOVA 转基因 (POET-3) 与表达荧光素酶的转基因 PTEN 敲除 (PTENfl/fl-luc) 杂交而生成的。 POET-3 和 POETPTEN 的初步数据表明，这两种模型均诱导炎症。 POET-3 研究表明炎症在开始后 84 天仍然存在。值得注意的是，晚至第 84 天的时间点，在发炎的前列腺中观察到前列腺上皮细胞增殖显着升高。同样，在开始后 45 天（这是最新的评估时间点），发炎的前列腺中细胞因子的产生仍然升高。由于前列腺特异性 PTEN 无效模型代表了前列腺癌进展的各个阶段，因此我们处于独特的地位，可以评估联合 POET-PTEN 模型中炎症对疾病进展的影响。这些数据为前列腺炎症调节肿瘤发生和进展的假设提供了基础。本申请中概述的研究提出表征肿瘤前和肿瘤环境中的前列腺炎症，并鉴定炎症期间存在的潜在免疫调节元件。为此，提出以下具体目标： 目标 1. 表征发炎前列腺中前列腺癌的发生和进展；目的2.肿瘤前(PTEN+/fl)、肿瘤(PTENfllfl)和良性(PTEN+/+)小鼠前列腺炎症期间炎症细胞浸润的表征。 公共健康相关性：拟议的研究引入了一种新的模型来评估炎症对前列腺癌发展的影响。拟议的研究将确定炎症对前列腺癌发生和进展的影响。