Inflammation and Prostate Cancer Development and Progression

炎症与前列腺癌的发生和进展

• 批准号: 8096809
• 负责人: Timothy L. Ratliff
• 金额: $ 16.65万
• 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 2013-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8096809
• 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; 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）：数据构成在前列腺癌中炎症作用的基础的数据来自各种领域。流行病学研究表明，与前列腺炎相关的前列腺癌的发生率增加，服用抗炎药的人的风险降低。值得注意的是，与先天性免疫反应，干扰素诱导核糖核酸酶（RNASEL）和巨噬细胞清除剂受体1（MSR1）相关的蛋白质的两种家族性前列腺癌基因代码（MSR1）。同样，在大多数前列腺癌中描述的谷胱甘肽S-转移酶（GST）的丧失会增加对炎症产生的氧自由基引起的突变的敏感性。此外，炎症诱导的前列腺上皮内萎缩（PIA）被认为是前列腺癌发展的前体。最后，IL-6与前列腺癌的生长有关。炎症和前列腺癌之间的多种关联是相关的，但强烈暗示了一种关系。因此，需要建立将为定义与炎症引起的前列腺癌发展和进展调节相关的机制提供系统的模型。我们已经开发了一种遗传修饰的小鼠模型，该模型表达了前列腺特异性模型抗原，膜结合的卵蛋白（MOVA），CRE/LOXP产生的前列腺特异性PTEN敲除以及前列腺上皮细胞中的荧光素酶表达，以进行想象（Poetpten）。该模型是通过将前列腺特异性转基因（Poet-3）与转基因的PTEN基因敲除表达荧光素酶（PTENFL/FL-LUC）的跨越。诗人3和诗人均证明了初步数据表明，这两种模型都诱发了炎症。诗人3的研究表明，启动后84天炎症仍然存在。值得注意的是，直到84天的时间点，在发炎的前列腺中观察到显着升高的前列腺上皮细胞增殖。同样，启动后45天发炎的前列腺中细胞因子的产生仍然升高，这是最新的评估时间点。由于前列腺特异性PTEN零模型代表了前列腺癌进展的各个阶段，因此我们处于一个独特的位置，可以评估炎症对诗人组合模型中疾病进展的影响。这些数据为前列腺炎症调节肿瘤发育和进展的假设提供了基础。该应用中概述的研究建议在肿瘤前和肿瘤环境中表征前列腺炎症，并确定炎症过程中存在的潜在免疫调节元件。为此，提出了以下特定目标：目标1。表征前列腺癌的发展和发炎的前列腺进展；和目标2。在前塑性（PTEN+/FL），肿瘤（PTENFLLFL）和良性（PTEN+/+）小鼠中前列腺炎症期间炎症细胞浸润的表征。 公共卫生相关性：拟议的研究介绍了一种新型模型，以评估炎症对前列腺癌发展的影响。提出的研究将确定炎症对前列腺癌发展和进展的影响。