Inflammation and 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基础的数据来自多个领域。流行病学研究表明，前列腺癌的发病率增加与前列腺炎和降低风险的个人服用抗炎药。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应答相关的蛋白质，干扰素诱导型核糖核酸酶（RNASEL）和巨噬细胞清道夫受体-1（MSR 1）。此外，谷胱甘肽S-转移酶（GST）表达的损失，这已在大多数前列腺癌中描述，增加了对由炎症产生的氧自由基诱导的突变的易感性。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前兆。最后，IL-6与前列腺癌的生长有关。炎症和前列腺癌之间的关联的多样性是相关的，但强烈暗示了一种关系。因此，需要建立将提供用于定义与炎症诱导的前列腺癌发展和进展的调节相关的机制的系统的模型。我们已经开发了一种基因修饰的小鼠模型，表达前列腺特异性模型抗原、膜结合卵清蛋白（mOVA）、由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）。通过将前列腺特异性mOVA转基因（POET-3）与表达荧光素酶的遗传修饰的PTEN敲除（PTENfl/fl-luc）杂交来产生模型。POET-3和POETPTEN中的初步数据表明，在两种模型中均诱导炎症。POET-3的研究显示，炎症在开始后84天仍然存在。值得注意的是，直到第84天时间点，在发炎的前列腺中观察到显著升高的前列腺上皮细胞增殖。同样，在开始后45天，即最新的评估时间点，炎症前列腺中的细胞因子产生仍然升高。由于前列腺特异性PTEN无效模型代表前列腺癌进展的各个阶段，因此我们处于独特的位置来评估炎症对组合POET-PTEN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展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，提出了以下具体目标：目标1。表征前列腺癌在发炎前列腺中的发展和进展;和目的2.肿瘤前（PTEN+/fl）、肿瘤（PTENfl/fl）和良性（PTEN+/+）小鼠中前列腺炎症期间炎性细胞浸润的表征。 公共卫生相关性：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。这些研究将确定炎症对前列腺癌发展和进展的影响。

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.