Inflammation and Prostate Cancer Development and Progression

描述（由申请人提供）：炎症在前列腺癌中作用的基础数据来自各个领域。流行病学研究表明，前列腺炎与前列腺癌的发病率增加有关，服用消炎药的人患前列腺癌的风险降低。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应答相关的蛋白，干扰素诱导核糖核酸酶（RNASEL）和巨噬细胞清零受体-1 （MSR1）。此外，谷胱甘肽s -转移酶（GST）表达的缺失（在大多数前列腺癌中已被描述）增加了对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）被认为是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，为定义炎症诱导的前列腺癌发生和进展的调节机制提供系统。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荧光素酶的表达（POETPTEN）。通过将前列腺特异性mOVA转基因基因（POET-3）与表达荧光素酶的PTEN基因敲除基因（PTENfl/fl-luc）杂交产生模型。初步数据显示，在poet3和POETPTEN中，两种模型均可诱导炎症。在POET-3的研究显示炎症在起始84天后仍然存在。值得注意的是，炎症前列腺中前列腺上皮细胞增殖明显升高，直至84天时间点。同样，在开始治疗后45天，炎症前列腺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零模型代表前列腺癌进展的各个阶段，我们在评估炎症对POET-PTEN联合模型中疾病进展的影响方面处于独特的地位。这些数据为前列腺炎症调节肿瘤发生和发展的假设提供了基础。本应用程序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，并确定炎症期间存在的潜在免疫调节因子。为此目的，提出了以下具体目标：目标1。表征前列腺癌的发展和进展在发炎的前列腺；和Aim 2。癌前（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特征

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.