Inflammation and Prostate Cancer Development and Progression

描述(由申请人提供)：构成前列腺癌炎症作用基础的数据来自不同的领域。流行病学研究表明，前列腺癌与前列腺炎相关的发病率增加，服用抗炎药物的个人风险降低。值得注意的是，两个候选的家族性前列腺癌基因编码与先天性免疫反应相关的蛋白质，干扰素诱导核糖核酸酶(RNASE)和巨噬细胞清道夫受体-1(MSR1)。此外，谷胱甘肽S转移酶(GST)的表达缺失(已在大多数前列腺癌中描述)增加了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)被认为是前列腺癌发生的先兆。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，但强烈地暗示着一种关系。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相关的机制。我们已经建立了一种转基因小鼠模型，表达前列腺特异性模型抗原、膜结合卵白蛋白(MOVA)、由Cre/loxP产生的前列腺特异性PTEN基因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)。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基因敲除(PTENfl/fl-Luc)杂交而产生的。初步数据显示，在POET-3和POETPTEN中，两种模型都诱导了炎症。对POTE-3的研究表明，炎症在开始后84天仍然存在。值得注意的是，在发炎的前列腺中，直到84天的时间点才观察到显著的前列腺上皮细胞增殖。同样，炎症的前列腺在发病45天后细胞因子的产生仍然升高，这是最新的评估时间点。因为前列腺特异性PTEN缺失模型代表了前列腺癌进展的不同阶段，所以我们处于独特的地位来评估炎症对疾病进展的影响在POET-PTEN联合模型中。这些数据为前列腺癌炎症调节肿瘤发展和进展的假说提供了基础。本申请中概述的研究建议描述肿瘤前和肿瘤环境中的前列腺癌炎症，并确定炎症过程中存在的潜在免疫调节因素。为此，提出了以下具体目标：目的1.表征前列腺癌在发炎的前列腺癌中的发展和进展；以及目的2.肿瘤前期(PTEN+/F1)、肿瘤(PTENfllf1)和良性(PTEN+/+)小鼠前列腺炎症过程中炎性细胞的特征。 公共卫生相关性：拟议的研究引入了一种新的模型，用于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生和发展的影响。

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.