Prostatitis and Prostate Cancer Development

描述(申请人提供)：前列腺炎和前列腺癌是男性非常常见的疾病，但这两种疾病之间的关系尚不清楚。虽然急性前列腺炎被认为是传染性的，但慢性前列腺炎和慢性盆腔疼痛综合征(CP/CPPS)以及无症状炎性前列腺炎的病因仍不清楚。通过对免疫耐受缺陷和自发性前列腺炎的Aire缺陷小鼠的研究，我们发现了一种新的前列腺自身抗原。此外，我们还发现，经活检证实前列腺炎症的CP/CPPS患者对类似的人类蛋白精胶蛋白(Sg)具有免疫反应。这些结果提供了新的证据，支持自身免疫是慢性前列腺炎的潜在原因。此外，通过评估对Sg的免疫反应，我们可能能够检测到有症状或无症状的男性的前列腺炎症。动物模型以及临床观察表明，慢性炎症可促进某些肿瘤的发生发展。我们假设慢性前列腺炎有助于前列腺癌的发生。这项建议的总体目标是检查：1)对前列腺癌自身抗原Sg的免疫反应与人类前列腺癌之间是否存在关联；以及2)慢性炎症是否会促进小鼠模型前列腺癌的发展。在特定的目标1中，我们将确定接受前列腺活检的男性对Sg的免疫反应是否与炎症和/或前列腺癌的存在有关。在具体目标2中，我们将确定慢性前列腺炎是否可以改变前列腺癌小鼠模型的肿瘤发展。这项建议将为慢性炎症和前列腺癌发展的作用提供洞察力。此外，这些结果可能为通过治疗慢性前列腺炎来预防前列腺癌提供理论依据。 公共卫生相关性：慢性炎症被认为是许多不同恶性肿瘤发展的原因，但炎症在前列腺癌中的作用尚不清楚。前列腺癌是男性最常见的非皮肤癌。慢性前列腺炎在男性中也是一个非常常见的问题。通过使用具有遗传缺陷的小鼠模型，使这些小鼠容易患上自身免疫性疾病，我们已经确定了免疫系统的一个蛋白质靶点，我们认为它在人类慢性前列腺炎中很重要。我们建议评估正在接受前列腺活检的男性对这种蛋白的免疫反应。我们将在活检中评估对该蛋白的免疫反应是否与前列腺炎和前列腺癌有关。我们还将确定前列腺炎是否会加速小鼠肿瘤的发展，这些小鼠是通过基因工程患上自发性前列腺癌的。通过这样做，我们可能会理解自身免疫是如何导致前列腺癌的。此外，这项工作可能为开发前列腺癌预防方法提供基础。

DESCRIPTION (provided by applicant): Prostatitis and prostate cancer are extremely common diseases in men, but the relationship between these two diseases is unknown. While acute prostatitis is thought to be infectious in nature, the etiology of chronic prostatitis and chronic pelvic pain syndrome (CP/CPPS) and asymptomatic inflammatory prostatitis remains unclear. By studying Aire-deficient mice that have defective immune tolerance and develop spontaneous prostatitis, we have identified a novel prostate autoantigen. Moreover, we have found that CP/CPPS patients with biopsy-proven inflammation in their prostate glands possess immune responses to the analogous human protein, semenogelin (Sg). These results provide new evidence to support autoimmunity as a potential cause for chronic prostatitis. Moreover, by assessing for immune responses to Sg, we may be able to detect prostate inflammation in symptomatic or asymptomatic men. Animal models as well as clinical observations demonstrate that chronic inflammation can enhance the development or certain tumors. We hypothesize that chronic prostatitis contributes to prostate cancer development. The overall objectives of this proposal are to examine: 1) whether there is an association between an immune responses to the prostate autoantigen Sg and prostate cancer in humans; and 2) whether chronic inflammation can enhance the development of prostate cancer in mouse models. In specific aim 1, we will determine whether immune responses to Sg are associated with the presence of inflammation and/or prostate cancer in men undergoing prostate biopsy. In the specific aim 2, we will determine whether chronic prostatitis can alter the development of tumors in mouse models of prostate cancer. This proposal will provide insight in the role of chronic inflammation and prostate cancer development. Moreover, these results could provide a rationale for prostate cancer prevention by treating chronic prostatitis. PUBLIC HEALTH RELEVANCE: Chronic inflammation is thought to contribute to the development of many different malignancies, but the role of inflammation in prostate cancer is unknown. Prostate cancer is the most common non-skin cancer in men. Chronic prostatitis is also an extremely common problem in men. By using a mouse model with a genetic deficiency that predisposes these mice to autoimmune disease, we have identified a protein target for the immune system that we believe to be important in chronic prostatitis in humans. We propose to assess for immune responses to this protein in men who are undergoing prostate biopsies. We will evaluate whether immune responses to this protein are associated with prostate inflammation and prostate cancer on biopsy. We will also determine whether prostatitis can accelerate the development of tumors in mice that are genetically engineered to develop spontaneous prostate cancer. In doing so, we may understand how autoimmunity can contribute to prostate cancer. Moreover, this work could provide the foundation for developing an approach to prostate cancer prevention.