Inflammation, autoimmunity and ovarian cancer

描述(申请人提供)：蛋鸡是一种新兴的自发性卵巢癌(OVCA)动物模型。这个模型解决了对自发的人类OVCA和非自发的OVCA工程模型的研究之间的差距。有证据表明，母鸡可以提供与炎症和自身免疫在OVCA病因中所起作用有关的早期事件的所需信息，因为人和母鸡在卵巢生理、抗卵巢自身抗体(AOA)、抗肿瘤抗体和OVCA以及免疫细胞向肿瘤的运输方面具有惊人的相似之处。有趣的是，在中年妇女和母鸡中，卵巢自身免疫和AOA与卵巢功能过早下降有相似的关系。我们发现，母鸡和人类OVCA都与AOA相关，并与相同肿瘤抗原的抗体(如间皮蛋白(MSLN)、硒结合蛋白1(SBP1)和P53)有关。在一项初步研究中，卵巢正常但产蛋率低(即卵巢功能降低)的母鸡 随着AOA在10个月内发展为OVCA，提示自身免疫可以先于OVCA或预测OVCA。自身免疫与癌症有关的概念并不新鲜。然而，考虑到在人类身上进行此类研究的后勤保障，对OVCA自身免疫的潜在进展进行了最低限度的探索。可以很容易地在母鸡身上测试自身抗体、炎症和自发肿瘤发展之间的关系。在这项研究中，我们将使用OVCA的蛋鸡模型来确定(目的1)血清中针对特定抗原的自身抗体，如抗间皮蛋白(MSLN)、抗p53和/或抗硒结合蛋白1(SBP1)是否可以预测OVCA，抗体是否与卵巢中淋巴细胞数量的增加相关，以及这些免疫变化是否更常与卵巢中的促炎环境有关，以及(目的2)证实FTY720(Fingolimod；FDA批准的一种用于改善自身免疫性疾病的S1P激动剂(多发性硬化症)可以逆转淋巴细胞浸润和炎症，改善卵巢功能，这与OVCA发病率的替代终点(血管生成)减少有关。这些目标的实现将为抗体作为OVCA的标志物以及通过免疫抑制剂减少OVCA提供进一步的证据。这将有助于了解OVCA发生中涉及的机制，该机制可以有针对性地预防或控制OVCA。

DESCRIPTION (provided by applicant): The laying hen is an emerging animal model of spontaneous ovarian cancer (OVCA). This model addresses a gap between studies of spontaneous human OVCA and non-spontaneous, engineered models of OVCA. Evidence suggests the hen can provide needed information on early events related to the role of inflammation and autoimmunity in the etiology of OVCA since humans and hens have striking similarities in ovarian physiology, anti-ovarian autoantibodies (AOA), anti-tumor antibodies and OVCA and immune cell trafficking into tumors. Interestingly, ovarian autoimmunity and AOA are associated similarly with prematurely decreased ovarian function in middle aged women and hens. We showed that both hen and human OVCA are associated with AOA and with antibodies to the same tumor antigens (e.g., mesothelin (MSLN), Selenium Binding Protein 1 (SBP1) and p53. In a pilot study, hens with normal ovaries but low egg laying (i.e., reduced ovarian function) with AOA developed OVCA within 10 months suggesting that autoimmunity could precede or predict OVCA. The concept that autoimmunity is linked to cancer is not new. However, the potential progression of autoimmunity to OVCA has been minimally explored given the logistics of carrying out such studies in humans. The relationship among autoantibodies, inflammation and spontaneous tumor development can easily be tested in hens. In this study we will use the laying hen model of OVCA to determine (Aim 1) whether serum autoantibodies to specific antigens such as anti-mesothelin (MSLN), anti-p53 and/or anti-selenium binding protein 1 (SBP1) predict OVCA, if antibodies are correlated with increased lymphocyte numbers in the ovary and if these changes in immunity are more often associated with a pro-inflammatory environment in the ovary, and (Aim 2) confirm that FTY720 (fingolimod; an S1P agonist that is FDA approved for amelioration of the autoimmune disease, multiple sclerosis) reverses lymphocyte infiltration and inflammation and improves ovarian function and that this is associated with a decrease in a surrogate endpoint (angiogenesis) for OVCA incidence. Accomplishment of these Aims will provide further evidence for antibodies as markers for OVCA and for reduction of OVCA by an immunosuppressant. This will contribute to knowledge of a mechanism involved in OVCA generation that can be targeted to prevent or control OVCA.