Modulation of colitis-associated cancer by cyclosporine A

描述（由申请人提供）：与正常人群相比，炎症性肠病（IBD）患者发生肠道恶性肿瘤的频率增加。这被认为部分是由于与这种使人衰弱的疾病相关的慢性炎症。环孢素A （CsA）是治疗严重类固醇难治性IBD，特别是溃疡性结肠炎（UC）的有效药物。然而，在动物模型中使用CsA与结直肠癌细胞的扩散增强有关。我们已经证明，用CsA治疗骨髓移植（BMT）小鼠会导致类似于其他IBD模型的结肠炎样疾病。重要的是，最近的研究已经证明了炎症小体在肠道内稳态和结肠炎相关肠道肿瘤发展中的作用。IBD患者炎症小体活性降低，这可能导致临床疾病的发展，炎症小体缺乏的动物会发展为增强的结肠炎和结肠肿瘤。我们已经证明，CsA治疗BMT小鼠抑制炎性体的激活，并可能参与结肠炎样疾病的发展，使CsA在难治性IBD中的临床应用受到怀疑。鉴于这些发现，将提出两个具体的目标来验证环孢素治疗将会有效的假设

DESCRIPTION (provided by applicant): Patients with inflammatory bowel disease (IBD) develop malignancies of the intestinal tract at an increased frequency compared to the normal population. This is thought to be due, in part, to the chronic inflammation associated with this debilitating disease. Cyclosporine A (CsA) is an effective treatment for patients with severe, steroid-refractory IBD, especially ulcerative colitis (UC). However, the use of CsA in animal models has been associated with enhanced spread of colorectal cancer cells. We have shown that treatment of bone marrow transplanted (BMT) mice with CsA leads to a colitis-like disease similar to other models of IBD. Importantly, recent studies have demonstrated a role for the inflammasome, in intestinal homeostasis and the development of colitis-associated intestinal tumors. IBD patients have decreased inflammasome activity which may contribute to the development of clinical disease and animals with deficiencies in the inflammasome develop enhanced colitis and colon tumors. We have documented that CsA-treatment of BMT mice inhibited the activation of the inflammasome and may have participated in the development of colitis-like disease, making suspect the clinical use of CsA in refractory IBD. Given these findings two specific aims will be proposed to test the hypothesis that cyclosporine treatment will alter intestinal homeostasis via inhibition of inflammasome function, resulting in enhanced tumor growth in the azoxymethane (AOM)/dextran sulfate sodium (DSS) model of colitis-associated colon cancer (CAC). Aim 1 will determine if treatment of AOM/DSS- treated animals with a therapeutic dose of CsA will enhance the severity of colitis and the development of CAC. Inflammasome expression and activity will be determined in CsA-treated mice after induction of AOM/DSS CAC. Preliminary results show that CsA therapy inhibits intestinal barrier function in BMT mice. Thus, we propose that intestinal damage which occurs during the induction of AOM/DSS also will be prolonged by CsA therapy. Aim 2 will test the hypothesis that CsA-induced alterations in intestinal epithelium will lead to increased permeability and decreased barrier function via inhibition of inflammasome function, which may contribute to increased colitis and development of CAC. As patients with IBD have reduced inflammasome activity, the potential exists that the use of CsA to treat refractory IBD may enhance development of the disease by further reducing inflammasome function, leading to and enhanced risk of CAC. It is imperative to analyze the effects of immunosuppressive therapy on intestinal damage, induction of colitis and CAC in model animal systems to understand the risk of CsA therapy in the treatment of IBD.