Modulation of colitis-associated cancer by cyclosporine A

描述（由申请方提供）：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）是治疗激素难治性IBD，尤其是溃疡性结肠炎（UC）的有效药物。然而，CsA在动物模型中的使用与结肠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性小体在肠道稳态和结肠炎相关肠道肿瘤的发展中的作用。IBD患者具有降低的炎性体活性，这可能有助于临床疾病的发展，并且具有炎性体缺陷的动物发展增强的结肠炎和结肠肿瘤。我们已经证明，CsA治疗BMT小鼠抑制炎症体的激活，并可能参与了结肠炎样疾病的发展，使怀疑CsA在难治性IBD的临床应用。鉴于这些发现，将提出两个具体目标来检验环孢菌素治疗将 通过抑制炎性小体功能改变肠道内稳态，导致结肠炎相关结肠癌（CAC）的氧化偶氮甲烷（AOM）/葡聚糖硫酸钠（DSS）模型中肿瘤生长增强。目的1将确定用治疗剂量的CsA处理AOM/DSS处理的动物是否会增强结肠炎的严重程度和CAC的发展。在诱导AOM/DSS CAC后，将在CsA处理的小鼠中测定炎性体表达和活性。初步结果显示CsA治疗抑制BMT小鼠的肠屏障功能。因此，我们建议，在AOM/DSS诱导过程中发生的肠损伤也将通过CsA治疗延长。目的2将检验以下假设：CsA诱导的肠上皮改变将通过抑制炎性小体功能导致通透性增加和屏障功能降低，这可能有助于结肠炎增加和CAC的发展。由于IBD患者的炎性小体活性降低，因此使用CsA治疗难治性IBD可能会通过进一步降低炎性小体功能来促进疾病的发展，从而导致CAC的风险增加。分析免疫抑制剂治疗对肠道损伤、诱导结肠炎和CAC的影响，有助于了解CsA治疗IBD的风险。

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.