Modulation of colitis-associated cancer by cyclosporine A

炎症性肠病(IBD)患者发生肠道恶性肿瘤的几率增加。 与正常人群相比，这一频率更高。这被认为是慢性炎症的部分原因。 与这种令人衰弱的疾病有关。环孢素A(CsA)是治疗慢性粒细胞白血病的有效药物。 严重的激素难治性IBD，尤其是溃疡性结肠炎(UC)。然而，CsA在动物模型中的使用已经 与结直肠癌细胞的扩散增强有关。我们已经证明了对骨骼的治疗 使用CsA的骨髓移植(BMT)小鼠会导致一种类似于其他IBD模型的结肠炎样疾病。 重要的是，最近的研究表明，炎性小体在肠道内稳态和 结肠炎相关性肠道肿瘤的发展。炎症性肠病患者炎性小体活性降低 可能有助于临床疾病的发展和炎性小体缺陷的动物 发展为增强型结肠炎和结肠肿瘤。我们已经证明CsA治疗对骨髓移植小鼠有抑制作用。 炎性小体的激活，可能参与了结肠炎样疾病的发展， 令人怀疑CsA在难治性IBD的临床应用。鉴于这些发现，两个具体目标将是 建议检验环孢素治疗将通过抑制 炎症小体功能，导致偶氮甲烷(AOM)/硫酸葡聚糖促进肿瘤生长 结肠炎相关性结肠癌(CAC)钠盐(DSS)模型。AIM 1将决定AOM/DSS的治疗是否- 用治疗剂量的环孢素A治疗的动物将增加结肠炎的严重程度和发展 CAC.CsA诱导后的小鼠炎症体表达和活性将被检测 AOM/DSS CAC.初步结果表明，CsA治疗抑制了骨髓移植小鼠的肠屏障功能。 因此，我们认为，在AOM/DSS诱导过程中发生的肠道损伤也将延长 采用环孢素A治疗。Aim 2将验证CsA诱导的肠上皮改变将导致 通过抑制炎性小体功能增加通透性和降低屏障功能，这可能 有助于增加结肠炎和CAC的发展。由于IBD患者的炎症性小体减少 活性，存在使用CsA治疗难治性IBD可能促进发展的潜力。 疾病通过进一步降低炎症小体功能，导致和增加CAC的风险。必须要做到 免疫抑制治疗对模型大鼠肠损伤、结肠炎和CAC的影响 动物系统了解CsA治疗IBD的风险。

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.