Abstract：
Colorectal cancer (CRC) is one of the most prevalent fatal neoplasias worldwide. Despite efforts to improve the early diagnosis of CRC, the mortality rate of patients is still nearly 50%. The primary treatment strategy for CRC is surgery, which may be accompanied by chemotherapy and radiotherapy. The conventional and first-line chemotherapeutic agent utilized is 5-fluorouracil (5FU). However, it has low efficiency. Combination treatment with leucovorin and oxaliplatin or irinotecan improves the effectiveness of 5FU therapy. Unfortunately, most patients develop drug resistance, leading to disease progression. Here, we evaluated the effect of a potential alternative adjuvant treatment for 5FU, helminth-derived Taenia crassiceps (TcES) molecules, on treating advanced colitis-associated colon cancer. The use of TcES enhanced the effects of 5FU on established colonic tumors by downregulating the expression of the immunoregulatory cytokines, Il-10 and Tgf-β, and proinflammatory cytokines, Tnf-α and Il-17a, and reducing the levels of molecular markers associated with malignancy, cyclin D1, and Ki67, both involved in apoptosis inhibition and the signaling pathway of β-catenin. TcES+5FU therapy promoted NK cell recruitment and the release of Granzyme B1 at the tumor site, consequently inducing tumor cell death. Additionally, it restored P53 activity which relates to decreased Mdm2 expression. In vitro assays with human colon cancer cell lines showed that therapy with TcES+5FU significantly reduced cell proliferation and migration by modulating the P53 and P21 signaling pathways. Our findings demonstrate, for the first time in vivo, that helminth-derived excreted/secreted products may potentiate the effect of 5FU on established colon tumors.
摘要：
结直肠癌(CRC)是全球最常见的致命性肿瘤之一。尽管努力改善CRC的早期诊断，患者死亡率仍近50%。CRC的主要治疗策略是手术，可能伴有化疗和放疗。所用的常规和一线化疗剂是5-氟尿嘧啶(5FU)。然而,效率低。用亚叶酸和奥沙利铂或伊立替康联合治疗可提高5FU治疗的有效性。不幸的是,大多数患者会产生耐药性，导致疾病进展。这里,我们评估了潜在的替代辅助治疗5FU的效果，蠕虫衍生的棘齿带虫(TcES)分子，关于治疗晚期结肠炎相关结肠癌。TcES的使用通过下调免疫调节细胞因子的表达来增强5FU对已建立的结肠肿瘤的作用，Il-10和Tgf-β，和促炎细胞因子，Tnf-α和Il-17a，并降低与恶性肿瘤相关的分子标志物水平，cyclinD1和Ki67均参与细胞凋亡抑制和β-catenin信号通路。TcES+5FU治疗促进NK细胞募集和颗粒酶B1在肿瘤部位的释放，从而诱导肿瘤细胞死亡。此外,它恢复了与Mdm2表达降低相关的P53活性。对人结肠癌细胞系的体外分析显示,用TcES+5FU治疗通过调节P53和P21信号传导途径显著降低细胞增殖和迁移。我们的发现表明,第一次在体内，蠕虫来源的排泄/分泌产物可能会增强5FU对已建立的结肠肿瘤的作用。
