Prebiotic effect of eicosapentaenoic acid treatment for colorectal cancer

项目摘要/摘要 结直肠癌(CRC)是美国第二大癌症死亡原因。 患者发生肝转移(CRCLM)，这是结直肠癌相关死亡的主要原因。作为外科手术切除 CRCLM变得越来越常规，改善CRCLM切除后患者的预后是当务之急。 二十碳五烯酸(EPA)，一种天然存在的海洋omega-3多不饱和脂肪酸可能会保护 反对中国铁路局。我们小组最近进行的一项II期随机安慰剂对照试验(RCT)显示，EPA 补充剂可提高区域癌症和CRCLM患者的存活率。然而，具体的 EPA影响术后存活率的机制尚不清楚。最近的数据来自 我们的小组和其他人支持EPA的抗结直肠癌益处可能是通过其在 调节肠道微生物区系和改善肿瘤允许的免疫抑制机制，包括 抑制调节性T细胞(Tregs)和髓系抑制细胞(MDSCs)的活性，以及 前列腺素E_2(PGE_2)和趋化因子(C-C基序)配体2等炎症介质的产生 (CCL2)。膳食脂肪组成也是肠道微生物群落结构的主要驱动力。给小鼠喂食一种 高EPA饮食显示肠道细菌数量增加，如双歧杆菌和乳杆菌 支持宿主免疫保护系统并提高癌症免疫治疗效果的属，以及 产生内毒素(LPS)的细菌数量减少，引发慢性炎症和 推广CRC。这些数据一起支持了我们的假设，即EPA的益生菌效应可以消除肿瘤内 免疫抑制和改善全身炎症以提高手术患者的存活率 CRCLM切除术。为了检验这一假设，我们将利用我们最近推出的第三阶段每日4-g随机对照试验 EPA-乙酯在448例肝切除CRCLM手术中的应用 转移试验2，EMT2)，参与者在CRCLM手术前至少2周开始治疗 肝切除后持续2-4年。使用从治疗后肝脏收集的组织标本 切除，并在随机、手术和每隔6个月收集一次血液、尿液和粪便样本， 我们将询问与生存相关的免疫和微生物途径。我们将讨论因果关系和 表征EPA影响宿主-微生物相互作用以增强抗肿瘤作用的机制 人源化粪便对新型无菌CRCLM小鼠模型的免疫和抑制作用 随机对照试验参与者。通过这些综合调查，我们的研究可能会开辟新的发展途径 基于EPA的结直肠癌治疗的组合策略。这一策略在临床上的应用尤其重要。 由于其成本和安全优势而具有吸引力。

PROJECT SUMMARY / ABSTRACT Colorectal cancer (CRC) is the second leading cause of cancer death in the U.S. Approximately 30-50% of CRC patients develop liver metastasis (CRCLM), a major contributor to CRC-related death. As surgical resection of CRCLM becomes increasingly routine, improving outcomes for patients post-CRCLM resection is a high priority. Eicosapentaenoic acid (EPA), a naturally-occurring marine omega-3 polyunsaturated fatty acid may protect against CRC. A recent Phase II randomized placebo-controlled trial (RCT) by our group showed that EPA supplementation improves survival in patients with regional cancer and CRCLM. However, the specific mechanisms through which EPA influences post-operative survival are not well understood. Recent data from our group and others support that the anti-CRC benefit of EPA may be mediated by its pleiotropic roles in modulating the gut microbiota and ameliorating tumor-permissive immunosuppressive mechanisms, including inhibition of the activity of regulatory T cells (Tregs) and myeloid-derived suppressor cells (MDSCs), and production of inflammatory mediators such as prostaglandin E2 (PGE2) and chemokine (C-C motif) ligand 2 (CCL2). Dietary fat composition is also a major driver of the gut microbial community structure. Mice fed with a high-EPA diet demonstrate increased abundance of gut bacteria, such as Bifidobacterium and Lactobacillus genera, that support the host immunoprotective system and improve the efficacy of cancer immunotherapy, and decreased abundance of lipopolysaccharide (LPS)-producing bacteria that trigger chronic inflammation and promote CRC. These data together support our hypothesis that the prebiotic effect of EPA abrogates intratumoral immunosuppression and ameliorates systemic inflammation to improve survival of patients with surgical resection of CRCLM. To test this hypothesis, we will leverage our recently launched, phase III RCT of 4-g daily EPA-ethyl ester treatment among 448 patients undergoing liver resection surgery for CRCLM (EPA for Metastasis Trial 2, EMT2), in which participants start treatment at least 2 weeks prior to CRCLM surgery and continue for 2-4 years post-liver resection. Using tissue specimens collected from the post-treatment liver resection, and blood, urine, and stool samples collected at randomization, surgery, and at 6-monthly intervals, we will interrogate immune and microbiome pathways in relation to survival. We will address causality and characterize the mechanisms by which EPA influences the host–microbial interactions to potentiate antitumor immunity and suppress CRCLM in a novel ‘avatar’ germ-free CRCLM mouse model humanized with stool from RCT participants. Through these integrated investigations, our study may open new avenues for developing EPA-based combinatorial strategies for CRC treatment. The clinical utility of this strategy is particularly appealing due to its cost and safety advantages.