Chronic Alcohol Consumption Promotes Diethylnitrosamine-Induced Hepatocarcinogenesis via Immune Disturbances.

Chronic alcohol consumption increases the risk of hepatocellular carcinoma (HCC). However, little is known about the potential immunological mechanisms by which ethanol affects tumor progression. Here, adult male mice were administered multiple doses of diethylnitrosamine (DEN). Four and a half months later, the DEN-treated mice were placed on a liquid Lieber-DeCarli control diet or diet containing 5% ethanol for 2.5 months. At the end of the study, liver tissue samples were obtained to analyze pathology, gene expression, and hepatic mononuclear cells (MNCs). Results showed that ethanol feeding exacerbates the progression of hepatic tumors (characterized by the ratio of liver weight to body weight, and the tumor volume and diameter) in DEN-treated mice. Mechanistically, chronic alcohol consumption decreased the number of antitumor CD8+ T cells but increased the number of tumor-associated macrophages (TAMs) in the liver in DEN-initiated tumorigenesis. Besides, TAMs were prone to be M2 phenotype after alcohol consumption. Moreover, chronic alcohol consumption aggravated inflammation, fibrosis, and epithelial-mesenchymal transition (EMT) in the pathological process of HCC. These data demonstrate that chronic alcohol consumption exacerbates DEN-induced hepatocarcinogenesis by enhancing protumor immunity, impairing antitumor immunity and aggravating hepatic pathological injury. Targeting the immune system is a potential therapeutic regimen for alcohol-promoted HCC.

长期饮酒会增加肝细胞癌（HCC）的风险。然而，对于乙醇影响肿瘤进展的潜在免疫学机制知之甚少。在此，给成年雄性小鼠多次施用二乙基亚硝胺（DEN）。四个半月后，给经DEN处理的小鼠喂食利伯 - 德卡利（Lieber - DeCarli）对照液体饲料或含5%乙醇的饲料，持续2.5个月。研究结束时，获取肝脏组织样本以分析病理学、基因表达以及肝脏单核细胞（MNCs）。结果显示，在经DEN处理的小鼠中，乙醇喂养加剧了肝脏肿瘤的进展（以肝脏重量与体重的比值以及肿瘤体积和直径为特征）。从机制上讲，在DEN引发的肿瘤发生过程中，长期饮酒减少了肝脏中抗肿瘤的CD8 + T细胞数量，但增加了肿瘤相关巨噬细胞（TAMs）的数量。此外，饮酒后TAMs易于呈现M2表型。而且，在HCC的病理过程中，长期饮酒会加重炎症、纤维化以及上皮 - 间质转化（EMT）。这些数据表明，长期饮酒通过增强促肿瘤免疫、削弱抗肿瘤免疫以及加重肝脏病理损伤，加剧了DEN诱导的肝癌发生。针对免疫系统是治疗酒精促进的HCC的一种潜在治疗方案。