Alcohol-sensitized macrophages enhance colorectal carcinoma metastasis in the liver

肝脏是结直肠癌(CRC)转移性疾病的终末部位，通常在没有干预的情况下 预示着死亡。肝脏也是受饮酒影响的主要器官。有趣的是，酒精的使用 已被确定为结直肠癌肝转移(CRLM)的重要危险因素，但其作用机制 仍然没有定义。尽管与酒精相关的CRLM对普通民众来说是一个严重的健康问题，但 退伍军人群体尤其脆弱，因为与服务相关的创伤和伤害显著 会导致酒精使用障碍和肝病。考虑到这一点，临床上重要的是要确定 酒精影响肝脏结直肠转移的机制和潜在的治疗靶点。的目标是 这项工作是为了确定酒精肝如何促进转移性CRC细胞的定植，这些细胞表达 癌胚抗原(CEA)。CEA肿瘤糖蛋白在转移性癌细胞中高表达 与慢性肾小球疾病的发生发展相关。据认为，CEA刺激宿主微环境中的细胞 产生炎症反应和促进转移性疾病的因子。具体地说，它是假设的 酒精使肝巨噬细胞对CEA的影响敏感，从而加速结直肠癌的生长 肝脏中的肿瘤。为了研究这一点，提出了三个具体目标来确定酒精的作用- 致敏巨噬细胞(Kupffer细胞、浸润性单核细胞和腹膜细胞)在CEA信号和 CRLm的发展。在第一项研究中，CEA作为促进转移的关键因素的作用将 使用最近开发的酒精性肝损伤的临床前模型和CRLM建立。在第二个 目的：巨噬细胞表型、活化和相关转移因子的产生的关键作用将是 根据CEA表达的癌细胞的反应而确定。在最后一个目标中，关键实验将定义 靶向CEA介导的事件对减轻结直肠肝转移负担的有效性。巨噬细胞 灭活和抗CEA治疗将单独测试或与肠道碱性磷酸酶联合测试 补充以抑制肠源性内毒素的酒精相关效应。这些项目的顺利完成 研究将通过确定酒精介导的有针对性的机制来为该领域做出贡献 CEA信号的恶化与CRLM的相关发展。此外，这项工作将提供有用的 关于未来旨在减少或消除结直肠癌肝转移的治疗策略的信息 癌症。这是一个与临床相关的话题，有可能对退伍军人的医疗保健产生重大影响， 尤其是那些酒精使用障碍的高危人群和与之相关的发展结直肠肝脏的人 肿瘤。

The liver is the terminal site of metastatic disease of colorectal cancer (CRC), that without intervention usually heralds death. The liver is also the main organ affected by alcohol consumption. Interestingly, alcohol use has been identified as a significant risk factor for colorectal liver metastasis (CRLM), yet contributing mechanisms remain undefined. Although alcohol-related CRLM is a serious health concern for the general population, the Veteran population is especially vulnerable because of service-connected trauma and injuries that significantly contribute to alcohol use disorders and liver disease. Considering this, it is clinically important to determine mechanisms and potential therapeutic targets for colorectal metastasis in the alcohol-affected liver. The goal of this work is to determine how the alcoholic liver facilitates the colonization of metastatic CRC cells that express carcinoembryonic antigen (CEA). The CEA tumor glycoprotein is overexpressed in metastatic cancer cells and correlates with the development of CRLM. It is believed that CEA stimulates cells of the host microenvironment to produce inflammatory responses and factors that promote metastatic disease. Specifically, it is hypothesized that alcohol sensitizes hepatic macrophages to the effects of CEA resulting in the accelerated growth of CRC tumors in the liver. To investigate this, three specific aims are proposed to determine the role of alcohol- sensitized macrophages (Kupffer cells, infiltrating monocytes, and peritoneal cells) in CEA signaling and development of CRLM. In the first studies, the role of CEA as a key factor in the promotion of metastases will be established using a recently developed preclinical model of alcoholic liver injury and CRLM. In the second aim, the critical role of macrophage phenotype, activation, and related production of prometastatic factors will be determined in response to CEA-expressing cancer cells. In the last aim, key experiments will define the effectiveness of targeting CEA-mediated events to reduce the burden of colorectal liver metastasis. Macrophage inactivation and anti-CEA therapy will be tested alone or in combination with intestinal alkaline phosphatase supplementation to inhibit alcohol-related effects of gut-derived endotoxin. The successful completion of these studies will contribute to the field by defining targetable mechanisms involved in the alcohol-mediated exacerbation of CEA signaling and the associated development of CRLM. Moreover, this work will provide useful information for future therapeutic strategies aimed at reducing or eliminating liver metastases of colorectal cancer. This is a clinically relevant topic which has the potential to significantly impact healthcare for Veterans, especially those who are at a high risk for alcohol use disorders and the associated development colorectal liver tumors.