Alcohol-sensitized macrophages enhance colorectal carcinoma metastasis in the liver

酒精敏感性巨噬细胞增强结直肠癌肝转移

• 批准号: 10265327
• 负责人: BENITA L. MCVICKER
• 金额: --
• 依托单位: OMAHA VA MEDICAL CENTER
• 依托单位国家: 美国
• 财政年份: 2019
• 资助国家: 美国
• 起止时间: 2019-01-01 至 2022-12-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10265327
• 关键词: Affect; Alcohol abuse; Alcohol consumption; Alcoholic Liver Diseases; Alcohols; Alkaline Phosphatase; Animals; Attenuated; Carcinoembryonic Antigen; Cell Adhesion; Cell Culture Techniques; Cells; Cessation of life; Clinical; Clinical Treatment; Colorectal; Colorectal Cancer; Combined Modality Therapy; Development; Disease; Disseminated Malignant Neoplasm; Effectiveness; Endotoxins; Environment; Evaluation; Event; Future; General Population; Glycoproteins; Goals; Growth; Health; Healthcare; Hepatic; Hepatocyte; Immune system; Immunocompetent; Inflammation; Inflammatory; Inflammatory Response; Injury; Intervention; Intervention Trial; Intestines; Kupffer Cells; Large Intestine Carcinoma; Link; Liver; Liver diseases; Liver neoplasms; Malignant Neoplasms; Malignant neoplasm of liver; Mediating; Metastatic Neoplasm to the Liver; Mus; Neoplasm Metastasis; Organ; Pathway interactions; Patients; Peritoneal; Phenotype; Pre-Clinical Model; Production; Research; Risk Factors; Role; Services; Severities; Signal Transduction; Site; Stress; Supplementation; T cell therapy; Testing; Therapeutic; Tissues; Trauma; Tumor Antigens; Veterans; Work; alcohol risk; alcohol use disorder; cancer cell; cell growth; chemokine; chimeric antigen receptor; clinically relevant; clinically significant; colorectal cancer metastasis; comorbidity; cytokine; experience; experimental study; high risk; human disease; in vivo; innovation; insight; liver injury; macrophage; metastatic colorectal; military veteran; monocyte; novel; overexpression; pathogen; post-traumatic stress; pre-clinical; problem drinker; response; therapeutic target; tumor

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.

肝脏是结直肠癌（CRC）转移性疾病的终末部位，通常无需干预即可发生转移 预示着死亡。肝脏也是受饮酒影响的主要器官。有趣的是，饮酒已 已被确定为结直肠肝转移 (CRLM) 的重要危险因素，但其影响机制 保持未定义。尽管酒精相关的 CRLM 对普通人群来说是一个严重的健康问题， 退伍军人群体尤其容易受到与服役相关的创伤和损伤的影响 导致酒精使用障碍和肝脏疾病。考虑到这一点，临床上确定 酒精影响肝脏结直肠转移的机制和潜在治疗靶点。目标是 这项工作是为了确定酒精肝如何促进表达的转移性结直肠癌细胞的定植 癌胚抗原（CEA）。 CEA 肿瘤糖蛋白在转移性癌细胞中过度表达， 与 CRLM 的发展相关。人们相信 CEA 会刺激宿主微环境的细胞 产生炎症反应和促进转移性疾病的因素。具体来说，假设 酒精会使肝巨噬细胞对 CEA 的作用敏感，导致 CRC 加速生长 肝脏肿瘤。为了研究这一点，提出了三个具体目标来确定酒精的作用： CEA 信号传导中的致敏巨噬细胞（库普弗细胞、浸润性单核细胞和腹膜细胞） 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和 CRLM 的临床前模型来建立。在第二个 目的，巨噬细胞表型、激活和相关的促转移因子的产生的关键作用将是 确定对表达 CEA 的癌细胞的反应。在最后一个目标中，关键实验将定义 针对 CEA 介导的事件减轻结直肠肝转移负担的有效性。巨噬细胞 灭活和抗 CEA 治疗将单独进行测试或与肠道碱性磷酸酶联合测试 补充以抑制肠道源性内毒素的酒精相关作用。这些工作的顺利完成 研究将通过定义涉及酒精介导的目标机制来对该领域做出贡献 CEA 信号传导的恶化和 CRLM 的相关发展。此外，这项工作将提供有用的 旨在减少或消除结直肠肝转移的未来治疗策略的信息 癌症。这是一个与临床相关的主题，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和相关结直肠肝脏发育风险较高的人 肿瘤。