Alcohol-altered CEA processing: Role in liver metastases in colorectal cancer

酒精改变 CEA 加工：在结直肠癌肝转移中的作用

• 批准号: 8654098
• 负责人: Carol A. Casey
• 金额: $ 19.34万
• 依托单位: UNIVERSITY OF NEBRASKA MEDICAL CENTER
• 依托单位国家: 美国
• 财政年份: 2013
• 资助国家: 美国
• 起止时间: 2013-09-30 至 2015-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8654098
• 关键词: Accounting; Affect; Alcohol consumption; Alcoholic Liver Diseases; Alcohols; Antigen Receptors; Asialoglycoprotein Receptor; Binding; Biological Assay; Biology; Blood Circulation; Cancer Patient; Carcinoembryonic Antigen; Carcinoma; Cell Adhesion Molecules; Cell Proliferation; Cells; Cessation of life; Coculture Techniques; Colon; Colon Carcinoma; Colorectal Cancer; Data; Defect; Development; Disease; Disseminated Malignant Neoplasm; Endocytosis; Endothelial Cells; Endothelium; Environment; Enzymes; Ethanol; Event; Excision; Extravasation; Funding Opportunities; Glycoproteins; Goals; Health; Hepatic; Hepatocyte; Impairment; Inflammation; Inflammatory; Inflammatory Response; Interleukin-6; Kupffer Cells; Laboratories; Lead; Ligand Binding; Ligands; Link; Liver; Malignant Epithelial Cell; Malignant Neoplasms; Measures; Mediating; Mediator of activation protein; Membrane Glycoproteins; Metastatic Neoplasm to the Liver; Modeling; National Institute on Alcohol Abuse and Alcoholism; Neoplasm Metastasis; Organ; Pathogenesis; Phosphorylation; Play; Principal Investigator; Process; Production; Publications; RNA Interference; Radiolabeled; Rattus; Regulation; Reporting; Role; Serum; Signal Transduction; System; TNF gene; Techniques; Therapeutic; Tumor Markers; United States; United States National Institutes of Health; Up-Regulation; alcohol effect; alcohol exposure; antigen binding; antigen processing; asialo-carcinoembryonic antigen; cancer cell; cofactor; cytokine; experience; feeding; injured; liver injury; neoplastic cell; problem drinker; public health relevance; radiotracer; response; success

DESCRIPTION (provided by applicant): This application is in response to the Funding Opportunity Announcement (FOA), PA-12-234, from NIH and NIAAA entitled "Unconventional Roles of Ethanol Metabolizing Enzymes, Metabolites, and Cofactors in Health and Disease (R21)". The goal of this multiple-PI application is to examine how ethanol exposure can lead to altered processing and degradation of carcinoembryonic antigen (CEA), a glycoprotein secreted by tumor cells, and whose increase in the circulation has been linked to increased potential of colon cancer cells to form liver metastases. Colorectal cancer (CRC) accounts for 11% of all cancers in the United States, and the majority of deaths are attributed to liver metastases. There is a positive correlation between circulating CEA levels and alcohol consumption in liver metastasis in CRC patients, although the mechanism is not clear. What is known is that circulating CEA is removed primarily by the liver, where it binds to the CEA receptor (CEAR) on Kupffer cells (KCs). CEA binding results in activation of the KCs and production of several pro-inflammatory cytokines, including TNF-¿ and IL-6. Ultimately, CEA is desialylated within the KCs, released and subsequently endocytosed by the hepatocyte-specific asialoglycoprotein receptor (ASGPR). Both KCs and hepatocytes are known to be significantly impacted by alcohol, and we hypothesize that those alcohol-related effects to both KCs and hepatocytes will contribute to altered CEA processing, resulting in changes to the liver microenvironment and enhancement in the metastatic potential of CRC cells. We also predict that CEA- mediated production of KC-derived cytokines will affect adhesion molecule expression on the hepatic sinusoidal endothelium, resulting in changes in the liver microenvironment, thus supporting development of liver metastases in the alcoholic. To examine this hypothesis, we have proposed two specific aims; in Aim 1 we will focus on the direct effect of alcohol administration on CEA processing in KCs isolated from control and ethanol-fed rats, and in Aim 2 we will characterize the indirect effect of alcohol administration on CEA processing by examining the role of hepatocellular degradation. The two principal investigators involved in this application have complementary strengths which are essential for the success of the project. Dr. Casey is an expert in alcoholic-induced liver damage, and has extensive experience with the effect of alcohol on liver cells in a rat model. Dr. Thomas is an expert in CEA and CEA receptor biology, who has over 40 years of experience and extensive publications in this field. Together, we will utilize a variety of state-of-the art techniques to evaluate the unique processing of CEA, including co-culture systems of liver parenchymal and non-parenchymal cells, RNA interference approaches and radiolabeled ligand binding assays. We anticipate that the successful completion of this project will provide key information that could lead to therapeutic strategies aimed at reducing or eliminating liver metastases and increase our understanding of how alcoholic liver injury exacerbates the effects of CEA.

描述（由申请人提供）：本申请是对NIH和NIAAA题为“乙醇代谢酶、代谢物和辅因子在健康和疾病中的非常规作用（R21）"的资助机会公告（FOA）PA-12-234的回应。这种多PI应用的目的是研究乙醇暴露如何导致癌胚抗原（CEA）的加工和降解改变，CEA是一种由肿瘤细胞分泌的糖蛋白，其在循环中的增加与结肠癌细胞形成肝转移的可能性增加有关。结直肠癌（CRC）占美国所有癌症的11%，大多数死亡归因于肝转移。循环CEA水平与结直肠癌肝转移患者的饮酒量呈正相关，但其机制尚不清楚。已知的是，循环CEA主要通过肝脏去除，在肝脏中它与枯否细胞（KCs）上的CEA受体（CEAR）结合。CEA结合导致KCs的活化和几种促炎细胞因子的产生，包括TNF-α和IL-6。最终，CEA在KC内被去唾液酸化，释放并随后被肝细胞特异性脱唾液酸糖蛋白受体（ASGPR）内吞。已知KC和肝细胞都受到酒精的显著影响，我们假设对KC和肝细胞的这些酒精相关作用将有助于改变CEA加工，导致肝脏微环境的变化和CRC细胞转移潜力的增强。我们还预测，CEA介导的KC衍生细胞因子的产生将影响肝窦内皮细胞上的粘附分子表达，导致肝脏微环境的变化，从而支持酒精性肝转移的发展。为了检验这一假设，我们提出了两个具体的目标;在目标1中，我们将集中在从控制和乙醇喂养的大鼠中分离的KC中，酒精给药对CEA加工的直接影响，在目标2中，我们将通过检查肝细胞降解的作用来表征酒精给药对CEA加工的间接影响。参与这项申请的两名主要研究人员具有互补的优势，这对项目的成功至关重要。凯西博士是酒精性肝损伤方面的专家，在酒精对大鼠模型肝细胞的影响方面拥有丰富的经验。托马斯博士是CEA和CEA受体生物学方面的专家，在该领域拥有40多年的经验和广泛的出版物。总之，我们将利用各种最先进的技术来评估CEA的独特处理，包括肝实质和非实质细胞的共培养系统，RNA干扰方法和放射性标记的配体结合测定。我们预计，该项目的成功完成将提供关键信息，可能导致旨在减少或消除肝转移的治疗策略，并增加我们对酒精性肝损伤如何加剧CEA影响的理解。