Mechanism of Alcohol/Alcoholism-induced Liver Neoplasia

酒精/酒精诱发肝肿瘤的机制

• 批准号: 7753908
• 负责人: Christian Maximillian Schmidt
• 金额: $ 22.87万
• 依托单位: INDIANA UNIV-PURDUE UNIV AT INDIANAPOLIS
• 依托单位国家: 美国
• 财政年份: 2009
• 资助国家: 美国
• 起止时间: 2009-01-01 至 2011-12-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7753908
• 关键词: Adult; Alcohol consumption; Alcoholism; Alcohols; Animal Model; Animals; Apoptosis; Blood alcohol level measurement; Breeding; Bromodeoxyuridine; CYP2E1 gene; Cancer Etiology; Cause of Death; Development; Eating; Enzymes; Etiology; Food; Grant; Hepatic; Histology; Incidence; Lesion; Liver; MAPK Signaling Pathway Pathway; MEKs; Malignant Neoplasms; Malignant neoplasm of liver; Measures; Metabolic; Modeling; Neoplasms; Nodule; Nutritional; Organ; PECAM1 gene; Pathologic; Placebo Control; Primary carcinoma of the liver cells; Rattus; Relative (related person); Research; Risk Factors; Role; S-Phase Fraction; Serum; Signal Transduction; Solid; Solutions; Testing; Time; Ultrasonography; United States National Institutes of Health; Water; Wistar Rats; alcohol availability; alcohol exposure; alcohol measurement; aldehyde dehydrogenases; angiogenesis; inhibitor/antagonist; male; neoplastic; preference; public health relevance; tool; tumor; tumorigenesis; uptake

DESCRIPTION (provided by applicant): Hepatocellular carcinoma (HCC) is a common cause of death among solid organ malignancies. Alcohol is an etiologic factor for HCC. No animal model to date has demonstrated that alcohol/alcoholism induces HCC in the absence of other HCC risk factors. Preliminary studies were conducted to determine whether rats which voluntarily consume large quantities of alcohol for prolonged periods can serve as an animal model of HCC. Adult male rats selectively bred for alcohol preference (P rats) were given free access to food and water ("non- drinkers"), or food, water and a 10% (v/v) alcohol solution ("drinkers") for 18 months. Average alcohol intake was 6.7 g/kg BW/day in P rat drinkers. At the end of 18 months, gross examination of livers of P drinkers revealed 100% tumor incidence, and liver histology showed multiple dysplastic foci, adenomatous high grade dysplastic nodules, and HCC. In contrast, no grossly detectable neoplastic lesions were found in P non- drinkers. To establish that the association between alcohol preference and hepatic tumorigenesis is not fortuitous, the proposed grant studies will characterize hepatic tumorigenesis in two separate lines of rats selectively bred for alcohol preference (P: Wistar background; HAD: NIH background). Extent and timing of hepatic tumorigenesis will be determined by ultrasound, pathologic and histopathologic (H&E, GSTp+) examination. Indices of proliferation (BrDU uptake), apoptosis (TUNNEL/ApopTag), and angiogenesis (CD31) will also be determined. To evaluate whether mechanisms of alcohol/alcoholism-induced liver neoplasia involve altered metabolic liver enzyme expression in these animals, basal levels of hepatic alcohol metabolizing enzymes (CYP2E1, ADH and ALDH) in P vs Wistar control and HAD vs NIH control rats will be determined; alcohol-induced levels of these enzymes will also be measured in P and HAD rats and correlated with tumorigenesis, blood alcohol level, serum nutritional parameters, alcohol intake and food intake over the timecourse of the study. Previously, we have demonstrated a role for MEK-ERK signaling in liver tumorigenesis in multiple models, but this has not been explored in alcohol/alcoholism-induced HCC. To evaluate whether mechanisms of alcohol/alcoholism-induced liver neoplasia depend upon altered ERK/MAPK pathway signaling, basal levels of total and phosphorylated ERK in P vs Wistar control and HAD vs. NIH control rats will be determined; alcohol-induced levels in P and HAD rats will also be measured and correlated with tumorigenesis, blood alcohol level, serum nutritional parameters, alcohol intake and food intake over the time course of the study. Finally, the role of ERK/MAPK pathway signaling will be further tested by treating P rats with an orally active MEK inhibitor vs placebo control to determine the effect on alcohol-induced liver neoplasia. This animal model of alcohol/alcoholism-induced HCC may prove to be an invaluable tool for studying the mechanisms which support this specific etiology of HCC and further our understanding of the general pathogenic mechanisms of alcohol-induced cancers. Public Health relevance: The proposed research will involve characterizing two distinct animal models to show that prolonged alcohol intake leads to the development of liver cancer in the absence of other risk factors. Possible mechanisms involved will also be investigated. Such an animal model will be an invaluable tool for studying the mechanism by which alcohol exposure causes liver cancer and also further our understanding of the mechanisms by which alcohol causes cancer in general.

描述（申请人提供）：肝细胞癌（HCC）是实体器官恶性肿瘤中常见的死亡原因。酒精是HCC的一个病因。迄今为止，没有动物模型证明在没有其他HCC危险因素的情况下，酒精/酒精中毒诱导HCC。进行了初步研究，以确定长期自愿大量饮酒的大鼠是否可以作为HCC的动物模型。在18个月的时间里，被选择性饲养的酒精偏好成年雄性大鼠（P大鼠）可以自由地获得食物和水（“不饮酒者”），或者食物、水和10% （v/v）酒精溶液（“饮酒者”）。P大鼠饮酒者平均酒精摄入量为6.7 g/kg BW/天。18个月后，P饮用者肝脏大体检查肿瘤发生率为100%，肝脏组织学表现为多发发育不良灶、腺瘤性高级别发育不良结节、HCC。相反，不喝P的人没有发现明显的肿瘤病变。为了证实酒精偏好与肝脏肿瘤发生之间的联系并非偶然，拟议的拨款研究将在两个独立的大鼠系中对酒精偏好进行选择性繁殖（P: Wistar背景；HAD: NIH背景）。肝肿瘤发生的范围和时间将通过超声、病理和组织病理学（H&E、GSTp+）检查确定。增殖（BrDU摄取）、凋亡（TUNNEL/ApopTag）和血管生成（CD31）指标也将被确定。为了评估这些动物中酒精/酒精诱导的肝脏肿瘤的机制是否涉及代谢性肝酶表达的改变，将测定P与Wistar对照和HAD与NIH对照大鼠肝脏酒精代谢酶（CYP2E1、ADH和ALDH）的基础水平；这些酶的酒精诱导水平也将在P和HAD大鼠中进行测量，并与研究过程中的肿瘤发生、血液酒精水平、血清营养参数、酒精摄入量和食物摄入量相关。先前，我们已经在多种模型中证明了MEK-ERK信号在肝脏肿瘤发生中的作用，但尚未在酒精/酒精中毒诱导的HCC中进行探讨。为了评估酒精/酒精中毒诱导的肝脏肿瘤的机制是否依赖于ERK/MAPK通路信号的改变，将确定P与Wistar对照和HAD与NIH对照大鼠的总ERK和磷酸化ERK的基础水平；在研究过程中，还将测量P和HAD大鼠的酒精诱导水平，并将其与肿瘤发生、血液酒精水平、血清营养参数、酒精摄入量和食物摄入量联系起来。最后，通过口服活性MEK抑制剂与安慰剂对照治疗P大鼠，进一步测试ERK/MAPK通路信号的作用，以确定对酒精诱导的肝肿瘤的影响。这种酒精/酒精性肝癌的动物模型可能被证明是一种宝贵的工具，用于研究支持这一特定HCC病因的机制，并进一步了解酒精性癌症的一般致病机制。