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.
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.
| Yip-Schneider, Michele T; Doyle, Courtney J; McKillop, Iain H et al. (2011) Alcohol induces liver neoplasia in a novel alcohol-preferring rat model. Alcohol Clin Exp Res 35:2216-25 |
| Hennig, Matthew; Yip-Schneider, Michele T; Wentz, Sabrina et al. (2010) Targeting mitogen-activated protein kinase kinase with the inhibitor PD0325901 decreases hepatocellular carcinoma growth in vitro and in mouse model systems. Hepatology 51:1218-25 |
| Hennig, Matthew; Yip-Schneider, Michele T; Klein, Patrick et al. (2009) Ethanol-TGFalpha-MEK signaling promotes growth of human hepatocellular carcinoma. J Surg Res 154:187-95 |
