S03 * ALCOHOL, CANCER, HEPATITIS AND FATTY LIVER: INTERACTIONS AND CO-MORBIDITIES

Autor: P. Thomas, L. Gobejishvili, D. Sindram, Benita L. McVicker, Kyle J. Thompson, K. Lazure, Dean J. Tuma, M. Neuman, I. McKillop, S. Barve, Carol A. Casey
Rok vydání: 2013
Předmět:
Zdroj: Alcohol and Alcoholism. 48:i4-i5
ISSN: 1464-3502
0735-0414
DOI: 10.1093/alcalc/agt076
Popis: S03.1 ROLE FOR ALTERED CEA PROCESSING BY LIVER CELLS IN ENHANCED COLORECTAL CANCER (CRC) LIVER METASTASIS IN THE ALCOHOLIC {#article-title-2} Background/Aims. Colorectal cancer (CRC) is the third most common cancer and accounts for nearly 51,000 deaths per year, the majority of which are associated with liver metastasis. Carcinoembryonic antigen (CEA), a cell surface glycoprotein that is produced and secreted by colorectal tumors, has been shown to predict the ability of CRC to metastasize. Of interest to our laboratory is that the consumption of alcohol has been shown to increase the risk of metastatic CRC. We hypothesize that ALD may actually contribute to the creation of a microenvironment that is conducive to CRC metastases. Since Kupffer cells (KCs) the resident liver macrophages, are known release proinflammatory cytokines in both ALD (Casey and McVicker laboratories) and when stimulated with CEA (Thomas laboratory), we are examining whether CEA contributes to the development of the hepatic inflammatory response in the setting of ALD. Methods. Male, Wistar rats were fed for 5-7 weeks with an ethanol-containing liquid diet (Lieber-DeCarli). We purified KCs from livers of these animals, and incubated the cells with 5 ug/ml CEA for 5 hours. After the 5 hour incubation period, media was analyzed for the presence of TNF-α and IL-6. Results/Conclusions. In the presence of CEA, KCs from both control and ethanol-fed rats showed significant increases in production of both TNF-α and IL-6. In addition, cytokine production from KCs from alcohol-fed animals was increased two-fold when compared to controls. We are extending these findings by measuring other cytokines known to be produced in the setting of CRC and CEA activation. # S03.2 ALCOHOL INDUCED ALTERATIONS IN HEPATIC HDACS: A POTENTIAL LINK TO HCC {#article-title-3} Alcohol consumption is a significant risk factor for the development of hepatocellular carcinoma (HCC). Alcoholic liver disease (ALD) consists of the spectrum of pathological changes including fatty liver, alcoholic hepatitis and alcoholic cirrhosis, which can progress to hepatocellular carcinoma (HCC). It is becoming increasingly clear that besides genomic changes, epigenetic alterations play a significant role in the development of HCC. Histone deacetylation constitutes a major epigenetic alteration responsible for chromatin remodeling involving chromatin condensation and transcriptional down-regulation in the affected genomic regions. Histone acetylation and deacetylation are highly active processes and are controlled by the opposing action of histone acetyltransferases (HATs) and histone deacetylases (HDACs); notably, altered expression and mutations of genes that encode HDACs have been linked to tumor development. Among the 18 HDAC isoforms divided in IV classes, class I HDACs are significantly involved in the development of cancer. Specifically, class I HDACs 1 - 3 are expressed at significantly higher levels in HCC than in normal liver. Our recent findings show that alcohol can significantly de-regulate the expression of hepatic Class I and II HDACs, thereby impacting both global and gene specific histone acetylation status with consequent alterations in gene expression. Moreover, Class I HDAC-3, which plays a significant role in regulating tumor cell proliferation and invasion in HCC, was solely and markedly increased in response to binge ethanol exposure. These data will be presented in the context of alcohol induced hepatic steatosis, injury and carcinogenesis. # S03.3 EFFECT OF ALCOHOL ON TUMOR PROGRESSION IN DIFFERENT MOUSE MODELS OF HEPATOCELLULAR CARCINOMA {#article-title-4} Chronic, heavy alcohol consumption and obesity are risk factors for HCC. Numerous rodent models of HCC exist as do methods of alcohol-feeding and obesity. This study sought to compare the effects of alcohol and/or obesity on HCC progression in mouse models of HCC, and to study miRNA profiles as markers of tumorigenesis. B6C3 mice readily (7/8) developed tumors 44-wks after DEN injection (1mg/Kg; 21d) and alcohol feeding in drinking water (10/20% alt.days, 8-wks) significantly increased tumor incidence and size. In contrast only 3/10 C57Bl/6 mice developed visible lesions following DEN initiation, despite DEN being administered at 5mg/Kg. Alcohol-feeding failed to significantly alter number or size of foci in the C57Bl/6 model. However, diet induced obesity (DIO) significantly increased incidence (8/9) and size of foci versus DEN-alone or DEN + alcohol. miRNA analysis demonstrated 34- and 17-dysregulated miRNAs, when comparing DIO-H2O-DEN and DIO-EtOH-DEN tumor to non-tumor liver respectively. Of these miRNAs, 7-were dysregulated in both groups. Finally, chronic alcohol intake significantly inhibited foci-tumor progression in a C57Bl/6 mouse model in which Hepa1-6 HCC cells were injected into the liver via a mesenteric vein. Our data highlight significant differences in the effect of alcohol on HCC progression based on both model and strain. Furthermore, these data suggest that in C57Bl/6, obesity is a more powerful promoter of HCC progression than alcohol. The (relatively) low number of miRNAs commonly dysregulated in these models also suggests miRNAs may be important links between models, and potential markers/targets in those patients at risk for HCC development. # S03.4 FAMILIAL NON-ALCOHOLIC STEATOHEPATITIS LEADING TO HEPATOCELLULAR CARCINOMA {#article-title-5} Introduction. Non-alcoholic steatohepatitis (NASH) has been associated with fibrosis that may progress to cirrhosis. The purpose of this study was to examine hepatocytes and Kupffer Cells (persinusoidal macrophages) in liver biopsies of 3 families (5 males and 4 females) with non-cirrhotic and cirrhotic NASH to determine unique histological changes during a period of 2–7 years from diagnosis. Aims&Methods. In this study, hepatocytes, stellate cells and Kupffer Cells were analyzed using light and electron microscopy, and immunohistochemistry with specific anti-macrophage antibody staining of liver biopsies. Evaluation for HBV, HCV, autoimmune hepatitis, PBC, PSC, alpha-1 anti-trypsin disease, Wilson's disease, and hemochromatosis were negative. Abdo ultrasound demonstrated diffuse, extensive steatosis in all the patients and nodules consistent with hepatocellular carcinoma (HCC) in two patients. Results. BMI for all patients was over 30, and alcohol consumption was not significant. In all liver biopsies diffuse, macrovesicular steatosis involved 40 to 70% of samples. The lobular hepatocytes showed prominent ballooning degeneration. Mallory Denkhyaline bodies (MDBs) in four patients along with foci of lobular inflammation. The MDBs were observed by electron microscopy and stained by cytokeratin 18. The trichrome stain revealed bridging fibrosis. In family #1, there was a three-fold increase in Kupffer Cells in the eldest sibling with NASH compared to livers of the younger siblings. In addition, lipid droplets were more numerous and larger in the hepatocytes and the collagen deposits were 5 times larger compared to the siblings. In family #2, the older brother had cirrhosis; minimal inflammation and mild fatty infiltration while the younger had fatty infiltration with no inflammation or fibrosis. In family #3, large lipid droplets and collagen deposition were observed in the siblings, one of whom had HCC. Over 2-4 year follow up, all patients had progressive severity of NASH one of whom developed HCC. Conclusion. The special finding in livers of patients with NASH was accumulation of groups of Kupffer Cells, which was not associated with focal necrosis. It is postulated that collections of these perisinusoidal macrophages in NASH are a unique response to chronic portal endotoxemia or bacteremia. The persistent activation of these macrophages could lead to the chronic release of cytokines and contribute to chronic inflammation, fibrosis and cirrhosis leading to HCC.
Databáze: OpenAIRE
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