Gores, Gregory J.

Extracellular vesicles (EVs) are nanometer‐sized, membrane‐bound vesicles released by cells into the extracellular milieu. EVs are now recognized to play a critical role in cell‐to‐cell communication. EVs contain important cargo in the form of proteins, lipids, and nucleic acids and serve as vectors for delivering this cargo from donor to acceptor or target cell. EVs are released under both physiologic and pathologic conditions, including liver diseases, and exert a wide range of effects on target cells. This review provides an overview on EV biogenesis, secretion, cargo, and target cell interactions in the context of select liver diseases. Specifically, the diverse roles of EVs in nonalcoholic steatohepatitis, alcoholic liver disease, viral hepatitis, cholangiopathies, and hepatobiliary malignancies are emphasized. Liver diseases often result in an increased release of EVs and/or in different cargo sorting into these EVs. Either of these alterations can drive disease pathogenesis. Given this fact, EVs represent a potential target for therapeutic intervention in liver disorders. Because altered EV composition may reflect the underlying disease condition, circulating EVs can be exploited for diagnostic and prognostic purposes as a liquid biopsy. Furthermore, ex vivo modified or synthesized EVs can be engineered as therapeutic nano‐shuttles. Finally, we highlight areas that merit further investigation relevant to understanding how EVs regulate liver disease pathogenesis. (H epatology 2016;64:2219‐2233).

BACKGROUNDThere is global variation in the onset of hepatocellular carcinoma (HCC). The objective of the current study was to investigate the impact of country of birth on age at the time of HCC diagnosis in the United States.METHODSIncident HCC cases diagnosed between 2000 and 2012 in the Surveillance, Epidemiology, and End Results program 18 registry were included. Factors associated with very early onset (age at diagnosis < 40 years) and early onset (age at diagnosis < 50 years) were identified by logistic regression.RESULTSA total of 59,907 patients were included. The median age at the time of diagnosis of HCC was 62 years and 76% of the patients were male. Of the 75% of patients for whom information regarding birth country was available, 29% were foreign born. In multivariate logistic regression, birth in West Africa (adjusted odds ratio [AOR], 16.3; 95% confidence interval [95% CI], 9.2‐27.9 [P<.01]), Central/South/other Africa (AOR, 11.0; 95% CI, 4.5‐23.7 [P<.01]), Oceania (AOR, 4.9; 95% CI, 2.9‐8.0 [P<.01]), and East Africa (AOR, 3.5; 95% CI, 1.5‐6.8 [P<.01]) was found to have the strongest association with very early‐onset HCC after adjusting for sex and race/ethnicity. Birth in West Africa, Central/South/other Africa, Oceania, or East Africa also was found to be strongly associated with early‐onset HCC.CONCLUSIONSBirth country was found to be independently associated with age at the time of HCC diagnosis in the United States. Birth in Africa (except for North Africa) and Oceania was strongly associated with very early‐onset HCC. These findings have implications for the design of comprehensive HCC surveillance programs in the United States. Cancer 2016. © 2016 American Cancer Society. Cancer 2017;81–89. © 2016 American Cancer Society.

c‐Myc induction drives cholestatic liver injury and cholangiocarcinoma (CCA) in mice, and induction of Maf proteins (MafG and c‐Maf) contributes to cholestatic liver injury, whereas S‐adenosylmethionine (SAMe) administration is protective. Here, we determined whether there is interplay between c‐Myc, Maf proteins, and methionine adenosyltransferase α1 (MATα1), which is responsible for SAMe biosynthesis in the liver. We used bile duct ligation (BDL) and lithocholic acid (LCA) treatment in mice as chronic cholestasis models, a murine CCA model, human CCA cell lines KMCH and Huh‐28, human liver cancer HepG2, and human CCA specimens to study gene and protein expression, protein‐protein interactions, molecular mechanisms, and functional outcomes. We found that c‐Myc, MATα1 (encoded by MAT1A), MafG, and c‐Maf interact with one another directly. MAT1A expression fell in hepatocytes and bile duct epithelial cells during chronic cholestasis and in murine and human CCA. The opposite occurred with c‐Myc, MafG, and c‐Maf expression. MATα1 interacts mainly with Mnt in normal liver, but this switches to c‐Maf, MafG, and c‐Myc in cholestatic livers and CCA. Promoter regions of these genes have E‐boxes that are bound by MATα1 and Mnt in normal liver and benign bile duct epithelial cells that switched to c‐Myc, c‐Maf, and MafG in cholestasis and CCA cells. E‐box positively regulates c‐Myc, MafG, and c‐Maf, but it negatively regulates MAT1A. MATα1 represses, whereas c‐Myc, MafG, and c‐Maf enhance, E‐box‐driven promoter activity. Knocking down MAT1A or overexpressing MafG or c‐Maf enhanced CCA growth and invasion in vivo. Conclusion: There is a novel interplay between MATα1, c‐Myc, and Maf proteins, and their deregulation during chronic cholestasis may facilitate CCA oncogenesis. (Hepatology 2016;64:439‐455)

Hepatocellular carcinoma (HCC) and intrahepatic cholangiocarcinoma (ICC) are the most prevalent types of primary liver cancer. These malignancies have limited treatment options, resulting in poor patient outcomes. Metabolism reprogramming, including increased de novo lipogenesis, is one of the hallmarks of cancer. Fatty acid synthase (FASN) catalyzes the de novo synthesis of long‐chain fatty acids from acetyl‐coenzyme A and malonyl‐coenzyme A. Increased FASN expression has been reported in multiple tumor types, and inhibition of FASN expression has been shown to have tumor‐suppressing activity. Intriguingly, we found that while FASN is up‐regulated in human HCC samples, its expression is frequently low in human ICC specimens. Similar results were observed in mouse ICC models induced by different oncogenes. Ablating FASN in the mouse liver did not affect activated AKT and Notch (AKT/Notch intracellular domain 1) induced ICC formation in vivo. Furthermore, while both HCC and ICC lesions develop in mice following hydrodynamic injection of AKT and neuroblastoma Ras viral oncogene homolog oncogenes (AKT/Ras), deletion of FASN in AKT/Ras mice triggered the development almost exclusively of ICCs. In the absence of FASN, ICC cells might receive lipids for membrane synthesis through exogenous fatty acid uptake. In accordance with the latter hypothesis, ICC cells displayed high expression of fatty acid uptake‐related proteins and robust long‐chain fatty acid uptake. Conclusion: Our data demonstrate that FASN dependence is not a universal feature of liver tumors: while HCC development is highly dependent of FASN and its mediated lipogenesis, ICC tumorigenesis can be insensitive to FASN deprivation; our study supports novel therapeutic approaches to treat this pernicious tumor type with the inhibition of exogenous fatty acid uptake. (Hepatology 2016;63:1900‐1913)