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Matter, M.S.* ; Marquardt, J.U.* ; Andersen, J.B.* ; Quintavalle, C.* ; Korokhov, N.* ; Stauffer, J.K.* ; Kaji, K.* ; Decaens, T.* ; Quagliata, L.* ; Elloumi, F.* ; Hoang, T.* ; Molinolo, A.* ; Conner, E.A.* ; Weber, A.* ; Heikenwälder, M. ; Factor, V.M.* ; Thorgeirsson, S.S.*

Oncogenic driver genes and the inflammatory microenvironment dictate liver tumor phenotype.

Hepatology 63, 1888-1899 (2016)
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The majority of hepatocellular carcinoma (HCC) develops in the background of chronic liver inflammation caused by viral hepatitis and alcoholic or non-alcoholic steatohepatitis. However, the impact of different types of chronic inflammatory microenvironments on the phenotypes of tumors generated by distinct oncogenes is largely unresolved. To address this issue, we generated murine liver tumors by constitutively active AKT-1 (AKT) and β-catenin (CAT) followed by induction of chronic liver inflammation by 3,5-diethoxycarbonyl-1,4-dihydrocollidine (DDC) and carbon tetrachloride (CCl4 ). Also, the impact of DDC-induced chronic liver inflammation was compared between two liver tumor models using a combination of AKT-CAT or AKT-NRAS(G12V) . Treatment with DDC and CCl4 significantly facilitated the adenoma-to-carcinoma conversion and accelerated the growth of AKT-CAT tumors. Furthermore, DDC treatment altered the morphology of AKT-CAT tumors and caused loss of lipid droplets. Transcriptome analysis of AKT-CAT tumors revealed that cellular growth and proliferation was mainly affected by chronic inflammation and caused upregulated of Cxcl16, Galectin-3 and Nedd9 among others. Integration with transcriptome profiles from human HCCs further demonstrated that AKT-CAT tumors generated in the context of chronic liver inflammation showed enrichment of poor prognosis gene sets or decrease of good prognosis gene sets. In contrast, DDC had a more subtle effect on AKT-NRAS(G12V) tumors and primarily enhanced already existent tumor characteristics as supported by transcriptome analysis. However, it also reduced lipid droplets in AKT-NRAS(G12V) tumors. CONCLUSION: Our study suggests that liver tumor phenotype is defined by a combination of driving oncogenes but also the nature of chronic liver inflammation.
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Publication type Article: Journal article
Document type Scientific Article
Keywords Chronic Inflammation ; Cirrhosis ; Hepatocellular Carcinoma ; Tumor Immunology ; Tumor Microenvironment; Hepatocellular-carcinoma; Expression; Cancer; Prognosis; Mice; Carcinogenesis; Metastasis; Recurrence; Activation; Mechanisms
ISSN (print) / ISBN 0270-9139
e-ISSN 1527-3350
Journal Hepatology
Quellenangaben Volume: 63, Issue: 6, Pages: 1888-1899 Article Number: , Supplement: ,
Publisher Wiley
Publishing Place Hoboken, NJ
Reviewing status Peer reviewed