{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,5]],"date-time":"2026-10-05T11:39:08Z","timestamp":1791200348628,"version":"4.2.0"},"reference-count":29,"publisher":"Ovid Technologies (Wolters Kluwer Health)","issue":"6","license":[{"start":{"date-parts":[[2015,9,1]],"date-time":"2015-09-01T00:00:00Z","timestamp":1441065600000},"content-version":"tdm","delay-in-days":0,"URL":"http:\/\/doi.wiley.com\/10.1002\/tdm_license_1.1"}],"content-domain":{"domain":["lww.com","ovid.com"],"crossmark-restriction":true},"short-container-title":["Hepatology"],"published-print":{"date-parts":[[2016,6]]},"abstract":"<jats:p>The majority of hepatocellular carcinoma develops in the background of chronic liver inflammation caused by viral hepatitis and alcoholic or nonalcoholic 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\u20101 (AKT) and \u03b2\u2010catenin (CAT), followed by induction of chronic liver inflammation by 3,5\u2010diethoxycarbonyl\u20101,4\u2010dihydrocollidine (DDC) and carbon tetrachloride. Also, the impact of DDC\u2010induced chronic liver inflammation was compared between two liver tumor models using a combination of AKT\u2010CAT or AKT\u2010NRAS<jats:sup>G12V<\/jats:sup>. Treatment with DDC and carbon tetrachloride significantly facilitated the adenoma\u2010to\u2010carcinoma conversion and accelerated the growth of AKT\u2010CAT tumors. Furthermore, DDC treatment altered the morphology of AKT\u2010CAT tumors and caused loss of lipid droplets. Transcriptome analysis of AKT\u2010CAT tumors revealed that cellular growth and proliferation were mainly affected by chronic inflammation and caused up\u2010regulation of Cxcl16, Galectin\u20103, and Nedd9, among others. Integration with transcriptome profiles from human hepatocellular carcinomas further demonstrated that AKT\u2010CAT 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\u2010NRAS<jats:sup>G12V<\/jats:sup> tumors and primarily enhanced already existent tumor characteristics as supported by transcriptome analysis. However, it also reduced lipid droplets in AKT\u2010NRAS<jats:sup>G12V<\/jats:sup> tumors. <jats:italic toggle=\"yes\">Conclusion<\/jats:italic>: Our study suggests that liver tumor phenotype is defined by a combination of driving oncogenes but also the nature of chronic liver inflammation. (H<jats:sc>epatology<\/jats:sc> 2016;63:1888\u20101899)<\/jats:p>","DOI":"10.1002\/hep.28487","type":"journal-article","created":{"date-parts":[[2016,2,4]],"date-time":"2016-02-04T23:26:25Z","timestamp":1454628385000},"page":"1888-1899","update-policy":"https:\/\/doi.org\/10.1097\/lww.0000000000001000","source":"Crossref","is-referenced-by-count":53,"title":["Oncogenic driver genes and the inflammatory microenvironment dictate liver tumor phenotype"],"prefix":"10.1097","volume":"63","author":[{"given":"Matthias S.","family":"Matter","sequence":"first","affiliation":[{"name":"Laboratory of Experimental Carcinogenesis, Center for Cancer Research, National Cancer Institute, National Institutes of Health,Bethesda,MD"},{"name":"Institute of Pathology, University Hospital of Basel,Basel,Switzerland"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jens U.","family":"Marquardt","sequence":"additional","affiliation":[{"name":"Laboratory of Experimental Carcinogenesis, Center for 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