title: Oncogenic driver genes and the inflammatory microenvironment dictate liver tumor phenotype.
abstract: 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-1 (AKT) and β-catenin (CAT), followed by induction of chronic liver inflammation by 3,5-diethoxycarbonyl-1,4-dihydrocollidine (DDC) and carbon tetrachloride. 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 carbon tetrachloride 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 were mainly affected by chronic inflammation and caused up-regulation of Cxcl16, Galectin-3, and Nedd9, among others. Integration with transcriptome profiles from human hepatocellular carcinomas 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.
  
  
  
  Our study suggests that liver tumor phenotype is defined by a combination of driving oncogenes but also the nature of chronic liver inflammation. (Hepatology 2016;63:1888-1899).
authors: Laboratory of Experimental Carcinogenesis, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, MD.|Institute of Pathology, University Hospital of Basel, Basel, Switzerland.
authors: Matthias S
authors: MS
authors: Matter
authors: Laboratory of Experimental Carcinogenesis, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, MD.|Department of Medicine I, Johannes Gutenberg University, Mainz, Germany.
authors: Jens U
authors: JU
authors: Marquardt
authors: Laboratory of Experimental Carcinogenesis, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, MD.|Biotech Research and Innovation Centre, University of Copenhagen, Copenhagen, Denmark.
authors: Jesper B
authors: JB
authors: Andersen
authors: Institute of Pathology, University Hospital of Basel, Basel, Switzerland.
authors: Cristina
authors: C
authors: Quintavalle
authors: Laboratory of Experimental Carcinogenesis, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, MD.
authors: Nikolay
authors: N
authors: Korokhov
authors: Cancer and Inflammation Program, National Cancer Institute-Frederick, Frederick, MD.
authors: Jim K
authors: JK
authors: Stauffer
authors: Laboratory of Experimental Carcinogenesis, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, MD.
authors: Kosuke
authors: K
authors: Kaji
authors: Laboratory of Experimental Carcinogenesis, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, MD.
authors: Thomas
authors: T
authors: Decaens
authors: Institute of Pathology, University Hospital of Basel, Basel, Switzerland.
authors: Luca
authors: L
authors: Quagliata
authors: National Cancer Institute, CCR at Leidos Inc., National Institutes of Health, Bethesda, MD.
authors: Fathi
authors: F
authors: Elloumi
authors: Institute of Pathology, University Hospital of Basel, Basel, Switzerland.
authors: Tanya
authors: T
authors: Hoang
authors: Oral and Pharyngeal Cancer Branch, National Institute of Dental and Craniofacial Research, National Institutes of Health, Bethesda, MD.
authors: Alfredo
authors: A
authors: Molinolo
authors: Laboratory of Experimental Carcinogenesis, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, MD.
authors: Elizabeth A
authors: EA
authors: Conner
authors: Institute of Surgical Pathology, University Hospital Zurich, Zurich, Switzerland.
authors: Achim
authors: A
authors: Weber
authors: Institute of Virology, Technische Universität München/Helmholtz Zentrum München, Munich, Germany.|Division of Chronic Inflammation and Cancer, German Cancer Research Center, Heidelberg, Germany.
authors: Mathias
authors: M
authors: Heikenwalder
authors: Laboratory of Experimental Carcinogenesis, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, MD.
authors: Valentina M
authors: VM
authors: Factor
authors: Laboratory of Experimental Carcinogenesis, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, MD.
authors: Snorri S
authors: SS
authors: Thorgeirsson
mesh_terms: D048868:Adaptor Proteins, Signal Transducing / Q000378:metabolism; D000818:Animals; D002251:Carbon Tetrachloride; D002460:Cell Line; D000075743:Chemokine CXCL16; D054427:Chemokine CXCL6 / Q000378:metabolism; D005260:Female; D037502:Galectin 3 / Q000378:metabolism; D006520:Hepatitis, Animal / Q000139:chemically induced / Q000150:complications*; D008114:Liver Neoplasms, Experimental / Q000209:etiology* / Q000378:metabolism; D051379:Mice; D009857:Oncogenes; D010641:Phenotype; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism*; D011725:Pyridines; D059467:Transcriptome; D059016:Tumor Microenvironment; D051176:beta Catenin / Q000378:metabolism*
chemical_list: C530773:3,5-diethoxycarbonyl-1,4-dihydrocollidine; D048868:Adaptor Proteins, Signal Transducing; D000075743:Chemokine CXCL16; D054427:Chemokine CXCL6; C498926:Cxcl16 protein, mouse; D037502:Galectin 3; C505592:NEDD9 protein, mouse; D011725:Pyridines; D051176:beta Catenin; D002251:Carbon Tetrachloride; C514862:Akt1 protein, mouse; D051057:Proto-Oncogene Proteins c-akt