Adverse genomic alterations and stemness features are induced by field cancerization in the microenvironment of hepatocellular carcinomas

摘要: // Darko Castven 1,* , Michael Fischer Diana Becker 1 Stefan Heinrich 2 Jesper B. Andersen 3 Dennis Strand Martin F. Sprinzl Susanne Carolin Czauderna Stefanie Heilmann-Heimbach 4 Stephanie Roessler 5 Arndt Weinmann Marcus A. Worns Snorri S. Thorgeirsson 6 Peter R. Galle Matthias Matter 7 Hauke Lang and Jens U. Marquardt Department of Medicine, Johannes Gutenberg University, Mainz, Germany Surgery, Health Medical Science, Biotech Research Innovation Centre, University Copenhagen, Denmark Genomics, Institute Human Genetics, Life & Brain Center, Bonn, Pathology, Hospital Heidelberg, Laboratory Experimental Carcinogenesis, Center for Cancer Research, National Institute, NIH, Bethesda, MD, USA Basel, Switzerland * These authors have contributed equally to this work Correspondence to: Marquardt, email: Keywords : liver cancer, microenvironment, hepatocarcinogenesis, stemness features, field effect Received February 22, 2017 Accepted March 03, Published 15, Abstract Hepatocellular Carcinoma (HCC) commonly develops in chronically damaged tissues. The resulting regenerative inflammatory processes create an adverse milieu that promotes tumor-initiation progression. A better understanding the hepatic tumor-microenvironment interaction might infer profound therapeutic implications. Integrative whole genome transcriptome analyses different tumor regions, invasive border tumor-surrounding (SL) were performed identify associated molecular alterations integrated with our existing HCC database. Expression levels localization established CSC markers assessed pre-neoplastic lesions confirmed two independent patient cohorts using qRT-PCR, immunohistochemistry immunofluorescence. Our results indicate genomic transcriptomic profiles between SL regions are quite distinct. Progressive increase genetic activation pathways related proliferation as well apoptosis observed tissue, while was present cirrhotic continuously decreased from HCC. Interestingly, characterized by EMT-related gene sets pro-survival signaling. Consistently, integration expression signatures databases containing 300 HCCs revealed predictive survival. Prognostic significance permissive microenvironment be a consequence pro-oncogenic is caused chronic processes. Activation key oncogenic features immune-response signaling indicates cross-talk promising and/or preventive target.