Adverse genomic alterations and stemness features are induced by field cancerization in the microenvironment of hepatocellular carcinomas
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Darko Castven1,*, Michael Fischer1,*, Diana Becker1, Stefan Heinrich2, Jesper B. Andersen3, Dennis Strand1, Martin F. Sprinzl1, Susanne Strand1, Carolin Czauderna1, Stefanie Heilmann-Heimbach4, Stephanie Roessler5, Arndt Weinmann1, Marcus A. Wörns1, Snorri S. Thorgeirsson6, Peter R. Galle1, Matthias S. Matter7, Hauke Lang2 and Jens U. Marquardt1
1 Department of Medicine, Johannes Gutenberg University, Mainz, Germany
2 Department of Surgery, Johannes Gutenberg University, Mainz, Germany
3 Department of Health and Medical Science, Biotech Research and Innovation Centre, University of Copenhagen, Copenhagen, Denmark
4 Department of Genomics, Institute of Human Genetics, Life & Brain Center, University of Bonn, Bonn, Germany
5 Institute of Pathology, University Hospital Heidelberg, Heidelberg, Germany
6 Laboratory of Experimental Carcinogenesis, Center for Cancer Research, National Cancer Institute, NIH, Bethesda, MD, USA
7 Department of Pathology, University of Basel, Basel, Switzerland
* These authors have contributed equally to this work
Jens U. Marquardt, email:
Keywords: liver cancer, microenvironment, hepatocarcinogenesis, stemness features, field effect
Received: February 22, 2017 Accepted: March 03, 2017 Published: March 15, 2017
Hepatocellular Carcinoma (HCC) commonly develops in chronically damaged liver tissues. The resulting regenerative and inflammatory processes create an adverse milieu that promotes tumor-initiation and progression. A better understanding of the hepatic tumor-microenvironment interaction might infer profound therapeutic implications.
Integrative whole genome and transcriptome analyses of different tumor regions, the invasive tumor border and tumor-surrounding liver (SL) were performed to identify associated molecular alterations and integrated with our existing HCC database. Expression levels and localization of established CSC markers were assessed in pre-neoplastic lesions and confirmed in two independent patient cohorts using qRT-PCR, immunohistochemistry and immunofluorescence.
Our results indicate that genomic and transcriptomic profiles between SL and different tumor regions are quite distinct. Progressive increase in genetic alterations and activation of pathways related to proliferation as well as apoptosis were observed in the tumor tissue, while activation of stemness markers was present in cirrhotic SL and continuously decreased from pre-neoplastic lesions to HCC. Interestingly, the invasive tumor border was characterized by inflammatory and EMT-related gene sets as well as activation of pro-survival signaling. Consistently, integration of gene expression signatures with two independent HCC databases containing 300 HCCs revealed that border signatures are predictive of HCC patient survival.
Prognostic significance of the permissive liver microenvironment might be a consequence of a pro-oncogenic field effect that is caused by chronic regenerative processes. Activation of key oncogenic features and immune-response signaling indicates that the cross-talk between tumor and microenvironment might be a promising therapeutic and/or preventive target.
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