Andersen, Jesper B

Becker, Diana

Castven, Darko

Czauderna, Carolin

Fischer, Michael

Galle, Peter R

Heilmann-Heimbach, Stefanie

Heinrich, Stefan

Lang, Hauke

Marquardt, Jens U

Matter, Matthias S

Roessler, Stephanie

Sprinzl, Martin F

Strand, Dennis

Strand, Susanne

Thorgeirsson, Snorri S

Weinmann, Arndt

Wörns, Marcus A

Oncotarget

English

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.</p

Copenhagen University Research Information System

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

Darko Castven

Michael Fischer

Diana Becker

Stefan Heinrich

Jesper B. Andersen

Dennis Strand

Martin F. Sprinzl

Susanne Strand

Carolin Czauderna

Stefanie Heilmann-Heimbach

Stephanie Roessler

Arndt Weinmann

Marcus A. Wörns

Snorri S. Thorgeirsson

Peter R. Galle

Matthias S. Matter

Hauke Lang

Jens U. Marquardt

Crossref

https://curis.ku.dk/ws/files/186448599/16231_238977_3_PB.pdf

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

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