Z Gastroenterol 2015; 53 - KG235
DOI: 10.1055/s-0035-1559261

Activation of hepatic stem-like cells in the tumor microenvironment is a critical determinant of the prognosis of HCC patients

D Castven 1, M Fischer 1, S Heinrich 2, J Andersen 3, M Sprinzl 1, I Gockel 4, S Heilmann 5, M Wörns 1, S Thorgeirsson 6, P Galle 1, H Lang 7, J Marquardt 1
  • 1Universitätsmedizin Mainz, 1. Medizinische Klinik und Poliklinik, Mainz, Deutschland
  • 2Universitätsmedizin Mainz, Klinik für Allgemein-, Viszeral- und Transplantationschirurgie, Mainz, Deutschland
  • 3University of Copenhagen, BRIC, Copenhagen, Dänemark
  • 4Universitätsklinikum Leipzig AöR, Klinik für Viszeral-, Transplantations-, Thorax- und Gefäßchirurgie, Leipzig, Deutschland
  • 5Life & Brain Center, University of Bonn, Institute of Human Genetics, Department of Genomics, Bonn, Deutschland
  • 6National Institute of Health, NCI/CCR, Bethesda, Vereinigte Staaten
  • 7Universitätsmedizin Mainz, Klinik für Allgemein-, Viszeral- und Transplantationschirurgie, Mainz, Deutschland

Background: HCCs commonly develop in chronically damaged liver tissues. The resulting regenerative and inflammatory processes create an adverse microenvironment that promotes tumor-initiation and progression. Expansion of cancer stem cells is commonly observed during this process. This putative cancer stem cell origin provides a plausible explanation for the observed phenotypic heterogeneity of hepatocellular cancers. However, despite profound therapeutic implications the prognostic relevance of CSCs and their cellular localization within the tumor formation remain controversial.

Methods: Expression levels and localization of established CSC markers were assessed in pre-neoplastic lesions as well as 30 HCCs using qRT-PCR, imunohistochemistry and Western-Blotting. Integrative whole genome and transcriptome analyses of different tumor regions as well as tumor-surrounding liver (SL) were performed to identify associated molecular alterations and integrated with our existing HCC database.

Results: Expression patterns of established CSC markers were surprisingly heterogeneous. While classical markers such as GPC3 were induced in tumor tissue, activation of CSCs was predominantly observed in SL and continuously decreased from pre-neoplastic lesions to HCC. Consistently, genomic and transcriptomic profiles between SL and different tumor regions were quite distinct. Progressive increase in genetic alterations and activation of pathways related to proliferation as well as apoptosis was observed in the tumor tissue, while the invasive tumor margin (TM) was characterized by inflammatory and EMT-related gene sets as well as activation of pro-survival signaling such as ERK and FOS. Consistently, integration of the different signatures with our database of 53 HCC revealed that the TM signature was associated with the survival of HCC patients.

Conclusion: The CSC phenotype is predominantly induced by the permissive tumor microenvironment. However, pro-oncogenic properties might originate in the TM. The activation of key oncogenic features as well as immune-response signaling indicates that the cross-talk between tumor and microenvironment might be a promising therapeutic and/or preventive target.