Z Gastroenterol 2015; 53 - A4_45
DOI: 10.1055/s-0034-1397197

Role of RAGE and its ligands S100A8/A9 in hepatocellular carcinoma onset and development

AM De Ponti 1, D Schneller 1, T Pusterla 1, L Wiechert 1, T Longerich 2, S Marhenke 3, P Schirmacher 2, A Vogel 3, E Pikarsky 4, J Hess 6, P Angel 1
  • 1Division of Signal Transduction and Growth Control, DKFZ-ZMBH Alliance, German Cancer Research Center (DKFZ), Heidelberg, Germany
  • 2Institute of Pathology, University Hospital Heidelberg, Heidelberg, Germany
  • 3Department of Hepatology, Medical School Hannover, Hannover, Germany
  • 4Lautenberg Center for Immunology and Department of Pathology, IMRIC, Hebrew University-Hadassah Medical School, Jerusalem, Israel
  • 5Junior Group Molecular Mechanisms of Head and Neck Tumors, DKFZ-ZMBH Alliance, German Cancer Research Center (DKFZ), Heidelberg, Germany
  • 6Department of Otolaryngology, Head and Neck Surgery, University Hospital Heidelberg, Heidelberg, Germany

The Receptor for Advanced Glycation-End products (RAGE) is a multi-ligand receptor, mainly involved in tissue damage and inflammatory disorders. RAGE and its ligands S100A8 and S100A9 have been shown to be overexpressed in tumors, including hepatocellular carcinoma (HCC), enhancing cancer progression and metastasis by still unknown mechanisms.

To address the role played by RAGE and S100A8/A9 in HCC onset and development, we took advantage of two mouse models: (i) the multidrug resistance 2 knock-out (Mdr2-/-) mouse and (ii) treatment with the procarcinogen diethylnitrosamine (DEN). The Mdr2-/- mouse shows chronic hepatitis, liver damage and fibrosis followed by HCC development. On the other side, DEN is an alkylating agent that promotes DNA-strand breaks, thus leading to HCC formation in a cirrhosis-free context.

Regarding HCC onset, we will investigate the role of RAGE and S100A8/A9 in HCC progenitor cells (HcPCs). It was already shown that HcPCs can be isolated from different mouse models, and that cells resembling HcPCs reside within dysplastic lesions that appear several months before HCC nodules.

Regarding HCC development, we demonstrated that Rage ablation impaired tumor development only in the Mdr2-/- model, where it reduced number and size of tumors and limited liver damage and oval cell activation. On the contrary, absence of S100a9 in the Mdr2-/- model did not affect HCC development nor liver damage, but lack of this protein significantly reduced the size of tumors in the DEN model.

These unexpected results underline the complexity of the cross-talk between RAGE and its ligands, which orchestrate neoplastic transformation and malignant progression. They also highlight the necessity of using more sophisticated genetic models in order to decipher the contribution of each ligand and receptor involved in HCC development.

Corresponding author: De Ponti, Aurora Maria

E-Mail: a.deponti@dkfz.de