Research Group Signalling - HCC

1) It has been known for more than one hundred years that there is a link between chronic inflammation and cancer development. Inflammatory bowel disease, especially ulcerative colitis is a risk factor for development of colorectal cancer. Chronic liver damage and liver cirrhosis caused by viral hepatitis B and C or alcoholic or non-alcoholic steatoheptitis lead to development of hepatocelluar carcinoma (HCC). More than 50 percent of all hepatocellular carcinomas develop as a result of chronic tissue damage caused by chronic inflammation.

In our research group we use transgenic, knock-out and chemical induced cancer mouse models

  • to develop new strategies for the treatment of liver cancer by inhibition of critical pathways by small molecule inhibitors, peptides, innovative viral vectors expressing shRNAs, combined targeting of cancer cells and tumor microenvironment, and improving tumor delivery of systemically administered drugs;
  • to develop new magnetic resonance imaging imaging techniques (e. g. nanoparticle contrast agents) to detect and follow the growth of murine HCC;
  • to elucidate critical regulators of inflammatory pathways for cancer development in the liver and the gut;
  • to discover new biomarkers for HCC.

2) As the diagnosis of hepatocelluar carcinoma (HCC) in the cirrhotic liver is still a challenge and only early detection of cancer can result in effective treatment like resection or liver transplantation we aim to investigate and validate new biomarkers for early HCC detection. Moreover, we examine diagnostic and prognostic markers in patients with liver cirrhosis and HCC in patient material.

3) Gs protein-coupled receptors are known to signal via the second messenger 3'-5'-cyclic adenosine monophosphate (cAMP) regulates diverse cell functions, e. g. cell proliferation, differentiation, apoptosis, cell-cell and cell-matrix interaction and migration and immune function. Classical effectors of cAMP are protein kinase A (PKA) and Epac1 and Epac2 (Exchange factor directly activated by cAMP). We are currently investigating novel signaling mechanisms of cAMP, in particular the interaction of cAMP and purinergic signaling.



Prof. Dr. Dr. Albrecht Piiper

+49 69 6301 87667

Prof. Dr. Oliver Waidmann

+49 69 6301 87664


Group members

Dr. Tivdar Feczko (Humboldt Stipendium) Fabian Finkelmeier

Bianca Kakoschky, MSc (PhD student)

Prof. Dr. phil. nat. Dr. med. Albrecht Piiper (Group leader)

Dr. rer. nat. Thomas Pleli (PostDoc)

Dr. phil. nat. Christian Schmithals (PostDoc)

Prof. Dr. med. Oliver Waidmann (Group leader)



Selected publications

Selected publications of the last 6 years

Bihrer V, Friedrich-Rust M, Kronenberger B, Haupenthal J, Forestier N, Shi Y, Peveling-Oberhag J, Radeke HH, Sarrazin C, Herrmann E, Zeuzem S, Waidmann O, Piiper A. Serum miR-122 as a biomarker of necroinflammatory activity in patients with chronic hepatitis C virus infection. AmJ Gastroenterol 2011;106, 1663-9

Wild P, Farhan H, McEwan DG, Wagner S, Rogov VV, Brady NR, Richter B, Korac J, Waidmann O, Choudhary C, Dötsch V, Bumann D, Dikic I. Phosphorylation of the autophagy receptor optineurin restricts Salmonella growth. Science 2011;333:228-33

Waidmann O, Bihrer V, Pleli T, Farnik H, Berger A, Zeuzem S, Kronenberger B, Piiper A. Serum microRNA-122 levels in different groups of patients with chronic hepatitis B virus infection. J Vir Hepat 2012;19, e58-65

Haupenthal J, Bihrer V, Korkusuz H, Kollmar O, Schmithals C., Kriener S, Engels K, Pleli T, Benz A, Canamero M, Longerich T, Kronenberger B, Waidmann O, Richter S, Vogl TJ, Zeuzem S, Piiper A. Reduced efficacy of the Plk1 inhibitor BI 2536 on the progression of hepatocellular carcinoma due to low intratumoral drug levels. Neoplasia 2012;14, 410-9

Kronenberger B, Rudloff I, Bachmann M, Brunner F, Kapper L, Fielmann N, Waidmann O, Herrmann E, Pfeilschifter J, Zeuzem S, Piiper A, Mühl H. Interleukin-22 predicts severity and death in advanced liver cirrhosis: A prospective cohort study. BMC Med 2012;10, 102

Korkusuz H, Ulbrich K, Welzel K, Koeberle V, Watcharin W, Chernikov V, Petersen S, Huebner F, Ackermann H, Gelperina S, Korkusuz Y, Kromen W, Hammerstingl R, Haupenthal J, Fiehler J, Vogl TJ, Kreuter J, Piiper A. Transferrin-coated gadolinium nanoparticles as MRI contrast agent. Mol Imaging Biol 2013;15, 148-54

Waidmann O, Brunner F, Herrmann E, Zeuzem S, Piiper A, Kronenberger B. Macrophage activation is a prognostic parameter for gastrointestinal bleeding and overall survival in patients with liver cirrhosis. J Hepatol 2013;58, 956–61

Waidmann O, Köberle V, Bettinger D, Trojan J, Zeuzem S, Schultheiß M, Kronenberger B, Piiper A.Diagnostic and prognostic significance of cell death and macrophage activation markers in patients with hepatocellular carcinoma. JHepatol 2013;59, 769-79

Köberle V, Kronenberger B, Pleli T, Trojan J, Peveling-Oberhag J, Welker MW, Elhendawy M, Imelmann E, Zeuzem S, Piiper A, Waidmann O. Serum microRNA-1 and microRNA-122 are prognostic markers in patients with hepatocellular carcinoma. Eur J Cancer 2013;49, 3442-9

Köberle V, Pleli T, Schmithals C, Augusto EA, Haupenthal J, BönigH, Peveling-Oberhag J, Biondi RM, Zeuzem S, Kronenberger B, Waidmann O, Piiper A. Differential stability of cell-free circulating microRNAs: Implications for their utilization as biomarkers. PLoS ONE 2013;8, e75184

Watcharin W, Schmithals C, Pleli T, Köberle V, Korkusuz H, Hübner F, Zeuzem S, Korf HW, Vogl T, Rittmeyer C, Terfort A, Piiper A, Gelperina S, Kreuter J. Biodegradable human serum albumin nanoparticles as contrast agents for the detection of hepatocellular carcinoma by magnetic resonance imaging. Eur J Pharm Biopharm 2014;87, 132–41

Finkelmeier F, Kronenberger B, Köberle V, Bojunga J, Zeuzem S, Trojan J, Piiper A, Waidmann O. Severe 25-hydroxyvitamin D deficiency identifies HCC patients with a poor prognosis. Aliment Pharmacol Ther 2014;39, 1204-12

Rosenberger I, Schmithals C, Vandooren J, Bianchessi S, Milani P, Locatelli E, Israel LL, Hübner F, Matteoli M, Lellouche JP, Franchini MC, Passoni L, Scanziani E, Opdenakker G, Piiper A, Kreuter J. Iron-containing albumin nanoparticles: a promising tool for medical imaging. J Control Release 2014;194, 130-7.

Waidmann O, Kronenberger B, Scheiermann P, Köberle V, Mühl H, Piiper A. Interleukin-22 serum levels are a negative prognostic indicator in patients with hepatocellular carcinoma. Hepatology 2014;59:1207

Finkelmeier F, Kronenberger B, Köberle V, Bojunga J, Zeuzem S, Trojan J, Piiper A, Waidmann O. Severe 25-hydroxyvitamin D deficiency identifies a poor prognosis in patients with hepatocellular carcinoma - a prospective cohort study. Aliment Pharmacol Ther 2014;39:1204-12.

Waidmann O, Kempf VA, Brandt C, Zeuzem S, Piiper A, Kronenberger B. Colonisation with multidrug-resistant bacteria is associated with increased mortality in patients with cirrhosis. Gut 2015;64:1183-4

Dultz G, Piiper A, Zeuzem S, Kronenberger B, Waidmann O. Proton pump inhibitor treatment is associated with the severity of liver disease and increased mortality in patients with cirrhosis. Aliment Pharmacol Ther 2015;41:459-66

Watcharin W, Schmithals C, Pleli T, Köberle V, Korkusuz H, Hübner F, Waidmann O, Zeuzem S, Korf HW, Terfort A, Gelperina S, Vogl TJ, Kreuter J, Piiper A. Detection of hepatocellular carcinoma in transgenic mice by Gd-DTPA- and rhodamine 123-conjugated human serum albumin nanoparticles in T1 magnetic resonance imaging. J Control Release 2015;199:63-71

Dultz G, Gerber L, Farnik H, Berger A, Vermehren J, Pleli T, Zeuzem S, Piiper A, Kronenberger B, Waidmann O. Soluble CD163 is an indicator of liver inflammation and fibrosis in patients chronically infected with the hepatitis B virus. J Viral Hepat 2015;22:427-32

Finkelmeier F, Kronenberger B, Zeuzem S, Piiper A, Waidmann O. Low 25-hydroxyvitamin D levels are associated with infections and mortality in patients with cirrhosis. PLoS ONE 2015;10:e0132119

 Schmithals C, Köberle V, Korkusuz H, Pleli T, Kakoschky B, Augusto EA, Ibrahim AA, Arencibia J, Vafaizadeh V, Groner B, Kronenberger B, Zeuzem S, Korf HW, Vogl TJ, Waidmann O, Piiper A. Improving drug tumor penetrability with iRGD leverages the therapeutic response to sorafenib and doxorubicin in hepatocellular carcinoma. Cancer Res 2015;75:3147-54

Köberle V, Kakoschky B, Ibrahim AA, Schmithals C, Zeuzem S, Kronenberger B, Waidmann O, Pleli T, Piiper A. MicroRNA release from blood cells in blood samples, in particular upon inhibition of RNase A. Transl Res 2016;168:40–6

Dropmann A, Dediulia T, Breitkopf K, Angel P, Heß J, Piiper A, Fabregat I, Weber S, Lammert F, Abshagen K, Thoma M, Kohornen H, Jaschinksi F, Janicot M, Dooley S, Meindl-Beinker N. TGF-β1 and TGF-β2 abundance in liver diseases of mice and men. Oncotarget 7;19499-518

Grammatikos G, Schoell N, Ferreiros N, Bon D, Herrmann E, Farnik H, Köberle V, Piiper A, Zeuzem S,Kronenberger B, Waidmann O, Pfeilschifter J. Serum sphingolipidomic analyses reveal an upregulation of C16-ceramide and sphingosine-1-phosphate in hepatocellular carcinoma. Oncotarget 2015;7:18095-105

Finkelmeier F, Canli Ö, Tal A, Pleli T, Trojan J, Schmidt M, Kronenberger B, Zeuzem S, Piiper A, Greten FR, Waidmann O. High levels of the soluble programmed death-ligand (sPD-L1) identify hepatocellular carcinoma patients with a poor prognosis. Eur J Cancer 31;59:152-9

Waidmann O, Brunner F, Herrmann E, Zeuzem S, Piiper A, Kronenberger B. Cytokeratin 18 based cell death markers indicate severity of liver disease and prognosis of cirrhotic patients. Liver Int 2016;36:1464-72.

Depner C, Zum Buttel H, Böğürcü N, Cuesta AM, Aburto MR, Seidel S, Finkelmeier F, Foss F, Hofmann J, Kaulich K, Barbus S, Segarra M, Reifenberger G, Garvalov BK, Acker T, Acker-Palmer A. EphrinB2 repression through ZEB2 mediates tumour invasion and anti-angiogenic resistance. Nat Commun 2016 Jul 29;7:12329

IbrahimAA, Schmithals C, Kowarz E, Köberle V, Kakoschky B, Pleli T, Kollmar O, Nitsch S, Waidmann O, Finkelmeier F, Zeuzem S, Korf HW, Schmid T, Weigert A, Kronenberger B, Marschalek R, Piiper A. Hypoxia causes down-regulation of Dicer in hepatocellular carcinoma, which is required for up-regulation of hypoxia inducible factor 1α and epithelial-mesenchymal transition. Clin Cancer Res [in principle accepted]