Project

Back to overview

Zelluläre und genetische Mechanismen der Entwicklung von hepatozellulären Karzinomen bei chronischer Hepatitis am Mausmodell und Validierung an humanen Leberproben.

English title Cellular and genetic mechanisms in the development of chronic hepatitis induced hepatocellular carcinoma in a mouse model and validation in human liver samples.
Applicant Heikenwälder Mathias
Number 130822
Funding scheme Project funding (Div. I-III)
Research institution Institut für Neuropathologie Universitätsspital Zürich
Institution of higher education University of Zurich - ZH
Main discipline Experimental Cancer Research
Start/End 01.04.2010 - 31.03.2013
Approved amount 593'892.00
Show all

All Disciplines (2)

Discipline
Experimental Cancer Research
Immunology, Immunopathology

Keywords (8)

chronic hepatitis; hepatocellular carcinoma (HCC); cytotoxic cytokines; oval cells; lymphotoxin alpha and beta; lymphotoxin beta receptor; liver cancer; hepatocellular carcinoma

Lay Summary (English)

Lead
Lay summary
Hepatocellular carcinoma (HCC) is the most common human liver cancer, causing approximately 500 000 deaths/year worldwide. HCC is caused by chronic hepatitis, but the exact mechanisms driving hepatitis-induced liver cancer remain elusive. Among others, aberrant expression of cytotoxic cytokines is thought to be critically involved. We have recently demonstrated that the cytokines lymphotoxin (LT) alpha and beta are overexpressed in livers of patients with chronic Hepatitis B- and C-virus infection as well as in HCC with viral origin. To test whether LT upregulation is causally linked to chronic hepatitis and liver cancer development we analyzed transgenic mice with hepatic LT alpha and beta overexpression (AlbLTalpha/beta mice). This induced Kupffer-cell activation, hepatocyte- and oval cell proliferation, chronic hepatitis and liver cell damage. Remarkably, ~35% of transgenic mice developed HCC at an age of >300 days. Chronic hepatitis and HCC were prevented by backcrossing to RAG1-/- mice, which lack B- and T-cells, ruling out a direct effect of LTalpha/beta on the development of carcinogenic events in liver cells. Moreover, we concluded from these results that immune cell infiltration is not an epiphenomenon of carcinogenesis but a key-player in the sequence of events from chronic hepatitis to HCC. Moreover, intercrosses to Ikkbeta hep mice prevent chronic hepatitis and HCC development indicating that NF-kB signaling within hepatocytes is necessary for both the development of chronic hepatitis and HCC. Here we aim to identify the specific molecular and cellular requirements for HCC development through liver inflammation and try to compare the various pathologies detected with the human pathological situation.
Direct link to Lay Summary Last update: 21.02.2013

Responsible applicant and co-applicants

Employees

Publications

Publication
The parallel universe: microRNAs and their role in chronic hepatitis, liver tissue damage and hepatocarcinogenesis
Haybaeck Johannes, Zeller Nicolas, Heikenwälder Mathias (2011), The parallel universe: microRNAs and their role in chronic hepatitis, liver tissue damage and hepatocarcinogenesis, in Swiss Med Wkly, 1-9.
Chronic liver inflammation and hepatocellular carcinoma: persistence matters
Weber Achim, Böge Yannik Timo, Reisinger Florian (2011), Chronic liver inflammation and hepatocellular carcinoma: persistence matters, in Heikenwälder, Mathias, 1-13.
Endothelial CCR2 signaling induced by colon carcinoma cells enables extravasation via the JAK2-Stat5 and p38MAPK pathway
Wolf Monika Julia, Hoos Alexandra, Bauer Judith, Boettcher Steffen, Knust Markus, Weber Achim, Simonavicius Nicole, Schneider Christoph, Lang Matthias, Stürzl Michael, Croner Roland S., Konrad Andreas, Manz Markus, Moch Holger, Aguzzi Adriano, van Loo Geert, Pasparakis Manolis, Prinz Marco, Borsig Lubor, Heikenwälder Mathias, Endothelial CCR2 signaling induced by colon carcinoma cells enables extravasation via the JAK2-Stat5 and p38MAPK pathway, in Cancer Cell.
Follicular dendritic cells emerge from ubiquitous perivascular precursors
Krautler Nike Julia, Kana Veronika, Kranich Jan, Tian Yinghua, Perera Dushan, Lemm Doreen, Schwarz Petra, Armulik Annika, Browning Jeffrey L., Tallquist Michelle, Buch Thorsten, Oliveira-Martins José, Zhu Caihong, Hermann Mario, Wagner Ulrich, Brink Robert, Heikenwälder Mathias, Aguzzi Adriano, Follicular dendritic cells emerge from ubiquitous perivascular precursors, in Cell.

Scientific events

Active participation

Title Type of contribution Title of article or contribution Date Place Persons involved
Liver Cancer meeting 23.03.2012 Jerusalem, Israel
Meeting in Ghent, invited by Prof. Geert van Loo 08.03.2012 Ghent
Falk workshop für Liver Cancer 22.02.2012 Hamburg, Germany
Russian-German meeting for cancer research 03.10.2011 Haigerloch, Germany
SFB Transregio Meeting on the Tumor vessel interface 18.09.2011 Kloster Seeon, Germany


Associated projects

Number Title Start Funding scheme
146940 Mechanisms of apoptosis-induced proliferation and regeneration in the intestinal tract: Implications for the pathogenesis of inflammatory bowel diseases (IBD) and intestinal carcinogenesis 01.05.2013 Project funding (Div. I-III)

Abstract

Hepatocellular carcinoma (HCC) is the most common human liver cancer, causing approximately 500 000 deaths/year worldwide. HCC is caused by chronic hepatitis, but the exact mechanisms driving hepatitis-induced liver cancer remain elusive. Among others, aberrant expression of cytotoxic cytokines is thought to be critically involved. We have recently demonstrated that the cytokines lymphotoxin (LT) a and b are overexpressed in livers of patients with chronic Hepatitis B- and C-virus infection as well as in HCC with viral origin (1). To test whether LT upregulation is causally linked to chronic hepatitis and liver cancer development we analyzed transgenic mice with hepatic LTa and b overexpression (AlbLTab mice) (2). This induced Kupffer-cell activation, hepatocyte- and oval cell proliferation, chronic hepatitis and liver cell damage. Remarkably, ~35% of transgenic mice developed HCC at an age of >300 days. Chronic hepatitis and HCC were prevented by backcrossing to RAG1-/- mice, which lack B- and T-cells (1), ruling out a direct effect of LTa and b on the development of carcinogenic events in liver cells. Moreover, we concluded from these results that immune cell infiltration is not an epiphenomenon of carcinogenesis but a key-player in the sequence of events from chronic hepatitis to HCC. Moreover, intercrosses to IkkbDhep mice prevent chronic hepatitis and HCC development indicating that NF-kb signaling within hepatocytes is necessary for both the development of chronic hepatitis and HCC. Here we aim to identify the specific molecular and cellular requirements for HCC development through liver inflammation. In the first set of experiments we plan to identify the cell types responsible for the development of chronic hepatitis and HCC: -1. The importance of different T-cell subsets and B-cells in controlling the development of chronic hepatitis and HCC in AlbLTab mice will be analysed. Therefore, we plan to deplete mature T- or B- cells in AlbLTab mice by intercrosses with MHCI-/-, MHCII-/- and JH-/- mice. -2. Further, we intend to investigate the role of pro-inflammatory macrophages in liver cancer formation. Therefore, we will intercross CCR2-/- mice, which lack pro-inflammatory macrophages. -3. The impact of regenerative processes on HCC formation will be studied by intercrosses to TPH-/- mice, which display reduced liver regeneration (3). To assess whether chronic hepatitis in combination with strong liver fibrosis increases HCC incidence, Alb-PDGFb transgenic mice, which display strong liver fibrosis, will be intercrossed with AlbLTab mice.In the second set of experiments inflammation induced HCC of AlbLTab mice will be compared to HCC from other mouse models to determine whether HCC arising from chronic hepatitis are fundamentally different from HCC of other origins (e.g. chemically induced). Further, these different mouse models will be compared to human HCC of different aetiologies (e.g. of viral; autoimmune). Analyses will include real-time PCR, array comparative genomic hybridization (aCGH), Western blot and immunohistochemistry. A particular focus of this analysis will also be the molecular characterization of oval cells, which are putative liver-cancer stem cells. Oval cells of normal bile duct epithelia, chronically damaged murine livers as well as HCC-derived from various mouse models will be analyzed.
-