Elevated Lymphotoxin Expression In Liver Leads To Chronic Hepatitis And Causes HCC

The research was performed in the Department of Pathology, Institutes of Clinical Pathology and Neuropathology at the University Hospital in Zurich.

HBV and HCV cause chronic hepatitis and can lead to hepatocellular carcinoma (HCC), the most prevalent primary liver cancer in humans. "Although aberrant expression of cytotoxic cytokines is thought to be critically involved in hepatitis-induced liver cancer, the exact mechanisms driving this progression remain elusive," explains senior study author Dr. Mathias Heikenwalder.

The cytokines lymphotoxin (LT) α and β are mainly produced by white blood cells called lymphocytes and play an important role in organ development and control of the immune response. Previous work had shown that, when compared with normal livers, HCV-infected livers exhibit dramatically increased expression of LTαβ. Dr. Heikenwalder's laboratory, in collaboration with the laboratory of Professor Adriano Aguzzi and colleagues investigated a possible causal relationship between aberrant sustained hepatic LT signaling, chronic hepatitis and the development of HCC.

The researchers found that LTα, LTβ and the LT receptor (LTβR) were upregulated in HBV- or HCV-induced hepatitis and HCC and identified both lymphocytes and liver cells called hepatocytes as the main expressing cells. Liver specific expression of LTα and LTβ induced chronic liver inflammation and HCC in mice. It was the hepatocytes themselves which were the major LT-responsive liver cells and, importantly, when LTβR signaling was blocked in mice with chronic hepatitis, inflammation was partially attenuated and HCC was prevented.

It appears as if LTβR signaling might be beneficial in some cases and detrimental in others. Previous work has shown that LTβR signaling in liver cells supported liver regeneration. However, as is evidenced in this study, there is a causal link between chronic LTβR signaling and both chronic hepatitis and HCC development.

Taken together, the findings indicate that sustained LTβR signaling in liver leads to chronic hepatitis-induced HCC. "Our results show that LT signaling is critically involved in the development of chronic hepatitis and subsequent HCC formation and imply that blocking LTβR signaling might become a beneficial therapeutic approach in the context of HBV- or HCV-induced chronic hepatitis and other liver diseases displaying sustained hepatic LTβR signaling," concludes Dr. Heikenwalder.

The researchers include Johannes Haybaeck, University Hospital Zurich, Zurich, Switzerland; Nicolas Zeller, University Hospital Zurich, Zurich, Switzerland; Monika Julia Wolf, University Hospital Zurich, Zurich, Switzerland; Achim Weber, University Hospital Zurich, Zurich, Switzerland; Ulrich Wagner, University Zurich, Zurich, Switzerland; Michael Odo Kurrer, Cantonal Hospital Aarau, Aarau, Switzerland; Juliane Bremer, University Hospital Zurich, Zurich, Switzerland; Giandomenica Iezzi, Swiss Federal Institute of Technology (ETH), Zurich, Schlieren, Switzerland; Rolf Graf, University Hospital Zurich, Zurich, Switzerland; Pierre-Alain Clavien, University Hospital Zurich, Zurich, Switzerland; Robert Thimme, University of Freiburg, Freiburg, Germany; Hubert Blum, University of Freiburg, Freiburg, Germany; Sergei A. Nedospasov, Engelhardt Institute of Molecular Biology, Moscow, Russia, German Rheumatism Research Center, Berlin, Germany; Kurt Zatloukal, Institute of Pathology, Medical University of Graz, Graz, Austria; Muhammad Ramzan, INSERM and Universite´ Joseph Fourier-Grenoble, Grenoble, France; Sandra Ciesek, Medical School Hannover (MHH) and the Helmholtz Centre for Infection Research (HZI), Hannover, Germany; Thomas Pietschmann, Medical School Hannover (MHH) and the Helmholtz Centre for Infection Research (HZI), Hannover, Germany; Patrice N. Marche, INSERM and Universite´ Joseph Fourier-Grenoble, Grenoble, France; Michael Karin, University of California, San Diego and University of California, Los Angeles, CA; Manfred Kopf, Swiss Federal Institute of Technology (ETH), Zurich, Schlieren, Switzerland; Jeffrey L. Browning, Biogen Idec, Cambridge, MA; Adriano Aguzzi, University Hospital Zurich, Zurich, Switzerland; and Mathias Heikenwalder, University Hospital Zurich, Zurich, Switzerland.