Inflammation induced liver cancer: a lymphotoxin driven pathway to hepatocellular carcinoma


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Mathias Heikenwälder
Department of Pathology, Zürich, Switzerland

Abstract

A causal relationship between chronic hepatitis, hepatocellular damage, fibrosis and carcinogenesis is well established. Various etiologies, including chronic alcohol consumption, chronic drug abuse, autoimmune disorders, toxins (e.g. aflatoxin B) or infections with hepatotropic viruses (e.g. Hepatitis B and C viruses (HBV, HCV)) can lead to chronic hepatitis, liver fibrosis and cirrhosis further leading to liver cancer. HBV- and HCV-infections are by far the most common cause of chronic hepatitis in humans. We show that cytokines lymphotoxin (LT) a, b and their receptor (LTbR) are upregulated in HBV- or HCV-induced hepatitis and HCC. Liver-specific LTab expression in mice induces liver inflammation and HCC causally linking hepatic LT overexpression to hepatitis and HCC. Development of HCC, composed in part of A6+ oval cells, depends on lymphocytes and IKappa B kinase b expressed by hepatocytes but is independent of TNFR1. In vivo LTbR stimulation implicates hepatocytes as the major LT-responsive liver cells and LTbR inhibition in LTab-transgenic mice with hepatitis suppresses HCC formation. Thus, sustained LT signaling represents a pathway involved in hepatitis-induced HCC.