Abstract

Chronic inflammation, obesity and old age greatly increase cancer risk. To understand the association and interplay between these risk factors, we have focused on cancer of the liver, one of the most metabolically active tissues, which also has important immune functions. The most common form of liver cancer, hepatocellular carcinoma (HCC), usually arises in the context of chronic liver disease, such as cirrhosis, viral hepatitis and non alcoholic fatty liver disease (NAFLD). Using chemically induced HCC in mice as an experimental model, we found that inactivation of NF-kappaB or p38alpha signaling in hepatocytes results in enhanced accumulation of reactive oxygen species (ROS) and augmented hepatocyte death, changes that accelerate HCC development. ROS accumulation and oxidative stress lead to activation of Jun kinases (JNK) and JAK2 , resulting in elevated AP-1 and STAT3 activities. Accordingly, total JNK1 ablation and hepatocyte-specific deletions of c-Jun or STAT3 inhibit the development of chemically-induced HCC . We also investigated how obesity enhances HCC development using a model of obesity-promoted chemically-induced HCC . Our results indicate that obesity leads to hepatosteatosis which results in metabolic alterations and chronic inflammation. Inhibition of steatohepatitis through ablation of either type 1 TNF receptor (TNFR1) or interleukin 6 (IL-6) abolishes the tumor promoting effect of obesity. Another important factor in obesity-promoted HCC is TORC1 , whose activation results in inhibition of autophagy and its sequella. Although HCC is one of the most lethal cancers with a 5-year survival rate of 5%, it is very slow growing. Thus, early detection of HCC may provide an opportunity for therapeutic intervention before the cancer becomes too aggressive and refractory to therapy. To this end, we have isolated from livers of mice treated with the chemical carcinogen diethylnitrosamine (DEN) a population of pre-malignant cells that can give rise to HCC when transplanted into a suitable host. These cells, which we named HCC initiating cells (HIC), are not as transformed as HCC cells and display unique properties that should enable both their early detection as well as elimination.