Hepatocellular carcinoma (HCC) is a common and often fatal malignancy that develops in chronically inflamed livers. The transcription factor NF-kB and its activator – IkB kinase (IKK) play important pathogenic roles in liver inflammation and are often activated in human HCC. However, mouse model studies have produced conflicting results whether IKK and NF-kB play stimulatory or inhibitory roles in HCC development.
Mice with constitutive activation of IKKb in hepatocytes (IKKb(EE)Hep) exhibit constitutive NF-kB activation and develop significantly more HCCs than control mice, both spontaneously and after carcinogen exposure. The IKKb(EE)Hep HCCs displayed an aggressive signature compared to HCCs from control mice. Histological analysis revealed a disease continuum starting with the appearance of lymphoid follicles, emergence of atypical epithelial hepatocytes in these follicles which gradually overtake and replace the follicle to form full blown HCCs. We termed these follicles IFWACs (Inflammatory Foci With Atypical Cells). Interestingly, very similar tertiary inflammatory follicles are a hallmark of HCV hepatitis in humans, the most important chronic liver disease leading to HCC in the Western world.
Lymphotoxin-β (LTβ), a major inducer of lymphoid tissues, was recently mechanistically linked to HCC. Indeed, the IFWACs express multiple inflammatory cytokines, in particular lymphotoxins, and their downstream effectors. Pharmacological blockade of lymphotoxin dramatically attenuates HCC development despite ongoing constitutive NF-kB activation.
Since LTbR and its ligands are drastically increased in human HBV- and HCV-induced hepatitis and HCC, suppression of LTbR pathway might be of great clinical importance.
We propose that suppression of the heterotypic crosstalk that takes place in IFWACS may be beneficial in liver diseases characterized by chronic NF-kB activation and increased HCC risk, such as HCV-induced hepatitis. Our studies suggest that focally defined inflammatory niches may be a specialized form of chronic inflammation with particular relevance to tumors – serving as a cradle for tumor progenitor cells.
