Immune Pathogenesis of Hepatocellular Carcinoma

Abstract

Hepatocellular carcinoma (HCC) is a common complication of chronic hepatitis B virus (HBV) infection. The pathogenetic mechanisms potentially responsible for HCC during chronic HBV infection are not well defined. This study demonstrates that chronic immune-mediated liver cell injury triggers the development of HCC in the absence of viral transactivation, insertional mutagenesis, and genotoxic chemicals. These results strongly suggest that the immune response to HBV is both necessary and sufficient to cause liver cancer during chronic HBV infection, and that all other procarcinogenic events associated with HCC are probably dependent on this process.

Viruses, Immunity, and Cancer: Lessons from Hepatitis B

“…Subsequently, all of these mice developed chronic hepatitis and HCC. 101 The pathogenetic importance of immune-mediated hepatocellular injury in hepatocarcinogenesis in this study is strengthened by the fact that hepatocellular carcinoma occurs in the context of necrosis, inflammation and regeneration (cirrhosis) in several human liver diseases other than hepatitis B, including chronic hepatitis C, 102 alcoholism, 103 hemochromatosis, 104 glycogen storage disease, 105 ␣-1-antitrypsin deficiency, 106,107 and primary biliary cirrhosis. 108 Irrespective of etiology or pathogenesis, therefore, it would appear that chronic liver cell injury is a premalignant condition that initiates a cascade of events characterized by increased rates of cellular DNA synthesis and production of endogenous mutagens coupled with compromised cellular detoxification and repair functions.…”

The Multifaceted Roles Neutrophils Play in the Tumor Microenvironment

“…This is well demonstrated in chronic Hepatitis B virus infection [255], where the persisting insult and chronic inflammation ultimately leads to hepatocellular carcinoma. Another well-studied example is the correlation between inflammatory bowel (IBD) disease and colorectal cancer (CRC) with up to 30 % of IBD patients developing CRC [256].…”

Hepatitis B virus-related hepatocellular carcinoma: paradigms for viral-related human carcinogenesis

“…In particular, targeting in the liver, using an albumin promoter, of an accumulation of the large PreS1/S2/S HBV envelope protein induces a direct toxic effect on hepatocytes, independent of the immune response to the viral protein (Toshkov et al, 1994). In another context, the immune response to HBV-expressing hepatocytes in transgenic mice can also trigger such liver cell regeneration and give rise to HCC (Nakamoto et al, 1998;Chen et al, 2005b;Wang et al, 2005). Furthermore, HBV-positive, transgenic mice exhibit extensive oxidative DNA damage, possibly related to cytokine synthesis (Hagen et al, 1994;Hsieh et al, 2004); this observation may explain their increased sensitivity to chemical carcinogens and is probably relevant in humans exposed to both hepatitis viruses and chemical carcinogens (Bannasch et al, 1989;Sell, 1993).…”