A dual role for interferon γ signalling in hepatocellular carcinoma

Abstract

Hepatocellular carcinoma (HCC) is a malignant disease with heterogeneous aetiology. Despite this heterogeneity, HCCs have been classified into distinct subtypes based on candidate approaches or global screening methods [1–6]. Moreover, whole genome sequencing of HCCs and putative secondary growths have defined genetic changes associated with intrahepatic metastasis [7]. However, the identification of driver mutations in HCC is still a challenging task [8]. Mouse models are valuable tools to identify the contribution of defined genetic changes to HCC formation. As recently reviewed by Gen-Sheng Feng, controversial results have been obtained in mice for several candidate genes that seemed to display both, tumour-promoting and tumour-suppressive activities [9]. These controversial findings are reconciled by the fact that gene activities can influence HCC formation by two mechanisms: (1) a candidate gene is required for tumour cell proliferation or survival (oncogenic function); (2) a candidate gene is essential for survival of hepatocytes, thereby preventing chronic liver injury and regeneration (anti-oncogenic function). These mechanisms might operate in all tissues with high regenerative capacity. Consequently, chronic liver injury induced by ablation of an essential candidate gene could drive formation of HCCs with specific mutations that override tumour cell-autonomous requirements for the candidate gene. This dual mechanism exacerbates our interpretations of cell-autonomous gene functions in HCC formation when corresponding mouse models differ from control groups with respect to chronic liver injury. Moreover, many models do not reflect the human aetiology of HCC, which is associated with inflammation, chronic liver damage, and liver fibrosis.