• HEPATOCELLULAR CARCINOMA
• MOLECULAR CARCINOGENESIS
• STEM CELLS

Hepatocellular carcinoma (HCC) represents the fifth most common cancer and the third leading cause of cancer mortality worldwide, with a minority of patients surviving at 5 years from diagnosis, despite treatment.1 HCC usually develops in conditions of chronic liver disease (CLD), mostly on the background of a cirrhotic liver, with liver transplantation at present being the only treatment strategy to cure both HCC and the specific CLD. All the other therapeutic strategies, because of the underlying liver cirrhosis, have to take into account, and may be limited in their feasibility, by the residual liver function of the individual patient, a critical parameter affecting the patient's prognosis.2 Indeed, even when the surgical intervention is feasible, according to current guidelines, efficient removal of the primary lesions is not often conclusive since intrahepatic recurrence, as well as extrahepatic metastasis, are very frequent and associated with poor prognosis for patients.3 Along these lines, current literature suggests that both the progression of CLD towards HCC development as well as HCC progression and acquisition of resistance to therapy are highly affected by the microenvironment, in which several cells (including tumour-associated macrophages or fibroblasts and cancer stem cells (CSCs)), inflammation, fibrosis as well as hypoxia, oxidative stress and autophagy are believed to play a critical role.4 In particular, hepatic hypoxia (ie, very common in CLD and HCC) and hypoxia-inducible factors (HIFs) are currently believed to be major determinant players that, in agreement with data in other tumours, can contribute to cancer development and progression by promoting and/or modulating transcriptional programmes (metabolic adaptation, …