Risk factors of primary liver cancer initiation associated with tumour initiating cell emergence: novel targets for promising preventive therapies

Abstract

Primary liver cancers ranked as the sixth most commonly diagnosed cancers and the third-leading cause of cancer-related death in 2020. Despite encouraging findings on diagnosis and treatments, liver cancer remains a life-threatening disease with a still increasing incidence.Therefore, it is of interest to better characterise and understand the mechanistic process occurring at early steps of carcinogenesis. Inflammatory responses in liver diseases participate in the activation of liver progenitor cells (LPCs) facultative compartment but also to their transformation into cancer stem cells (CSCs) and give rise to primary liver cancer including hepatocellular carcinoma and cholangiocarcinoma. Higher intratumoural heterogeneity has been associated with poorer prognosis and linked to tumour escape from the immune surveillance and to resistance to chemotherapy. A better understanding of the malignant transformation of LPC as tumour initiating cells (ie, CSC) should also provide a potential new therapeutic target for anticancer therapy. In this review, we summarise the recent reports identifying underlying mechanisms by which chronic liver inflammatory responses could trigger the early steps in liver carcinogenesis, notably through the transformation of LPCs into tumour initiating cells.