Hepatic Cancer Stem Cells: Molecular Mechanisms, Therapeutic Implications, and Circulating Biomarkers

Simple Summary The high heterogeneity of hepatocellular carcinoma (HCC), and the lack of druggable mutations, hamper the identification of unequivocal molecular classifiers and limit the discovery of selective therapeutic treatments. Moreover, the lack of circulating biomarkers guiding the choice of personalized treatments and identifying the occurrence of acquired resistance to treatments still represents an unmet clinical need in HCC. The cancer stem cell (CSC) compartment underlies tumor heterogeneity, disease recurrence, and drug resistance in all cancer types, including HCC. Knowledge of the molecular mechanisms supporting the maintenance and proliferation of CSCs may help to identify novel biomarkers and therapeutic targets to improve and refine HCC management. Hepatocellular carcinoma (HCC) is one of the deadliest cancers. HCC is associated with multiple risk factors and is characterized by a marked tumor heterogeneity that makes its molecular classification difficult to apply in the clinics. The lack of circulating biomarkers for the diagnosis, prognosis, and prediction of response to treatments further undermines the possibility of developing personalized therapies. Accumulating evidence affirms the involvement of cancer stem cells (CSCs) in tumor heterogeneity, recurrence, and drug resistance. Owing to the contribution of CSCs to treatment failure, there is an urgent need to develop novel therapeutic strategies targeting, not only the tumor bulk, but also the CSC subpopulation. Clarification of the molecular mechanisms influencing CSC properties, and the identification of their functional roles in tumor progression, may facilitate the discovery of novel CSC-based therapeutic targets to be used alone, or in combination with current anticancer agents, for the treatment of HCC. Here, we review the driving forces behind the regulation of liver CSCs and their therapeutic implications. Additionally, we provide data on their possible exploitation as prognostic and predictive biomarkers in patients with HCC.