Abstract
Simple SummaryThe 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.
Highlights
Hepatocellular carcinoma (HCC) is the second leading cause of cancer-related death worldwide, and is one of the most aggressive cancers with an increasing incidence [1]
It is likely that the choice of different isolation procedures and heterogeneous cancer stem cells markers allow the selection of CSC-enriched subpopulations, even though there is high heterogeneity among studies
Much remains to be done in order to: (1) validate these preliminary data; (2) establish a shared panel of biomarkers; (3) characterize the subpopulations identified by specific biomarker panels; and (4) assess their clinical usefulness in HCC patients
Summary
Hepatocellular carcinoma (HCC) is the second leading cause of cancer-related death worldwide, and is one of the most aggressive cancers with an increasing incidence [1]. In contrast to other types of cancer, neither specific mutations in driver genes, nor druggable mutated genes, guide treatment choices in HCC In this context, the identification of biomarkers to stratify patients toward optimal therapeutic regimens, or to predict early tumor escape, is still an unmet clinical need. Since CSCs are responsible for tumor heterogeneity and treatment failure in cancers [9], it is of utmost importance to hit the tumor mass, and the small fraction of drug-resistant cells that give rise to tumor initiation and recurrence, in order to achieve complete disease control.
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