Contribution of the Cancer Stem Cell Phenotype to Hepatocellular Carcinoma Resistance

Abstract

The cancer stem cell (CSC) hypothesis is an increasingly accepted concept in cancer research that provides a plausible explanation for the considerable phenotypic and molecular heterogeneities observed in hepatocellular carcinoma (HCC) which hampers therapeutic progress. The hypothesis infers that CSCs share functional properties similar to adult stem cells, such as self-renewal and differentiation capacity, and are exclusively responsible for tumor evolution. By definition, CSCs are held responsible not only for tumor initiation and progression but also acquisition of chemoresistance and the fueling of relapse after therapy. Therefore, the CSC model has significant implications both for translational research as well as clinical applications, in particular for the development of novel treatment strategies. Implicit in the concept is the need for therapeutic targeting of CSCs to effectively diminish tumor growth. Therefore, a better understanding of the molecular mechanisms that lead to induction of stemness and drive CSCs in HCC is of crucial importance. In this chapter, we aim to highlight important aspects of the CSC biology in the context of clinical and therapeutic progress. Besides a critical reflection of the cellular origin of CSCs, this will also include discussion on the importance of the diseased hepatic microenvironment for oncogenic reprogramming and induction of stemness in HCC. Moreover, we will highlight the relevance of CSC markers as diagnostic and/or predictive biomarkers. Most importantly, we will delineate the potential of therapeutic targeting of CSCs to overcome therapeutic resistance and improve the HCC patients’ outcome.