Epigenetic regulation of cancer stem cells in liver cancer: current concepts and clinical implications

Abstract

The two dominant models of carcinogenesis postulate stochastic (clonal evolution) or hierarchic organization of tumor (cancer stem cell model). According to the latter, at the germinal center of tumor evolution is a cancer stem cell (CSC) which, similar to normal adult stem cells, possesses the capacity of self-renewal and a differentiation potential. Over the past few years, compelling evidence has emerged in support of the hierarchic cancer model for many solid tumors including hepatocellular cancers. The CSCs are posited to be responsible not only for tumor initiation but also for the generation of distant metastasis and relapse after therapy. These characteristics are particularly relevant for a multi-resistant tumor entity like human hepatocellular carcinoma and may herald a paradigm shift in the management of this deadly disease. Identification and detailed characterization of liver CSCs is therefore imperative for improving prevention approaches, enhancing early detection, and extending the limited treatment options. Despite the current progress in understanding the contribution of CSCs to the generation of heterogeneity of tumors, the molecular complexity and exact regulation of CSCs is poorly understood. This review focuses on the genetic and epigenetic mechanisms that regulate and define the unique CSC properties with an emphasis on key regulatory pathways of liver CSCs and their clinical significance.

Fig. 1

CSC properties and mechanisms of regulation. The Cancer Stem Cell (CSC) hypothesis places CSCs at the center of neoplastic development. The scheme simplifies our understanding of how CSCs are regulated and emphasizes the contribution of both genetics and epigenetics in tumor initiation, development of metastasis, and tumor relapse. CSCs share the fundamental properties of normal stem cells, including regulatory pathways (representative molecules are shown) and the ability to undergo symmetric (self-renewal) and asymmetric (pluripotency) division. The unique features of CSCs (arrows) provide attractive targets (red arrows) for developing novel therapeutic tools directed specifically at the CSC. RNAi, RNA interference machinery; LOH, loss of heterozygosity; CNV, copy number variations; SNP, single nucleotide polymorphism.