Targeting cancer stem cells in HCC

Abstract

Many lines of evidence have demonstrated that cancer stem cells (CSCs) or tumor-initiating cells residing within the bulk tumor are a subpopulation of tumor cells that possess the ability to self-renew and differentiate. They are also capable of maintaining tumor propagation and metastasis and confer chemoand radio-resistance. As a consequence, CSCs are believed to play a crucial role in tumor initiation and tumor relapse clinically; hence CSCs are considered a pivotal target for the eradication of cancers. Hence besides killing the bulk tumor, there is a need to also target this specific CSC subpopulation for novel treatment. In hepatocellular carcinoma (HCC), using in vitro and in vivo models, a number of liver CSC markers have been identified, including, among others, CD133, CD24, CD47, and EpCAM. Notably, liver CSCs can be enriched by chemotherapeutic agents. Using cell sorting approach from patients’ HCC samples and HCC cell lines and lenti-viral based knockdown approach, HCC cells positive for these markers are more chemoresistant than the marker-negative cells. These cells also have the functional features of CSCs. Furthermore, they are functional liver CSC markers that drive hepatocarcinogenesis through specific signaling pathways such as the STAT3-mediated NANOG pathway. Translational work using antibodies targeting these markers has shown promising data in animal models. In addition, tumor microenvironment is now known to play an important role in regulating cancer stemness. The potential interaction of liver CSCs and the tumor microenvironment as exemplified by cancer-associated fibroblasts and other cellular components will also be presented. This presentation attempts to highlight the importance of CSCs implicated in the pathogenesis of hepatocellular carcinoma as well as potential targets for therapy. Detailed understanding of the molecular pathogenesis is crucial for the development of new therapeutic approaches against cancers.