Hepatic cancer stem cells and drug resistance: Relevance in targeted therapies for hepatocellular carcinoma

Abstract

Hepatocellular carcinoma (HCC) is one of most common malignancies in the world. Systemic treatments for HCC, particularly for advanced stages, are limited by the drug resistance phenomenon which ultimately leads to therapy failure. Recent studies have indicated an association between drug resistance and the existence of the cancer stem cells (CSCs) as tumor initiating cells. The CSCs are resistant to conventional chemotherapies and might be related to the mechanisms of the ATP Binding Cassette (ABC) transporters and alterations in the CSCs signaling pathways. Therefore, to contribute to the development of new HCC treatments, further information on the characterization of CSCs, the modulation of the ABC transporters expression and function and the signaling pathway involved in the self renewal, initiation and maintenance of the cancer are required. The combination of transporters modulators/inhibitors with molecular targeted therapies may be a potent strategy to block the tumoral progression. This review summarizes the association of CSCs, drug resistance, ABC transporters activities and changes in signaling pathways as a guide for future molecular therapy for HCC.

Keywords: Cancer stem cells; Drug resistance; Hepatocellular carcinoma; Hepatocellular carcinoma therapy; Liver.

Figure 1

The liver cancer initiation hypothesis based on CSCs theory. The hepatic stem cells (SC) and oval progenitor (OC) cells have specific capacities to self renew and differentiate into multiple hepatic lineages. Mutations in SC and/or OC may modify the cells genetic property and switch the normal SC into CSCs leading to tumor initiation.

Figure 2

The CSCs-targeted therapy strategy. Conventional therapies affecting mainly the differentiated cells might not be sufficient to eradicate total tumor. In the CSCs-targeted therapy, chemotherapeutic agents is specially designed to target the CSCs. This strategy may primary block the main source and consistently inhibit the growth of tumor. Some factors such as CSCs pathways, tumor subtypes and drugs transporters inhibitions should be considered to increase the efficiency and safety of the treatment.

Figure 3

A collaborative approach to target the CSCs. The hepatic CSCs identifications and their functional significances, including multidrugs resistance behavior and aberrant signaling pathways should be clearly identified. Together with CSCs markers, clinical aspects such as drug delivery system, single or combination therapy, drug dose and toxicity will support the potential of therapy. Both biological and clinical considerations will be potent means to improve the safety and efficiency of CSCs-targeted therapy.