Further understanding of mechanisms involved in liver cancer chemoresistance

摘要

An important limitation for the success of chemotherapy in the treatment of primary liver cancer (hepatocellular carcinoma,hepatoblastoma and cholangiocarcinoma) is the marked efficacy of mechanisms of chemoresistance (MOC).These have been previously classified into five groups depending on whether they result in:a reduced drug uptake or enhanced drug export (MOC-1);poor intracellular activation of prodrugs or higher inactivation of active drugs (MOC-2);changes in the molecular targets that impairs the action of the drug by increasing the activity of the metabolic route to be inhibited or stimulating alternative routes (MOC-3);ability of tumor cells to repair drug-induced modifications in the target molecule,usually DNA (MOC-4);and the activation or inhibition of intracellular signaling pathways that lead to a change in the balance between proand anti-apoptotic factors favoring tumor cell survival (MOC-5).Nevertheless,novel information appeared over the last few years has recommended to consider two additional groups,MOC-6 and MOC-7,based on changes in tumor microenvironment,mainly hypoxia and acidity,and epithelial-mesenchymal transition,respectively.These contribute to the defensive armamentaria developed or enhanced in liver cancer cells to resist the pharmacological attack,which accounts for a negligible beneficial effect of commonly used antitumor drugs and only a modest response to novel targeted therapies based on tyrosine kinase inhibitors,such as sorafenib.Therefore,further advances are urgently needed to better understand the molecular and cellular bases of the chemoresistant barrier and help scientists in this field to develop new tools able to overcome cancer cell defenses.