Abstract
The lack of response to pharmacological treatment constitutes a substantial limitation in the handling of patients with primary liver cancers (PLCs). The existence of active mechanisms of chemoresistance (MOCs) in hepatocellular carcinoma, cholangiocarcinoma, and hepatoblastoma hampers the usefulness of chemotherapy. A better understanding of MOCs is needed to develop strategies able to overcome drug refractoriness in PLCs. With this aim, several experimental models are commonly used. These include in vitro cell-free assays using subcellular systems; studies with primary cell cultures; cancer cell lines or heterologous expression systems; multicellular models, such as spheroids and organoids; and a variety of in vivo models in rodents, such as subcutaneous and orthotopic tumor xenografts or chemically or genetically induced liver carcinogenesis. Novel methods to perform programmed genomic edition and more efficient techniques to isolate circulating microvesicles offer new opportunities for establishing useful experimental tools for understanding the resistance to chemotherapy in PLCs. In the present review, using three criteria for information organization: (1) level of research; (2) type of MOC; and (3) type of PLC, we have summarized the advantages and limitations of the armamentarium available in the field of pharmacological investigation of PLC chemoresistance.
Highlights
Hepatocellular carcinoma (HCC) is the most frequent primary liver cancer (PLC), representing approximately 90% of primary liver cancers (PLCs) in adults, whereas the remaining cases are mainly intrahepatic, ductular, and perihilar cholangiocarcinoma (CCA); hepatoblastoma (HB) being the most common type of PLC in pediatric patients
A variant of primary culture of cancer cells consists of the selection of cancer stem cells (CSCs), which are believed to play an essential role in the failure of long-term chemotherapy because of their marked multidrug resistance (MDR) phenotype and the fact that they can remain mitotically inactive in hypovascular regions of solid tumors, due to specific characteristics absent in healthy stem cells, which include hyper-efficient DNA repair mechanisms, overexpression of anti-apoptotic proteins, resistance to a hypoxic microenvironment, and overexpression of ATP-binding cassette (ABC) pumps [77,78]
The results revealed that HCC nodules overexpressed miR-221, which was involved in sorafenib resistance through inhibition of apoptosis (MOC-5) [105]
Summary
Hepatocellular carcinoma (HCC) is the most frequent primary liver cancer (PLC), representing approximately 90% of PLCs in adults, whereas the remaining cases are mainly intrahepatic, ductular, and perihilar cholangiocarcinoma (CCA); hepatoblastoma (HB) being the most common type of PLC in pediatric patients. A critical limitation in the management of advanced PLCs is their poor response to pharmacological treatment, which is less inefficient in the case of HB. Even before starting the treatment, several of the approximately one hundred genes involved in these MOCs are already expressed. This results in a group of proteins that defines the intrinsic ‘resistome’, which accounts for the initial defense of the tumor against chemotherapeutic agents. Some of these genes are shared among HCC, CCA, and HB [2]. Cancers 2019, 11, 1677; doi:10.3390/cancers11111677 www.mdpi.com/journal/cancers apoptosis pathways (MOC-5) [40]
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