Liver Cancer: Therapeutic Challenges and the Importance of Experimental Models

Abstract

Liver cancer is one of the main causes of death related to cancer worldwide; its etiology is related with infections by C or B hepatitis virus, alcohol consumption, smoking, obesity, nonalcoholic fatty liver disease, diabetes, and iron overload, among other causes. Several kinds of primary liver cancer occur, but we will focus on hepatocellular carcinoma (HCC). Numerous cellular signaling pathways are implicated in hepatocarcinogenesis, including YAP-HIPPO, Wnt-β-catenin, and nuclear factor-κB (NF-κB); these in turn are considered novel therapeutic targets. In this review, the role of lipid metabolism regulated by peroxisome proliferator-activated receptor gamma (PPARγ) in the development of HCC will also be discussed. Moreover, recent evidence has been obtained regarding the participation of epigenetic changes such as acetylation and methylation of histones and DNA methylation in the development of HCC. In this review, we provide detailed and current information about these topics. Experimental models represent useful tools for studying the different stages of liver cancer and help to develop new pharmacologic treatments. Each model in vivo and in vitro has several characteristics and advantages to offer for the study of this disease. Finally, the main therapies approved for the treatment of HCC patients, first- and second-line therapies, are described in this review. We also describe a novel option, pirfenidone, which due to its pharmacological properties could be considered in the future as a therapeutic option for HCC treatment.

Figure 1

Main mechanisms involved in the development of hepatocarcinoma. The chronic exposure of hepatoxic agents causes the activation of the signaling pathways. YAZ-HIPPO receptors regulate the YAZ/TAZ transcriptional dimer genes involved in increased cell proliferation, mesenchymal epithelial transition, and metastasis. On the other hand, WNT/AXIN regulates the translocation of β-catenin to the nucleus, forming the YAZ/TAZ-β-catenin-TCF trimer activating profibrotic factors such as TGF-β and proliferative factors such as C-Myc, contributing to tumorigenesis and metastasis and inducing resistance to anticancer drugs. Similarly, NF−κB signaling pathway and the dimers IKK-α and IKK-β induce differential translocation of NF−κB P50/P65; on the one hand, an increase of P65 is induced to the nucleus while p50 is not translocated, causing an increase in cell proliferation, inhibition of apoptosis, transformation of malignant cells, and contributing to drug resistance. Finally, PPARγ bound to its ligands has a dual effect, inhibiting the signaling pathway of β-catenin and NF-κB, but by binding to the PPRE region it can increase the expression of genes involved in apoptosis, inhibition of cell proliferation, and metastasis. Acetylation and methylation of histones, regulated by the HATs/HDACs and HMTs/HDMs balance and DNA methylation regulated by DNMT1 activity, are the main epigenetic marks associated with tumorigenesis.