Experimental Models of Hepatocellular Carcinoma-A Preclinical Perspective

Abstract

Hepatocellular carcinoma (HCC), the most frequent form of primary liver carcinoma, is a heterogenous and complex tumor type with increased incidence, poor prognosis, and high mortality. The actual therapeutic arsenal is narrow and poorly effective, rendering this disease a global health concern. Although considerable progress has been made in terms of understanding the pathogenesis, molecular mechanisms, genetics, and therapeutical approaches, several facets of human HCC remain undiscovered. A valuable and prompt approach to acquire further knowledge about the unrevealed aspects of HCC and novel therapeutic candidates is represented by the application of experimental models. Experimental models (in vivo and in vitro 2D and 3D models) are considered reliable tools to gather data for clinical usability. This review offers an overview of the currently available preclinical models frequently applied for the study of hepatocellular carcinoma in terms of initiation, development, and progression, as well as for the discovery of efficient treatments, highlighting the advantages and the limitations of each model. Furthermore, we also focus on the role played by computational studies (in silico models and artificial intelligence-based prediction models) as promising novel tools in liver cancer research.

Keywords: 2D cell lines; 3D tumor spheroids; artificial intelligence algorithms; hepatocellular carcinoma; in silico; machine learning; mouse models; organ-on-a-chip; organoids.

Figure 1

The multistep process involved in HCC development. This image contains Servier Medical Art elements, which are licensed under a Creative Commons Attribution 3.0 Unported License; https://smart.servier.com, accessed on 20 June 2021. The following abbreviations are used in the figure: HBV—hepatitis B virus; HCV—hepatitis C virus; NK—natural killer cells; TNK—natural killer T cells; KC—Kupffer cells; ROS—reactive oxygen species; TERT—telomerase reverse transcriptase; TP53—tumor protein 53; YAP-HIPPO—Yes-Associated Protein-Hippo Pathway, PPARγ—peroxisome proliferator-activated receptor gamma; FGF—fibroblast growth factor.

Figure 2

Schematic overview of the preclinical models of HCC discussed in the present study. This image contains Servier Medical Art elements, which are licensed under a Creative Commons Attribution 3.0 Unported License; https://smart.servier.com accessed on 20 June 2021.

Figure 3

Overview of the in vitro established models for HCC. This image contains Servier Medical Art elements, which are licensed under a Creative Commons Attribution 3.0 Unported License; https://smart.servier.com accessed on 20 June 2021.

Figure 4

Morphological aspect of some of the most frequently used cell lines as in vitro models for HCC of human (HepG2, HepaRG, and C3A) and murine (Hepa1-6) origin. The scale bar represents 50 µM.

Figure 5

Chemically induced and xenograft mouse models of HCC. This image contains Servier Medical Art elements, which are licensed under a Creative Commons Attribution 3.0 Unported License; https://smart.servier.com, accessed on 20 June 2021.