Abstract
Simple SummaryHepatocellular carcinoma (HCC) is a highly incident and deadly malignant neoplasia, and only a few anti-HCC drugs are currently available. Thus, the development of HCC models has become essential for both basic and translational research, improving the understanding of HCC pathophysiology and molecular landscape. The present paper provides a state-of-the-art overview of in vivo and in vitro models used for translational modeling of HCC, focusing on their molecular hallmarks. Our paper depicts the key features, advantages and disadvantages of the main bioassays available, shedding light on standard HCC model choice.Hepatocellular carcinoma (HCC) is the sixth most common cancer worldwide and the third leading cause of cancer-related death globally. HCC is a complex multistep disease and usually emerges in the setting of chronic liver diseases. The molecular pathogenesis of HCC varies according to the etiology, mainly caused by chronic hepatitis B and C virus infections, chronic alcohol consumption, aflatoxin-contaminated food, and non-alcoholic fatty liver disease associated with metabolic syndrome or diabetes mellitus. The establishment of HCC models has become essential for both basic and translational research to improve our understanding of the pathophysiology and unravel new molecular drivers of this disease. The ideal model should recapitulate key events observed during hepatocarcinogenesis and HCC progression in view of establishing effective diagnostic and therapeutic strategies to be translated into clinical practice. Despite considerable efforts currently devoted to liver cancer research, only a few anti-HCC drugs are available, and patient prognosis and survival are still poor. The present paper provides a state-of-the-art overview of in vivo and in vitro models used for translational modeling of HCC with a specific focus on their key molecular hallmarks.
Highlights
Considering the current myriad of Hepatocellular carcinoma (HCC) models in the literature, we provide a comprehensive overview of the main in vivo and in vitro bioassays applied for HCC modelling, depicting their key molecular hallmarks
The difference with 3D spheroid models is that organoids contain various tissue-specific cells, which are all developed from the stem cell starting material through in vivo-like processes mediated by the provided extracellular matrix (ECM), namely Matrigel® [367,368]
The use of syngeneic and xenographic models has been widely used in studies of the combination of drugs used in HCC therapy, such as sorafenib, and drugs that enhance its effects by reducing tumor resistance to treatment [272,385,386,387], in immunotherapeutic studies [273,388,389,390] and new drug trials [391,392]
Summary
Mainly represented by hepatocellular carcinoma (HCC), accounted for about 840,000 incident cases and 780,000 deaths in 2018 [1]. Excessive and chronic alcohol intake leading to alcoholic liver disease (ALD) is another important risk factor associated with 26% of HCC cases, standing only behind HBV infection. Since some authors consider chronic viral infections as the most important risk factors for HCC development, HBV/HCV-related HCC attributable fraction may in part explain the geographical disparity feature. Another important epidemiological feature is the marked male disparity (two to three-fold higher in males), whose mechanisms may involve the predominance of risk factors in men and the promoting/protective roles of sex hormones [2]. The influence of dietary factors on HCC emergence is not fully understood, but many epidemiological studies point to a marked protective effect of coffee consumption [8,9]
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