Abstract
Primary liver cancer, consisting predominantly of hepatocellular carcinoma (HCC) and cholangiocarcinoma (CCA), remains one of the most lethal malignancies worldwide. This high malignancy is related to the complex and dynamic interactions between tumour cells, stromal cells and the extracellular environment. Novel in vitro models that can recapitulate the tumour are essential in increasing our understanding of liver cancer. Herein, primary liver cancer-derived organoids have opened up new avenues due to their patient-specificity, self-organizing ability and potential recapitulation of many of the tumour properties. Organoids are solely of epithelial origin, but incorporation into co-culture models can enable the investigation of the cellular component of the tumour microenvironment. However, the extracellular component also plays a vital role in cancer progression and representation is lacking within current in vitro models. In this review, organoid technology is discussed in the context of liver cancer models through comparisons to other cell culture systems. In addition, the role of the tumour extracellular environment in primary liver cancer will be highlighted with an emphasis on its importance in in vitro modelling. Converging novel organoid-based models with models incorporating the native tumour microenvironment could lead to experimental models that can better recapitulate liver tumours in vivo.
Highlights
Primary liver cancer (PLC) is the second leading cause of cancer mortality worldwide, with a steady increase in incidence over the last few years [1,2]
PLC compromises a heterogeneous group of tumours, the most common subtypes including hepatocellular carcinoma (HCC) and cholangiocarcinoma (CCA)
Each subtype vastly differs in its clinical presentation and associated treatment regimen, and they are relatively easy to distinguish, the plethora of subtypes in PLC makes it a very complex cancer to tackle [11,12]. distal cholangiocarcinoma (dCCA) is beyond the scope of this manuscript because it is not PLC
Summary
Primary liver cancer (PLC) is the second leading cause of cancer mortality worldwide, with a steady increase in incidence over the last few years [1,2]. One pertinent cause of the lack of effective treatments in liver cancer is the limited number of reproducible, reliable models that are able to faithfully recapitulate the complex in vivo situation. Mouse disease models and two-dimensional (2D) cell line cultures have historically been important pillars for preclinical development of cancer therapeutics. They have enabled deeper insights into cancer biology and tumorigenesis, their characteristics contain inherent limitations towards their overall applicability. Animal models and their relevance in PLC have been extensively reviewed elsewhere [24,25,26,27] and is beyond the scope of this review. We highlight the significance of the extracellular environment in the development of PLC, and argue for the potential benefit of incorporating the extracellular environment into future in vitro models
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