Hepatocellular-Carcinoma-Derived Organoids: Innovation in Cancer Research

Abstract

Hepatocellular carcinomas (HCCs) are highly heterogeneous malignancies. They are characterized by a peculiar tumor microenvironment and dense vascularization. The importance of signaling between immune cells, endothelial cells, and tumor cells leads to the difficult recapitulation of a reliable in vitro HCC model using the conventional two-dimensional cell cultures. The advent of three-dimensional organoid tumor technology has revolutionized our understanding of the pathogenesis and progression of several malignancies by faithfully replicating the original cancer genomic, epigenomic, and microenvironmental landscape. Organoids more closely mimic the in vivo environment and cell interactions, replicating factors such as the spatial organization of cell surface receptors and gene expression, and will probably become an important tool in the choice of therapies and the evaluation of tumor response to treatments. This review aimed to describe the ongoing and potential applications of organoids as an in vitro model for the study of HCC development, its interaction with the host's immunity, the analysis of drug sensitivity tests, and the current limits in this field.

Keywords: drug sensitivity; hepatocellular carcinoma; liver organoids; tumor microenvironment.

Figure 1

Clinical applications of HCC-derived organoids. Hepatocellular carcinoma liver organoids’ current applications: Considering the complexity of these three-dimensional models, organoids are increasingly used in cancer research in order to mimic real-life cell-to-cell interactions in tumors. Concerning hepatocellular carcinoma, organoids are useful for the in vitro and in vivo study of cancer cell and cancer stem cell behavior, to evaluate cell signaling, and to unravel the specific alterations in inflammatory, metabolic, and proliferative pathways that lead to tumorigenesis, growth maintenance, immune suppression, angiogenesis, and the mechanisms of resistance and tumor escape through the replication and analysis of the tumor microenvironment. Organoids can also be used for drug screening, for investigating the key drivers of HCC development, and to identify markers of aggressiveness.