Deciphering the underlying mechanism of liver diseases through utilization of multicellular hepatic spheroid models

Abstract

Hepatocellular carcinoma (HCC) is a very common form of cancer worldwide and is often fatal.Although the histopathology of HCC is characterized by metabolic pathophysiology, fibrosis, and cirrhosis, the focus of treatment has been on eliminating HCC. Recently, three-dimensional (3D) multicellular hepatic spheroid (MCHS) models have provided a) new therapeutic strategies for progressive fibrotic liver diseases, such as antifibrotic and anti-inflammatory drugs, b) molecular targets, and c) treatments for metabolic dysregulation. MCHS models provide a potent anti-cancer tool because they can mimic a) tumor complexity and heterogeneity, b) the 3D context of tumor cells, and c) the gradients of physiological parameters that are characteristic of tumors in vivo.However, the information provided by an MCTS model must always be considered in the context of tumors in vivo. This mini-review summarizes what is known about tumor HCC heterogeneity and complexity and the advances provided by MCHS models for innovations in drug development to combat liver diseases. clinical utility of drugs that proved effective in vitro is low. Also, assays of liver function, including cell polarization, albumin synthesis, bile secretion, and urea synthesis, are better when they are performed in three-dimensional (3D) cell cultures that more accurately reflect the normal context of liver cells (7). Similarly, 3D cells provide a better model system for cancer drug discovery.The interactions between the tumor and the tumor microenvironment (TME) play a critical role in cell differentiation, tumorigenesis, metastasis, and the efficacy of drug therapies. Therefore it was important to develop a 3D TME platform to discover new therapeutics for liver cancer drug discovery. These platforms are complex and expensive to produce; however, the recently developed multicellular tumor spheroid (MCTS) models provide a new platform for highthroughput screening (HTS) of drugs to treat a variety of diseases, including cancers and infections.The development of 3D multicellular hepatic spheroid (MCHS) models has had a major impact on drug discovery and the identification of novel targets for the treatment of HCC and fibrosis. MCHS models should greatly increase the number of potential new drugs to treat HCC and reduce the time to drug discovery.In this review, we describe the influence of components of the TME on tumorigenesis, fibrogenesis, and chemoresistance in HCC, as well as advanced strategies that exploit 3D multicellular spheroid models to identify novel cancer targets and therapeutics.