Three-Dimensional Cell Culture Models of Hepatocellular Carcinoma - a Review

Three-dimensional (3D) cell culture studies are becoming extremely common because of their capability to mimic tumor architecture, such as cell-cell and cell-ECM interactions, more efficiently than 2D monolayer systems. These interactions have important roles in defining the tumor cell behaviors, such as proliferation, differentiation, and most importantly, tumor drug response.

This review aims to provide an overview of the methods for 3D tumor spheroid formation to model human tumors, specifically concentrated on studies using hepatocellular carcinoma (HCC) cells.

We obtained information from previously published articles. In this review, there is discussion of the scaffold and non-scaffold-based approaches, including hanging drop, bioreactors and 3D bioprinting.

The mimicking of the tumor microenvironment (TME) as tumor spheroids could provide a valuable platform for studying tumor biology. Multicellular tumor spheroids are self-assembled cultures of mixed cells (tumor and stromal cells) organized in a 3D arrangement. These spheroids closely mimic the main features of human solid tumors, such as structural organization, central hypoxia, and overall oxygen and nutrient gradients. Hepatocellular carcinoma (HCC) is the most common liver malignancy, and most difficult to overcome because of its drug resistance and tumor heterogeneity. In order to mimic this highly heterogeneous environment, 3D cell culture systems are needed.