Bioengineering facets of the tumor microenvironment in 3D tumor models: insights into cellular, biophysical and biochemical interactions

Abstract

The hallmarks of cancer extend beyond genetic anomalies to encompass a sophisticated tumor microenvironment, involving interactions between cancer and non-cancer cells within a dynamic biophysical setting, influencing cancer progression. The tumor microenvironment is multifaceted, and it is increasingly clear that the interaction and interdependence of these different facets need to be better understood. Tissue engineering of 3D in vitro models of the tumor microenvironment provides an opportunity to study these interactions and their interdependence on cancer progression. Cancer metastasis still poses a major challenge, accounting for 90% of cancer-related deaths. This accentuates the critical need to establish patient-specific model systems that replicate tumor complexity at all stages of progression. Herein, we outline the latest advancements of in vitro 3D models of the tumor microenvironment and the different tools utilized to analyze such models. Henceforth, the interaction of the multifaceted tumor microenvironment can be elucidated using such sophisticated in vitro tools.

Keywords: 3D models; cancer; tissue engineering; tumor microenvironment; tumor‐stroma interaction.

Fig. 1

Schematic of the key component dictating the TME. Cellular components; cancer cells and stromal cells (fibroblasts, immune cells, mesenchymal stem cells, endothelial cells). Non‐cellular components include biophysical components: mechanical forces, tissue stiffness and geometry. The biophysical components dictate the formation of gradients of nutrients, oxygen and pH across different regions, which impact biochemical components including growth factors, enzymes, chemokines. Schematic generated using Servier Medical Art. TME, tumor microenvironment.

Fig. 2

Schematic of the multiple approaches taken to analyze 3D models. We start with general techniques and then show methods that provide details on spatial analysis. Specialized techniques can be modified to provide analysis for 3D tumor models, including the use of atomic force microscopy to measure tissue/matrix remodeling by cancer cells. Schematic generated using Servier Medical Art.