Review: Challenges of In Vitro CAF Modelling in Liver Cancers

Abstract

Primary and secondary liver cancer are the third cause of death in the world, and as the incidence is increasing, liver cancer represents a global health burden. Current treatment strategies are insufficient to permanently cure patients from this devastating disease, and therefore other approaches are under investigation. The importance of cancer-associated fibroblasts (CAFs) in the tumour microenvironment is evident, and many pre-clinical studies have shown increased tumour aggressiveness in the presence of CAFs. However, it remains unclear how hepatic stellate cells are triggered by the tumour to become CAFs and how the recently described CAF subtypes originate and orchestrate pro-tumoural effects. Specialized in vitro systems will be needed to address these questions. In this review, we present the currently used in vitro models to study CAFs in primary and secondary liver cancer and highlight the trend from using oversimplified 2D culture systems to more complex 3D models. Relatively few studies report on the impact of cancer (sub)types on CAFs and the tumour microenvironment, and most studies investigated the impact of secreted factors due to the nature of the models.

Interactions between cancer-associated fibroblasts and T-cells: functional crosstalk with targeting and biomarker potential

“…A century after Virchow, near the end of the 20th century, the concept of cancer-associated fibroblasts (CAFs) emerged as it has been recognized that tumour stroma could play a pivotal role in cancer biology ( 4 ). It has been thought that CAFs are a uniform cell population, characterized by the expression of vimentin, alpha smooth muscle actin (aSMA) and fibroblast activating protein (FAP) ( 5 ). Today it is an accepted truth that the stromal compartment of solid tumours contains a highly heterogeneous CAF population, the most abundant and one of the most important components of the tumour microenvironment (TME) ( 6 – 9 ).…”

In vitro vascularized immunocompetent patient-derived model to test cancer therapies

“… 18 However, some limitations were reported for integrating CAFs in the 3D model, particularly functional heterogeneity, strong pro-tumorigenic effects, and high-immunosuppressive effects. 19 , 20 This might negatively impact the prediction of response to treatment, and we thus explored another approach based on a vascularized PDT model.…”