Modeling the Role of Cancer-Associated Fibroblasts in Tumor Cell Invasion

Abstract

The major cause of cancer-related deaths can be attributed to the metastatic spread of tumor cells—a dynamic and complex multi-step process beginning with tumor cells acquiring an invasive phenotype to allow them to travel through the blood and lymphatic vessels to ultimately seed at a secondary site. Over the years, various in vitro models have been used to characterize specific steps in the cascade to collectively begin providing a clearer picture of the puzzle of metastasis. With the discovery of the TME’s supporting role in activating tumor cell invasion and metastasis, these models have evolved in parallel to accommodate features of the TME and to observe its interactions with tumor cells. In particular, CAFs that reside in reactive tumor stroma have been shown to play a substantial pro-invasive role through their matrix-modifying functions; accordingly, this warranted further investigation with the development and use of invasion assays that could include these stromal cells. This review explores the growing toolbox of assays used to study tumor cell invasion, from the simple beginnings of a tumor cell and extracellular matrix set-up to the advent of models that aim to more closely recapitulate the interplay between tumor cells, CAFs and the extracellular matrix. These models will prove to be invaluable tools to help tease out the intricacies of tumor cell invasion.

Exosomal cargos-mediated metabolic reprogramming in tumor microenvironment

“…Up-regulated FAP, FGF2 and α-SMA can promote the activation and heterogeneity of CAFs [28]. Activated CAFs contribute to the remodeling of ECM, which is conducive to tumor cell migration, invasion and treatment resistance [29]. In addition, the growth factor and chemokine secreted by CAFs are conducive to angiogenesis and the recruitment of immune cells [25,30].…”

Crosstalk between colorectal cancer cells and cancer-associated fibroblasts in the tumor microenvironment mediated by exosomal noncoding RNAs

“…The extensive, multi-level interactions between tumor cells and mesenchymal cells provide TME to support tumor survival, growth, and metastasis ( 134 – 136 ). CAFs, one of the most copious mesenchymal cells in TME, are in an activated state and are phenotypically and functionally altered to interact with immune cells and cancer cells through multiple signaling pathways, including autocrine and paracrine, to form complex molecular networks and perform their biological functions ( 137 , 138 ).…”

Heterotypic tumor spheroids: a platform for nanomedicine evaluation

“…Tumor invasion is a critical phase in tumor metastasis since cancerous cells must leave the primary tumor to invade their surroundings or enter circulatory systems [ 37 ]. Extensive research has shown that the invasive potential of tumor cells is correlated with their cellular/nuclear morphology and TME.…”

“…Hanging drop and liquid overlay techniques have been extensively used for co-culture model development among other spheroid fabrication methods (Fig. 7 B) [ 36 , 37 ]. The hanging drop method is a simple technique for spheroid formation, where flipping a universal 96-well plate can easily prepare spheroids without require any special instruments.…”