3D Cell Cultures as Prospective Models to Study Extracellular Vesicles in Cancer

SIMPLE SUMMARY: 3D cell cultures are a qualitative improvement in cancer research because these models preserve cancer physiological characteristics better than traditional bi-dimensional cultures. Moreover, they facilitate the study of complex 3D interactions using extracellular matrices and the co-culture of different cell types. In this manner, the cells can contact themselves in a fully physiological but also controlled arrangement. In the context of tumor interactions, extracellular vesicles are essential in number of key aspects in oncology: as major interactors with extracellular matrix, as cell-to-cell messengers, as carriers of diagnostic-valuable biomarkers, and as target-specific treatment-deliver agents. The present article aims to discuss the findings achieved using 3D culture models in oncology. We further review the involvement of extracellular vesicles in the pathogenesis of cancer as well as their potential use in diagnostics and therapeutics. ABSTRACT: The improvement of culturing techniques to model the environment and physiological conditions surrounding tumors has also been applied to the study of extracellular vesicles (EVs) in cancer research. EVs role is not only limited to cell-to-cell communication in tumor physiology, they are also a promising source of biomarkers, and a tool to deliver drugs and induce antitumoral activity. In the present review, we have addressed the improvements achieved by using 3D culture models to evaluate the role of EVs in tumor progression and the potential applications of EVs in diagnostics and therapeutics. The most employed assays are gel-based spheroids, often utilized to examine the cell invasion rate and angiogenesis markers upon EVs treatment. To study EVs as drug carriers, a more complex multicellular cultures and organoids from cancer stem cell populations have been developed. Such strategies provide a closer response to in vivo physiology observed responses. They are also the best models to understand the complex interactions between different populations of cells and the extracellular matrix, in which tumor-derived EVs modify epithelial or mesenchymal cells to become protumor agents. Finally, the growth of cells in 3D bioreactor-like systems is appointed as the best approach to industrial EVs production, a necessary step toward clinical translation of EVs-based therapy.