Embedded Spheroids as Models of the Cancer Microenvironment.

To more accurately study the complex mechanisms behind cancer invasion, progression, and response to treatment, researchers require models that replicate both the multicellular nature and 3D stromal environment present in an in vivo tumor. Multicellular aggregates (i.e., spheroids) embedded in an extracellular matrix mimic are a prevalent model. Recently, quantitative metrics that fully utilize the capability of spheroids are described along with conventional experiments, such as invasion into a matrix, to provide additional details and insights into the underlying cancer biology. The review begins with a discussion of the salient features of the tumor microenvironment, introduces the early work on non-embedded spheroids as tumor models, and then concentrates on the successes achieved with the study of embedded spheroids. Examples of studies include cell movement, drug response, tumor cellular heterogeneity, stromal effects, and cancer progression. Additionally, new methodologies and those borrowed from other research fields (e.g., vascularization and tissue engineering) are highlighted that expand the capability of spheroids to aid future users in designing their cancer-related experiments. The convergence of spheroid research among the various fields catalyzes new applications and leads to a natural synergy. Finally, the review concludes with a reflection and future perspectives for cancer spheroid research.