Heterotypic tumor spheroids: a platform for nanomedicine evaluation

Abstract

Nanomedicine has emerged as a promising therapeutic approach, but its translation to the clinic has been hindered by the lack of cellular models to anticipate how tumor cells will respond to therapy. Three-dimensional (3D) cell culture models are thought to more accurately recapitulate key features of primary tumors than two-dimensional (2D) cultures. Heterotypic 3D tumor spheroids, composed of multiple cell types, have become more popular than homotypic spheroids, which consist of a single cell type, as a superior model for mimicking in vivo tumor heterogeneity and physiology. The stromal interactions demonstrated in heterotypic 3D tumor spheroids can affect various aspects, including response to therapy, cancer progression, nanomedicine penetration, and drug resistance. Accordingly, to design more effective anticancer nanomedicinal therapeutics, not only tumor cells but also stromal cells (e.g., fibroblasts and immune cells) should be considered to create a more physiologically relevant in vivo microenvironment. This review aims to demonstrate current knowledge of heterotypic 3D tumor spheroids in cancer research, to illustrate current advances in utilizing these tumor models as a novel and versatile platform for in vitro evaluation of nanomedicine-based therapeutics in cancer research, and to discuss challenges, guidelines, and future directions in this field. Graphical Abstract

Advances in screening hyperthermic nanomedicines in 3D tumor models

“… 169–172 These models can be comprised of only one cell type (monotypic) or several cell types (heterotypic). 173,174 Heterotypic spheroids can be bioengineered with tunable cell density/size, and have been used to screen different types of candidate therapeutics. 174,175 Since heterotypic spheroids better mimic the cellular complexity of native tumors, these are considered more clinically relevant models.…”

In Vitro Models of Head and Neck Cancer: From Primitive to Most Advanced

“…To reproduce the heterogeneous composition of tumor tissue, it was proposed to use heterospheroids (or heterotypic spheroids, co-culture spheroids) [73], consisting of a well-characterized immortalized line and an additional cellular component usually associated with tumor cells in vivo, for example, immune cells, fibroblasts, or endothelial cells. Currently, there is active research work using heterospheroids; however, in most cases they are used to model liver and pancreatic tumors, and only a few studies have been performed with heterospheroids based on HNSCC tumor lines (Table 2).…”

Architectural organization and molecular profiling of 3D cancer heterospheroids and their application in drug testing

“…During the last decade, several studies have focused on developing more complex cancer spheroids, where different components of the TME are included. Thus, fibroblasts, endothelial and immune cells have been introduced to the cancer cells grown in 3D structures ( 11 ). In particular, cancer cell lines grown in co-culture with fibroblasts as 3D hetero-cellular spheroids (heterospheroids) represent interesting novel models for drug testing ( 11 – 13 ).…”

“…Thus, fibroblasts, endothelial and immune cells have been introduced to the cancer cells grown in 3D structures ( 11 ). In particular, cancer cell lines grown in co-culture with fibroblasts as 3D hetero-cellular spheroids (heterospheroids) represent interesting novel models for drug testing ( 11 – 13 ). A variety of heterospheroids, a subgroup of MCTS ( 13 ), have been developed and comprise human cancer cell lines originating from e.g.…”