3D Cancer Models: Depicting Cellular Crosstalk within the Tumour Microenvironment

Abstract

The tumour microenvironment plays a critical role in tumour progression and drug resistance processes. Non-malignant cell players, such as fibroblasts, endothelial cells, immune cells and others, interact with each other and with the tumour cells, shaping the disease. Though the role of each cell type and cell communication mechanisms have been progressively studied, the complexity of this cellular network and its role in disease mechanism and therapeutic response are still being unveiled. Animal models have been mainly used, as they can represent systemic interactions and conditions, though they face recognized limitations in translational potential due to interspecies differences. In vitro 3D cancer models can surpass these limitations, by incorporating human cells, including patient-derived ones, and allowing a range of experimental designs with precise control of each tumour microenvironment element. We summarize the role of each tumour microenvironment component and review studies proposing 3D co-culture strategies of tumour cells and non-malignant cell components. Moreover, we discuss the potential of these modelling approaches to uncover potential therapeutic targets in the tumour microenvironment and assess therapeutic efficacy, current bottlenecks and perspectives.

An Optimized Workflow for the Analysis of Metabolic Fluxes in Cancer Spheroids Using Seahorse Technology

“…As single-cell technologies [ 47 , 48 , 49 , 50 , 51 , 52 , 53 ] progress, it will also be possible to assess the role of cell-to-cell heterogeneity in metabolic properties and drug interactions. Extending the analysis to more cancer cell lines and primary cultures derived from different cancer types (e.g., colon, gastric, lung, skin, ovarian), to heterotypic spheroids including different cell types [ 54 , 55 ]—exploring a broader interval of spheroid dimensions and/or incubation times—may provide an even more complex picture. Finally, 3D structures formed from patient-derived cells [ 33 , 34 , 35 ] will provide an appropriate platform for designing personalized (multi)drug therapies.…”

The Functional Role of Extracellular Matrix Proteins in Cancer

“…Engineering approaches can be used to examine the effects of tumor-associated alterations in the ECM or ECM composition [ 378 ]. To explore the molecular mechanisms of tumor progression and metastasis, 3D cancer models can be used for the imitation of key steps of cancer dissemination (invasion, intravasation and angiogenesis) [ 379 , 380 ]. The decellularized matrix allows a comprehensive study of the ECM role in the regulation of cancer cell behavior [ 381 , 382 ].…”

Ex Vivo Modeling of Human Neuroendocrine Tumors in Tissue Surrogates

“…This trade-off may be particularly impactful in the case of slow-growing cell populations such as those of neuroendocrine cancers. These tradeoffs are largely responsible for Matrigel’s continued popularity in cancer research particularly, although advances in synthetic scaffolds will likely replace Matrigel in the future ( 81 , 82 ). Among the trade-offs of using Matrigel is the nature of its biological derivation.…”