Abstract
Today, innovative three-dimensional (3D) cell culture models have been proposed as viable and biomimetic alternatives for initial drug screening, allowing the improvement of the efficiency of drug development. These models are gaining popularity, given their ability to reproduce key aspects of the tumor microenvironment, concerning the 3D tumor architecture as well as the interactions of tumor cells with the extracellular matrix and surrounding non-tumor cells. The development of accurate 3D models may become beneficial to decrease the use of laboratory animals in scientific research, in accordance with the European Union's regulation on the 3R rule (Replacement, Reduction, Refinement). This review focuses on the impact of 3D cell culture models on cancer research, discussing their advantages, limitations, and compatibility with high-throughput screenings and automated systems. An insight is also given on the adequacy of the available readouts for the interpretation of the data obtained from the 3D cell culture models. Importantly, we also emphasize the need for the incorporation of additional and complementary microenvironment elements on the design of 3D cell culture models, towards improved predictive value of drug efficacy.
Highlights
The scientific community and the pharmaceutical industry have been investing in the development of novel antitumor drugs, which have to be evaluated using various in vitro and in vivo assays
3D tumor sphere models can be divided into four types, which differ in terms of culture methods and sphere biology: multicellular tumor spheroids (MCTS), tumorospheres, tissue-derived tumor spheres (TDTS), and organotypic multicellular spheres (OMS)
Live cell imaging of spheroids can be achieved through time-lapse microscopy. This technique has been used in several studies such as: (i) to visualize stem cell activity in pancreatic cancer expansion by direct genetic lineage tracing with a dual-recombinase system [125]; (ii) to assess the role of cancer-associated fibroblasts (CAFs) in the migration of epithelial tumor cells [126] and endometrial tumor cells [127]; and (iii) to monitor invasion and metastasis of fluorescently labeled cancer cells [128]
Summary
The scientific community and the pharmaceutical industry have been investing in the development of novel antitumor drugs, which have to be evaluated using various in vitro and in vivo assays These assays are essential for the preclinical screening of the drug development process, and support the transition of the best-performing compounds for human clinical trials [1]. The poor clinical performance of new drugs is possibly explained by the low correlation of the preclinical in vitro and in vivo data with the results from the clinical trials [6] This is a consequence of the lack of disease-relevant preclinical models able to recreate the physiopathology of the tumor and recapitulate the tumor complexity regarding the matrix microenvironment as well as the interactions between tumor cells and the surrounding niche [7,8]. We summarize the 3D tumor models available for drug screening, the challenges and limitations of these models, and the most adequate readouts and their potential to extract predictive drug response data
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