Three-Dimensional Spheroids as In Vitro Preclinical Models for Cancer Research

Pinto, Bárbara Fernandes; Henriques, Ana C.; Silva, Patrícia; Bousbaa, Hassan

doi:10.3390/pharmaceutics12121186

Cited by 230 publications

(240 citation statements)

References 269 publications

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“…To evaluate the feasibility of using 3D bioluminescence spheroids of HEK293 for improving the predictivity of the method [32], we developed a 3D cell-based assay to monitor homodimerization of the human androgen receptor in real time using the NanoBiT split-luciferase system. To the best of our knowledge, no PCA assays have been reported in spheroids or 3D cell models.…”

Section: Discussionmentioning

confidence: 99%

A Genetically Encoded Bioluminescence Intracellular Nanosensor for Androgen Receptor Activation Monitoring in 3D Cell Models

Calabretta

Lopreside

Montali

et al. 2021

Sensors

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In recent years, there has been an increasing demand for predictive and sensitive in vitro tools for drug discovery. Split complementation assays have the potential to enlarge the arsenal of in vitro tools for compound screening, with most of them relying on well-established reporter gene assays. In particular, ligand-induced complementation of split luciferases is emerging as a suitable approach for monitoring protein–protein interactions. We hereby report an intracellular nanosensor for the screening of compounds with androgenic activity based on a split NanoLuc reporter. We also confirm the suitability of using 3D spheroids of Human Embryonic Kidney (HEK-293) cells for upgrading the 2D cell-based assay. A limit of detection of 4 pM and a half maximal effective concentration (EC50) of 1.7 ± 0.3 nM were obtained for testosterone with HEK293 spheroids. This genetically encoded nanosensor also represents a new tool for real time imaging of the activation state of the androgen receptor, thus being suitable for analysing molecules with androgenic activity, including new drugs or endocrine disrupting molecules.

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Section: Discussionmentioning

confidence: 99%

A Genetically Encoded Bioluminescence Intracellular Nanosensor for Androgen Receptor Activation Monitoring in 3D Cell Models

Calabretta

Lopreside

Montali

et al. 2021

Sensors

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“…This "metabolic zonation" also mirrors different metabolic activities among tumour cells placed in different layers [31]. Thus, the unique cyto-architecture of spheroids mimics in vivo cell morphology, proliferation, oxygenation, nutrient uptake, waste excretion and drug uptake and allows the maintenance of cell-ECM interactions and signalling, thereby regulating molecular functions and cellular phenotypes [32][33][34][35]. The presence of ECM is crucial for controlling key parameters of spheroids, such as pH, oxygen and nutrient concentration gradient, cell morphology and size [36,37].…”

Section: Back To the Past: Restarting From 3d Spheroidsmentioning

confidence: 90%

Multicellular 3D Models to Study Tumour-Stroma Interactions

Colombo

Cattaneo

2021

IJMS

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Two-dimensional (2D) cell cultures have been the standard for many different applications, ranging from basic research to stem cell and cancer research to regenerative medicine, for most of the past century. Hence, almost all of our knowledge about fundamental biological processes has been provided by primary and established cell lines cultured in 2D monolayer. However, cells in tissues and organs do not exist as single entities, and life in multicellular organisms relies on the coordination of several cellular activities, which depend on cell–cell communication across different cell types and tissues. In addition, cells are embedded within a complex non-cellular structure known as the extracellular matrix (ECM), which anchors them in a three-dimensional (3D) formation. Likewise, tumour cells interact with their surrounding matrix and tissue, and the physical and biochemical properties of this microenvironment regulate cancer differentiation, proliferation, invasion, and metastasis. 2D models are unable to mimic the complex and dynamic interactions of the tumour microenvironment (TME) and ignore spatial cell–ECM and cell–cell interactions. Thus, multicellular 3D models are excellent tools to recapitulate in vitro the spatial dimension, cellular heterogeneity, and molecular networks of the TME. This review summarizes the biological significance of the cell–ECM and cell–cell interactions in the onset and progression of tumours and focuses on the requirement for these interactions to build up representative in vitro models for the study of the pathophysiology of cancer and for the design of more clinically relevant treatments.

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“…Amongst the three-dimensional models utilized, spherical models have shown the most significant promise for creating the appropriate microenvironment [ 132 ]. Three-dimensional spherical cell culture models allow for the cell–cell and cell-extracellular matrix interactions that are necessary to mimic the native TME [ 133 ]. Three-dimensional constructs that contain patient-derived cells may be propagated in vitro to mimic the native TME that exists in vivo [ 132 ].…”

Section: Three-dimensional Bioprinting: Applications To Neuroblastmentioning

confidence: 99%

Artificial Tumor Microenvironments in Neuroblastoma

Quinn

Beierle

2021

Cancers

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In the quest to advance neuroblastoma therapeutics, there is a need to have a deeper understanding of the tumor microenvironment (TME). From extracellular matrix proteins to tumor associated macrophages, the TME is a robust and diverse network functioning in symbiosis with the solid tumor. Herein, we review the major components of the TME including the extracellular matrix, cytokines, immune cells, and vasculature that support a more aggressive neuroblastoma phenotype and encumber current therapeutic interventions. Contemporary treatments for neuroblastoma are the result of traditional two-dimensional culture studies and in vivo models that have been translated to clinical trials. These pre-clinical studies are costly, time consuming, and neglect the study of cofounding factors such as the contributions of the TME. Three-dimensional (3D) bioprinting has become a novel approach to studying adult cancers and is just now incorporating portions of the TME and advancing to study pediatric solid. We review the methods of 3D bioprinting, how researchers have included TME pieces into the prints, and highlight present studies using neuroblastoma. Ultimately, incorporating the elements of the TME that affect neuroblastoma responses to therapy will improve the development of innovative and novel treatments. The use of 3D bioprinting to achieve this aim will prove useful in developing optimal therapies for children with neuroblastoma.

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Three-Dimensional Spheroids as In Vitro Preclinical Models for Cancer Research

Cited by 230 publications

References 269 publications

A Genetically Encoded Bioluminescence Intracellular Nanosensor for Androgen Receptor Activation Monitoring in 3D Cell Models

A Genetically Encoded Bioluminescence Intracellular Nanosensor for Androgen Receptor Activation Monitoring in 3D Cell Models

Multicellular 3D Models to Study Tumour-Stroma Interactions

Artificial Tumor Microenvironments in Neuroblastoma

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