Advances in establishment and analysis of three-dimensional tumor spheroid-based functional assays for target validation and drug evaluation
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Background: There is overwhelming evidence that in vitro three-dimensional tumor cell cultures more accurately reflect the complex in vivo microenvironment than simple two-dimensional cell monolayers, not least with respect to gene expression profiles, signaling pathway activity and drug sensitivity. However, most currently available three-dimensional techniques are time consuming and/or lack reproducibility; thus standardized and rapid protocols are urgently needed. Results: To address this requirement, we have developed a versatile toolkit of reproducible three-dimensional tumor spheroid models for dynamic, automated, quantitative imaging and analysis that are compatible with routine high-throughput preclinical studies. Not only do these microplate methods measure three-dimensional tumor growth, but they have also been significantly enhanced to facilitate a range of functional assays exemplifying additional key hallmarks of cancer, namely cell motility and matrix invasion. Moreover, mutual tissue invasion and angiogenesis is accommodated by coculturing tumor spheroids with murine embryoid bodies within which angiogenic differentiation occurs. Highly malignant human tumor cells were selected to exemplify therapeutic effects of three specific molecularly-targeted agents: PI-103 (phosphatidylinositol-3-kinase (PI3K)-mammalian target of rapamycin (mTOR) inhibitor), 17-N-allylamino-17-demethoxygeldanamycin (17-AAG) (heat shock protein 90 (HSP90) inhibitor) and CCT130234 (in-house phospholipase C (PLC)γ inhibitor). Fully automated analysis using a Celigo cytometer was validated for tumor spheroid growth and invasion against standard image analysis techniques, with excellent reproducibility and significantly increased throughput. In addition, we discovered key differential sensitivities to targeted agents between two-dimensional and three-dimensional cultures, and also demonstrated enhanced potency of some agents against cell migration/invasion compared with proliferation, suggesting their preferential utility in metastatic disease. Conclusions: We have established and validated a suite of highly reproducible tumor microplate three-dimensional functional assays to enhance the biological relevance of early preclinical cancer studies. We believe these assays will increase the translational predictive value of in vitro drug evaluation studies and reduce the need for in vivo studies by more effective triaging of compounds.
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Three-dimensional multicellular tumor spheroids capture essential features of tumor architecture, stromal interactions, and microenvironmental resistance mechanisms.
“Three-dimensional multicellular tumor spheroids have emerged as more representative in vitro models that capture essential features of tumor architecture, stromal interactions, and microenvironmental resistance mechanisms.”
From Modeling Tumor Microenvironment Complexity In Vitro: Spheroids as Physiologically Relevant Tumor Models and Strategies for Their Analysis (2025) · cites this paper as [15]
The Background (page not available) says three-dimensional cultures better reflect tumor architecture and microenvironmental features. The Results (page not available) report that tumor cells were generally less drug-sensitive in three-dimensional culture, but offer reduced drug access and hypoxia-related effects as possible explanations rather than established resistance mechanisms. The Discussion (page not available) describes stromal-cell incorporation as a modification to spheroids, not a feature of spheroids generally. (LLM, conf=0.87)
Experimental — accuracy not yet measuredCommercial kits such as CellTiter-Glo® 3D and Cultrex® 3D viability assays are designed to enhance lysis efficiency and signal uniformity in spheroids.
“Commercial kits, such as CellTiter-Glo® 3D and Cultrex® 3D viability assays, are designed to enhance lysis efficiency and signal uniformity in spheroids [15,307].”
From Modeling Tumor Microenvironment Complexity In Vitro: Spheroids as Physiologically Relevant Tumor Models and Strategies for Their Analysis (2025) · cites this paper as [15]
The Methods (Cell viability assay; page unavailable) report using a CellTiter-Glo kit to measure spheroid viability, and the Results describe its luminescent measurements as reproducible. The paper does not identify the kit as CellTiter-Glo 3D, mention Cultrex 3D, or say either kit is designed to improve lysis efficiency or signal uniformity. (LLM, conf=0.84)
Experimental — accuracy not yet measuredScientists have been making an effort to develop standard and rapid protocols for using 3D cultures in drug screening.
“Scientists have been making an effort to develop standard and rapid protocols for using 3D cultures in drug screening. 71”
From Three-dimensional cell culture systems and their applications in drug discovery and cell-based biosensors (2014) · cites this paper as [71]
Formation of single large spheroids (>500 μm diameter) enables the formation of a hypoxic core, and drug, oxygen and metabolite gradients that mimic solid tumor physiology.
“Formation of single large spheroids (>500 μm diameter) enables the formation of a hypoxic core, and drug, oxygen and metabolite gradients that mimic solid tumor physiology (Vinci et al., 2012; Heredia-Soto et al., 2018).”
From Three-dimensional modelling of ovarian cancer: from cell lines to organoids for discovery and personalized medicine (2022) · cites this paper as Vinci et al., 2012
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- Authors
- Vinci, M., Gowan, S., Boxall, F., Patterson, L., Zimmermann, M., Court, W., Lomas, C., Mendiola, M., Hardisson, D., & Eccles, S. A.
- Affiliations
- Institute of Cancer Research (GB)
- Hospital Universitario La Paz (ES)
- Corresponding author
- Eccles, Suzanne A
- Venue
- BMC Biology
- Published
- 2012-03-22
- Volume
- 10
- Issue
- 1
- Pages
- 29-29
- ISSN
- 1741-7007 (ISSN-L)
- PMC
- PMC3349530
- OpenAlex
- W2000744297
- Cited by
- 1,024
- References
- 59
- Citations by year
- 2026: 56 · 2025: 74 · 2024: 63 · 2023: 79 · 2022: 81 · 2021: 86 · 2020: 99 · 2019: 86 · 2018: 82 · 2017: 86 · 2016: 82 · 2015: 58 · 2014: 51 · 2013: 34 · 2012: 6
- FWCI
- 23.56
- Type
- journal article
- Language
- en
- Open access
- gold
- doi.org
- Licence
- cc-by
- Locations
- BMC Biology (publishedVersion, cc-by)
- Europe PMC (PubMed Central) (publishedVersion, cc-by)
- PubMed Central (publishedVersion, cc-by)
- PubMed (publishedVersion)
- Tesis Doctorals en Xarxa (Consorci de Serveis Universitaris de Catalunya) (publishedVersion)
- LA Referencia (Red Federada de Repositorios Institucionales de Publicaciones Científicas) (acceptedVersion)
- DOAJ (DOAJ: Directory of Open Access Journals) (submittedVersion, cc-by-sa)
- Hispana (submittedVersion)
- Biblos-e Archivo (Universidad Autónoma de Madrid) (submittedVersion, public-domain)
- Funders
- Cancer Research UK (RD06/0020, 11566, C309/A8274)
- National Institute for Health and Care Research (RD06/0020)
- National Centre for the Replacement, Refinement and Reduction of Animals in Research (G1000121/1)
- Topics
- Health Sciences › Medicine › Oncology › Cancer Cells and Metastasis
- Physical Sciences › Engineering › Biomedical Engineering › 3D Printing in Biomedical Research
- Physical Sciences › Mathematics › Modeling and Simulation › Mathematical Biology Tumor Growth
- Keywords
- multicellular spheroids, automated image analysis, drug target validation, drug evaluation, cell motility, matrix invasion, angiogenesis, PI3K/mTOR inhibition, HSP90 inhibition, metastasis, tumor microenvironment
- MeSH terms
- Animals, Antineoplastic Agents, Cell Movement, Drug Evaluation, Furans, Models, Biological, Pyridines, Pyrimidines, Signal Transduction, Benzoquinones, HSP90 Heat-Shock Proteins, Cell Line, Tumor, Lactams, Macrocyclic, Cell Proliferation, Mice, Embryonic Stem Cells, Tumor Microenvironment
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