3D tumor models: History, advances and future perspectives
Abstract
Evaluation of cancer therapeutics by utilizing 3D tumor models, before clinical studies, could be more advantageous than conventional 2D tumor models (monolayer cultures). The 3D systems mimic the tumor microenvironment more closely than 2D systems. The following review discusses the various 3D tumor models present today with the advantages and limitations of each. 3D tumor models replicate the elements of a tumor microenvironment such as hypoxia, necrosis, angiogenesis and cell adhesion. The review introduces application of techniques such as microfluidics, imaging and tissue engineering to improve the 3D tumor models. Despite their tremendous potential to better screen chemotherapeutics, 3D tumor models still have a long way to go before they are used commonly as in vitro tumor models in pharmaceutical industrial research.
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Spheroids can incorporate non-tumor cells to mimic tumor-stroma crosstalk.
“Spheroids exhibit spatially organized regions of proliferation, quiescence, and hypoxia, and can incorporate non-tumor cells to mimic tumor–stroma crosstalk.”
From Modeling Tumor Microenvironment Complexity In Vitro: Spheroids as Physiologically Relevant Tumor Models and Strategies for Their Analysis (2025) · cites this paper as [101]
Drug efficacy within a tumor mass is frequently inversely correlated with the distance from the tumor periphery.
“Drug efficacy within a tumor mass is frequently observed to be inversely correlated with the distance from the tumor periphery [101].”
From Modeling Tumor Microenvironment Complexity In Vitro: Spheroids as Physiologically Relevant Tumor Models and Strategies for Their Analysis (2025) · cites this paper as [101]
These interactions are absent in monolayers but are necessary for recapitulating drug responses observed in vivo.
“These interactions are absent in monolayers but are necessary for recapitulating drug responses observed in vivo [101,186].”
From Modeling Tumor Microenvironment Complexity In Vitro: Spheroids as Physiologically Relevant Tumor Models and Strategies for Their Analysis (2025) · cites this paper as [101]
Spheroid models can be co-cultured with stromal elements such as fibroblasts, endothelial cells, or immune cells, permitting reconstitution of cell-cell and cell-ECM interactions essential for modeling tumor-stroma crosstalk, which governs survival signaling, drug resistance, and cell migration.
“Importantly, spheroid models can be co-cultured with stromal elements such as fibroblasts, endothelial cells, or immune cells. This permits the reconstitution of cell–cell and cell–ECM interactions that are essential for modeling tumor–stroma crosstalk, which governs processes such as survival signaling, drug resistance, and cell migration (Figure 2).”
From Modeling Tumor Microenvironment Complexity In Vitro: Spheroids as Physiologically Relevant Tumor Models and Strategies for Their Analysis (2025) · cites this paper as [101]
Spheroids have a distinct spatial organization that reflects intratumoral gradients observed in solid tumors.
“Spheroids are characterized by a distinct spatial organization that reflects intratumoral gradients observed in solid tumors [101,184].”
From Modeling Tumor Microenvironment Complexity In Vitro: Spheroids as Physiologically Relevant Tumor Models and Strategies for Their Analysis (2025) · cites this paper as [101]
Cells in the central core of a spheroid exist in a hypoxic state.
“those in the central core exist in a hypoxic state [101,184,186,187]”
From Modeling Tumor Microenvironment Complexity In Vitro: Spheroids as Physiologically Relevant Tumor Models and Strategies for Their Analysis (2025) · cites this paper as [101]
Cells in the intermediate zone of a spheroid are often senescent.
“cells located in the intermediate zone are often senescent”
From Modeling Tumor Microenvironment Complexity In Vitro: Spheroids as Physiologically Relevant Tumor Models and Strategies for Their Analysis (2025) · cites this paper as [101]
Spheroids allow for the evaluation of drug penetration, metabolic adaptation, and regional sensitivity within a tumor-like context.
“As a result, spheroids allow for the evaluation of drug penetration, metabolic adaptation, and regional sensitivity within a tumor-like context [101,186].”
From Modeling Tumor Microenvironment Complexity In Vitro: Spheroids as Physiologically Relevant Tumor Models and Strategies for Their Analysis (2025) · cites this paper as [101]
Cells in the outermost layer of a spheroid are typically highly proliferative due to proximity to nutrients and oxygen.
“Cells in the outermost layer of the spheroid are typically highly proliferative due to their proximity to nutrients and oxygen.”
From Modeling Tumor Microenvironment Complexity In Vitro: Spheroids as Physiologically Relevant Tumor Models and Strategies for Their Analysis (2025) · cites this paper as [101]
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- Authors
- Benien, P., & Swami, A.
- Affiliations
- Massachusetts College of Pharmacy and Health Sciences (US)
- Brigham and Women's Hospital (US)
- ORCID
- Benien, Parul
- Venue
- Future Oncology
- Publisher
- Informa UK Limited
- Published
- 2014-05
- Volume
- 10
- Issue
- 7
- Pages
- 1311-1327
- ISSN
- 1479-6694 (ISSN-L)
- 1744-8301
- OpenAlex
- W2144499341
- Cited by
- 208
- References
- 135
- Citations by year
- 2026: 7 · 2025: 14 · 2024: 22 · 2023: 21 · 2022: 26 · 2021: 35 · 2020: 24 · 2019: 16 · 2018: 13 · 2017: 12 · 2016: 11 · 2015: 7
- FWCI
- 0.86
- Type
- journal article
- Language
- en
- Open access
- closed
- Locations
- Future Oncology (publishedVersion)
- PubMed (publishedVersion)
- Topics
- Physical Sciences › Engineering › Biomedical Engineering › 3D Printing in Biomedical Research
- Health Sciences › Medicine › Oncology › Cancer Cells and Metastasis
- Physical Sciences › Mathematics › Modeling and Simulation › Mathematical Biology Tumor Growth
- Keywords
- 3D tumor models, tumor microenvironment, anticancer drug screening, monolayer culture, hypoxia, tumor necrosis, angiogenesis, cell adhesion, microfluidics, in vitro imaging, tissue engineering
- MeSH terms
- Animals, Cell Adhesion, Diagnostic Imaging, Humans, Models, Biological, Neoplasms, Tissue Engineering, Microfluidics, Tumor Microenvironment
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