Three-dimensional culture systems in cancer research: Focus on tumor spheroid model

Nath, Sritama; Devi, Gayathri R.

doi:10.1016/j.pharmthera.2016.03.013

Cited by 920Cancer Cells and Metastasis3D Printing in Biomedical ResearchMathematical Biology Tumor Growth

Three-dimensional culture systems in cancer research: Focus on tumor spheroid model

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Nath, Sritama, Devi, Gayathri R.·2016·Pharmacology & Therapeutics

DOI 10.1016/j.pharmthera.2016.03.013PMC PMC4961208

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Abstract

Cancer cells propagated in three-dimensional (3D) culture systems exhibit physiologically relevant cell-cell and cell-matrix interactions, gene expression and signaling pathway profiles, heterogeneity and structural complexity that reflect in vivo tumors. In recent years, development of various 3D models has improved the study of host-tumor interaction and use of high-throughput screening platforms for anti-cancer drug discovery and development. This review attempts to summarize the various 3D culture systems, with an emphasis on the most well characterized and widely applied model - multicellular tumor spheroids. This review also highlights the various techniques to generate tumor spheroids, methods to characterize them, and its applicability in cancer research.

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The physiochemical gradient generally induces formation of three concentric zones on a spheroid: an anoxic core with necrotic cells, a middle hypoxic zone with low oxygen and nutrients, and an outer zone with highly proliferative cells.
“This physiochemical gradient generally induces the formation of three concentric zones on a spheroid -an anoxic core in the center containing necrotic cells, a middle hypoxic zone that has a low concentration of oxygen and nutrients, and an outer zone containing highly proliferative cells [53].”
From 3D In Vitro Model (R)evolution: Unveiling Tumor–Stroma Interactions (2021) · cites this paper as [53]
Section 2.3 (page unavailable) describes diffusion-related gradients in large multicellular tumor spheroids and three concentric regions: a necrotic core, a middle layer of viable quiescent cells, and a highly proliferative outer layer. It does not specifically characterize the core as anoxic or the middle layer as low in both oxygen and nutrients, and it limits the gradient description to large spheroids rather than spheroids generally. (LLM, conf=0.86)
Experimental — accuracy not yet measured
Cancer spheroids are arguably the simplest in vitro 3D tumor models.
“Cancer spheroids are arguably the simplest in vitro 3D tumor models [114,115].”
From The Tumor-on-Chip: Recent Advances in the Development of Microfluidic Systems to Recapitulate the Physiology of Solid Tumors (2019) · cites this paper as [114]
Section 2.3 identifies multicellular tumor spheroids as 3D cancer models that can be constructed from tumor cells alone, and the Concluding remarks call them widely used in vitro 3D models. Neither passage compares their simplicity with other models, so the claim that they are arguably the simplest is not established by this source. (LLM, conf=0.79)
Experimental — accuracy not yet measured
Various tumor spheroids have been fabricated by embedding cancer cells into protein-based hydrogels such as Matrigel, fibrin, and collagen as they incorporate specific cell-adhesive motifs and enzymatic-mediated matrix degradation beneficial to cell proliferation.
“Currently, various tumor spheroids have been fabricated by embedding cancer cells into protein‐based hydrogels such as Matrigel,[ 64 ] fibrin,[ 65 ] and collagen[ 66 ] as they incorporate specific cell‐adhesive motifs and enzymatic‐mediated matrix degradation which are beneficial to cell proliferation.”
From 3D Biomimetic Models to Reconstitute Tumor Microenvironment In Vitro: Spheroids, Organoids, and Tumor‐on‐a‐Chip (2023) · cites this paper as [66]
Split into 2 atoms — 0 confirmed, 2 partially supported, 0 disputed, 0 misattributed, 0 unverifiable. Expand the claim to see per-atom verdicts.
Experimental — accuracy not yet measured
Uniformity in size and homogeneity is an important aspect to consider to ensure that results are not influenced by these factors.
“An important aspect to consider is uniformity in size and homogeneity to ensure that the results are not in fl uenced by these factors [53].”
From 3D In Vitro Model (R)evolution: Unveiling Tumor–Stroma Interactions (2021) · cites this paper as [53]
Tumor cell spheroids are especially useful for studying cancers that form tumor embolus, as happens in inflammatory breast cancer.
“Tumor cell spheroids are especially useful for studying cancers that form tumor embolus, or a closely packed tumor cell cluster, as happens in in fl ammatory breast cancer [53].”
From 3D In Vitro Model (R)evolution: Unveiling Tumor–Stroma Interactions (2021) · cites this paper as [53]

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 [17]
Spheroids exhibit spatially organized regions of proliferation, quiescence, and hypoxia.
“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 [17]
Multicellular tumor spheroids provide a more physiologically relevant context for evaluating anticancer agents and delivery systems by mimicking the hierarchical structure, proliferation gradients, and stromal interactions found in native tumor tissues.
“By mimicking the hierarchical structure, proliferation gradients, and stromal interactions found in native tumor tissues, spheroids provide a more physiologically relevant context for evaluating anticancer agents and delivery systems [16,17].”
From Modeling Tumor Microenvironment Complexity In Vitro: Spheroids as Physiologically Relevant Tumor Models and Strategies for Their Analysis (2025) · cites this paper as [17]
These gradients typically emerge when spheroids exceed ~500 μm in diameter, with proliferative cells localized to the outer rim, quiescent cells residing in intermediate zones, and hypoxic or necrotic cores forming at the center due to limited diffusion.
“These gradients typically emerge when spheroids exceed ~500 μm in diameter, with proliferative cells localized to the outer rim, quiescent cells residing in intermediate zones, and hypoxic or necrotic cores forming at the center due to limited diffusion [17,184,185].”
From Modeling Tumor Microenvironment Complexity In Vitro: Spheroids as Physiologically Relevant Tumor Models and Strategies for Their Analysis (2025) · cites this paper as [17]
2D cultured cells are artificially polarized when their cytoskeleton rearranges as they are stretched on the culture plate, causing them to express atypical genes and proteins.
“Furthermore, 2D cultured cells are artificially polarized when their cytoskeleton rearranges as they are stretched on the culture plate, which in turn causes these cultured cells to express genes and proteins which are atypical [56].”
From Microfluidic modelling of the tumor microenvironment for anti-cancer drug development (2019) · cites this paper as [56]
Spheroids are generally considered similar to an early vascular stage of tumors.
“Spheroids [98, 99] are, in general, considered similar to an early vascular stage of tumors”
From A novel tumor-immune microenvironment (TIME)-on-Chip mimics three dimensional neutrophil-tumor dynamics and neutrophil extracellular traps (NETs)-mediated collective tumor invasion (2021) · cites this paper as [99]
The oxygen/nutrient gradient in spheroids leads to concentric zones: an anoxic necrotic core, a hypoxic middle zone, and an outer zone of highly proliferative cells.
“Moreover, this gradient leads to the formation of concentric zones in the spheroids with a center containing an anoxic core with necrotic cells, a middle zone containing hypoxic cells, and an outer zone of highly proliferative cells, recapitulating the properties of an in vitro tumor [379].”
From Tumor microenvironment signaling and therapeutics in cancer progression (2023) · cites this paper as [379]

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Authors: Nath, S., & Devi, G. R.
Affiliations: Duke University (US)
Corresponding author: Devi, Gayathri R.
ORCID: Devi, Gayathri R.
Venue: Pharmacology & Therapeutics
Publisher: Elsevier BV
Published: 2016-07
Volume: 163
Pages: 94-108
ISSN: 0163-7258 (ISSN-L)
DOI: 10.1016/j.pharmthera.2016.03.013
PMC: PMC4961208
OpenAlex: W2332155194
Cited by: 919
References: 175
Citations by year: 2026: 67 · 2025: 95 · 2024: 100 · 2023: 92 · 2022: 110 · 2021: 125 · 2020: 137 · 2019: 81 · 2018: 63 · 2017: 38 · 2016: 11
FWCI: 6.47
Type: journal article
Language: en
Open access: bronze
doi.org
Licence: www.elsevier.com/tdm/userlicense/1.0/ (tdm)
www.elsevier.com/open-access/userlicense/1.0/ (am, 331 d)
doi.org/10.15223/policy-017 (stm-asf)
doi.org/10.15223/policy-037 (stm-asf)
doi.org/10.15223/policy-012 (stm-asf)
doi.org/10.15223/policy-029 (stm-asf)
doi.org/10.15223/policy-004 (stm-asf)
Locations: Pharmacology & Therapeutics (acceptedVersion)
PubMed (publishedVersion)
PubMed Central (acceptedVersion)
Funders: NIH (CA014236)
Department of Defense (W81XWH-13-1-0047)
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: tumor spheroids, tumor cell culture, cell-matrix interactions, tumor heterogeneity, tumor-host interaction, high-throughput drug screening, anticancer drug discovery
MeSH terms: Antineoplastic Agents, Cell Communication, Cell Movement, Flow Cytometry, Humans, Microscopy, Electron, Scanning, Neoplasm Invasiveness, Neoplasms, Tumor Cells, Cultured, Microscopy, Confocal, Spheroids, Cellular, Cell Culture Techniques, Hydrogels, Tumor Microenvironment

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Three-dimensional culture systems in cancer research: Focus on tumor spheroid model

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