Three-dimensional culture of melanoma cells profoundly affects gene expression profile: A high density oligonucleotide array study
Abstract
Growth in three-dimensional (3D) architectures has been suggested to play an important role in tumor expansion and in the resistance of cancers to treatment with drugs or cytokines or irradiation. To obtain an insight into underlying molecular mechanisms, we addressed gene expression profiles of NA8 melanoma cells cultured in bidimensional monolayers (2D) or in 3D multicellular tumor spheroids (MCTS). MCTS containing 10-30,000 cells were generated upon overnight culture in poly-Hydroxyethylmethacrylate (polyHEMA) coated plates. Kinetics of cell proliferation in MCTS was significantly slower than in monolayer cultures. Following long-term culture (>10 days), however, MCTS showed highly compact and organised cell growth in outer layers, with necrotic cores. Oligonucleotide microarray analysis of the expression of over 20,000 genes was performed on cells cultured in standard 2D, in the presence of collagen as model of extracellular matrix (ECM), or in MCTS. Gene expression profiles of cells cultured in 2D in the presence or absence of ECM were highly similar, with >/=threefold differences limited to five genes. In contrast, culture in MCTS resulted in the significant, >/=threefold, upregulation of the expression of >100 transcripts while 73 were >/=threefold downregulated. In particular, genes encoding CXCL1, 2, and 3 (GRO-alpha, -beta, and gamma), IL-8, CCL20 (MIP-3alpha), and Angiopoietin-like 4 were significantly upregulated, whereas basic FGF and CD49d encoding genes were significantly downregulated. Oligonucleotide chip data were validated at the gene and protein level by quantitative real-time PCR, ELISA, and cell surface staining assays. Taken together, our data indicate that structural modifications of the architecture of tumor cell cultures result in a significant upregulation of the expression of a number of genes previously shown to play a role in melanoma progression and metastatic process.
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In melanoma cells, gene expression remained largely unchanged between monolayer and monolayer-with-ECM conditions, while spheroid cultures exhibited substantial differences.
“transcriptomic analysis of melanoma cells cultured as monolayers, monolayers with ECM, and spheroids revealed that gene expression remained largely unchanged between the two monolayer conditions, while spheroid cultures exhibited substantial differences [194,195].”
From Modeling Tumor Microenvironment Complexity In Vitro: Spheroids as Physiologically Relevant Tumor Models and Strategies for Their Analysis (2025) · cites this paper as [194]
Over 100 transcripts were upregulated and approximately 70 downregulated in spheroid melanoma cultures, with many altered genes associated with tumor progression and metastatic behavior.
“Over 100 transcripts were found to be upregulated and approximately 70 downregulated, with many of the altered genes associated with tumor progression and metastatic behavior [194].”
From Modeling Tumor Microenvironment Complexity In Vitro: Spheroids as Physiologically Relevant Tumor Models and Strategies for Their Analysis (2025) · cites this paper as [194]
Gene expression patterns in spheroids more closely resemble those found in solid tumors than in monolayer cultures.
“gene expression patterns in spheroids more closely resemble those found in solid tumors than in monolayer cultures [112,193,194].”
From Modeling Tumor Microenvironment Complexity In Vitro: Spheroids as Physiologically Relevant Tumor Models and Strategies for Their Analysis (2025) · cites this paper as [194]
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- Authors
- Ghosh, S., Spagnoli, G. C., Martin, I., Ploegert, S., Demougin, P., Heberer, M., & Reschner, A.
- Affiliations
- University of Basel (CH)
- Corresponding author
- Reschner, Anca
- Venue
- Journal of Cellular Physiology
- Publisher
- Wiley
- Published
- 2005-03-02
- Volume
- 204
- Issue
- 2
- Pages
- 522-531
- ISSN
- 0021-9541 (ISSN-L)
- 1097-4652
- OpenAlex
- W2015893533
- Cited by
- 326
- References
- 28
- Citations by year
- 2026: 4 · 2025: 13 · 2024: 15 · 2023: 19 · 2022: 16 · 2021: 23 · 2020: 24 · 2019: 18 · 2018: 12 · 2017: 20 · 2016: 30 · 2015: 13 · 2014: 19 · 2013: 21 · 2012: 15
- FWCI
- 5.13
- Type
- journal article
- Language
- en
- Open access
- closed
- Locations
- Journal of Cellular Physiology (publishedVersion)
- PubMed (publishedVersion)
- Funders
- Schweizerischer Nationalfonds zur Förderung der Wissenschaftlichen Forschung
- Swiss Bridge Foundation
- Topics
- Health Sciences › Medicine › Oncology › Cancer Cells and Metastasis
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Cell Biology › Cellular Mechanics and Interactions
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Gene expression and cancer classification
- Keywords
- melanoma, 3D cell culture, tumor spheroids, gene expression profiles, extracellular matrix, collagen, tumor architecture, CXCL chemokines, interleukin-8, CCL20, ANGPTL4, basic FGF, CD49d, tumor necrosis, metastasis
- MeSH terms
- Cell Division, Enzyme-Linked Immunosorbent Assay, Humans, Melanoma, Staining and Labeling, Tumor Cells, Cultured, Down-Regulation, Up-Regulation, Polymerase Chain Reaction, Spheroids, Cellular, Oligonucleotide Array Sequence Analysis, Gene Expression Profiling
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