A Comprehensive Panel of Three-Dimensional Models for Studies of Prostate Cancer Growth, Invasion and Drug Responses
Open accessAbstract
Prostate epithelial cells from both normal and cancer tissues, grown in three-dimensional (3D) culture as spheroids, represent promising in vitro models for the study of normal and cancer-relevant patterns of epithelial differentiation. We have developed the most comprehensive panel of miniaturized prostate cell culture models in 3D to date (n = 29), including many non-transformed and most currently available classic prostate cancer (PrCa) cell lines. The purpose of this study was to analyze morphogenetic properties of PrCa models in 3D, to compare phenotypes, gene expression and metabolism between 2D and 3D cultures, and to evaluate their relevance for pre-clinical drug discovery, disease modeling and basic research. Primary and non-transformed prostate epithelial cells, but also several PrCa lines, formed well-differentiated round spheroids. These showed strong cell-cell contacts, epithelial polarization, a hollow lumen and were covered by a complete basal lamina (BL). Most PrCa lines, however, formed large, poorly differentiated spheroids, or aggressively invading structures. In PC-3 and PC-3M cells, well-differentiated spheroids formed, which were then spontaneously transformed into highly invasive cells. These cell lines may have previously undergone an epithelial-to-mesenchymal transition (EMT), which is temporarily suppressed in favor of epithelial maturation by signals from the extracellular matrix (ECM). The induction of lipid and steroid metabolism, epigenetic reprogramming, and ECM remodeling represents a general adaptation to 3D culture, regardless of transformation and phenotype. In contrast, PI3-Kinase, AKT, STAT/interferon and integrin signaling pathways were particularly activated in invasive cells. Specific small molecule inhibitors targeted against PI3-Kinase blocked invasive cell growth more effectively in 3D than in 2D monolayer culture, or the growth of normal cells. Our panel of cell models, spanning a wide spectrum of phenotypic plasticity, supports the investigation of different modes of cell migration and tumor morphologies, and will be useful for predictive testing of anti-cancer and anti-metastatic compounds.
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CSC-derived spheroids are typically larger, less organized, and display characteristics associated with increased malignancy, including loss of epithelial polarity, incomplete basement membrane coverage, and enhanced invasive behavior.
“CSC-derived spheroids are typically larger, less organized, and display characteristics associated with increased malignancy, including loss of epithelial polarity, incomplete basement membrane coverage, and enhanced invasive behavior [220].”
From Modeling Tumor Microenvironment Complexity In Vitro: Spheroids as Physiologically Relevant Tumor Models and Strategies for Their Analysis (2025) · cites this paper as [220]
The Results section on prostate-cell morphologies reports large, irregular spheroids with incomplete or missing basal lamina and less pronounced polarization. But it says these mass-phenotype spheroids usually did not invade; invasion was observed in other structures. The paper does not identify the described spheroids as CSC-derived, and the Discussion says its invasive cells did not acquire CSC properties. Page numbers are unavailable in our copy. (LLM, conf=0.88)
Experimental — accuracy not yet measuredThese results are consistent with a previous study demonstrating that PC3 cells probably retain some differentiation capabilities.
“These results are consistent with a previous study, which demonstrates that PC3 cells probably retain some differentiation capabilities (31).”
From Direct transfection of clonal organoids in Matrigel microbeads: a promising approach toward organoid-based genetic screens (2018) · cites this paper as [31]
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“These results are consistent with a previous study, which demonstrates that PC3 cells probably retain some differentiation capabilities (31).”
ResultSelf-citationMatrigel Basement Membrane Matrix influences expression of microRNAs in cancer cell lines
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- Authors
- Härmä, V., Virtanen, J., Mäkelä, R., Happonen, A., Mpindi, J.-P., Knuuttila, M., Kohonen, P., Lötjönen, J., Kallioniemi, O., & Nees, M.
- Affiliations
- VTT Technical Research Centre of Finland (FI)
- University of Turku (FI)
- University of Helsinki (FI)
- Corresponding author
- Nees, Matthias
- ORCID
- Venue
- PLoS ONE
- Publisher
- Public Library of Science (PLoS)
- Published
- 2010-05-03
- Volume
- 5
- Issue
- 5
- Pages
- e10431
- ISSN
- 1932-6203 (ISSN-L)
- PMC
- PMC2862707
- OpenAlex
- W2119975980
- Cited by
- 344
- References
- 67
- Citations by year
- 2026: 7 · 2025: 7 · 2024: 15 · 2023: 21 · 2022: 12 · 2021: 16 · 2020: 31 · 2019: 20 · 2018: 21 · 2017: 37 · 2016: 30 · 2015: 23 · 2014: 31 · 2013: 33 · 2012: 21
- FWCI
- 19.14
- Type
- journal article
- Language
- en
- Open access
- gold
- doi.org
- Locations
- PLoS ONE (publishedVersion, cc-by)
- PubMed Central (publishedVersion, cc-by)
- PubMed (publishedVersion)
- DOAJ (DOAJ: Directory of Open Access Journals) (submittedVersion, cc-by-sa)
- Figshare (submittedVersion, cc-by)
- Työväentutkimus Vuosikirja (submittedVersion)
- Funders
- European Commission
- Nella and Leon Benoziyo Center for Neurological Diseases, Weizmann Institute of Science
- Karolinska Institutet
- Topics
- Health Sciences › Medicine › Pulmonary and Respiratory Medicine › Prostate Cancer Treatment and Research
- Health Sciences › Medicine › Oncology › Cancer Cells and Metastasis
- Physical Sciences › Engineering › Biomedical Engineering › 3D Printing in Biomedical Research
- Keywords
- prostate cancer, 3D cell culture, tumor spheroids, epithelial differentiation, tumor invasion, epithelial-mesenchymal transition, extracellular matrix, PI3K/Akt signaling, PI3K inhibitors, drug response, metastasis, cell migration, phenotypic plasticity, basement membrane, gene expression, epigenetic reprogramming, PC-3 cells
- MeSH terms
- Phosphoinositide-3 Kinase Inhibitors, Antineoplastic Agents, Cell Transformation, Neoplastic, Collagen, Drug Combinations, Epithelial Cells, Epithelium, Humans, Laminin, Male, Mesoderm, Models, Biological, Neoplasm Invasiveness, Neoplasm Proteins, Phenotype, Prostate, Prostatic Neoplasms, Proteoglycans, RNA, Messenger, Tumor Cells, Cultured, Signal Transduction, Gene Expression Regulation, Neoplastic, Protein Serine-Threonine Kinases, Spheroids, Cellular, Phosphatidylinositol 3-Kinases, Principal Component Analysis, Intracellular Signaling Peptides and Proteins, Cell Shape, Cell Proliferation, Proto-Oncogene Proteins c-akt, TOR Serine-Threonine Kinases
About these checks
Registry, retraction, Cites and statistics results are computed, not judged, with one exception: a printed reference that no index lists is read once by a model before it counts as a citation error. Claims are extracted by a model and kept only when their quote appears verbatim in the text; each cited source is then checked, with a model’s help, for whether it says what the claim relies on. Those verdicts can be wrong — read the claim’s quote and the cited source before relying on one.
Statistics and arithmetic are recomputed, not judged.
Confidence bands are shown only for fields calibrated on our annotated test set. None is calibrated yet, so no band is shown.
What counts as a claim ›How we measure confidence ›How we check this ›
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