Three-Dimensional Breast Cancer Models Mimic Hallmarks of Size-Induced Tumor Progression
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Abstract
Tumor size is strongly correlated with breast cancer metastasis and patient survival. Increased tumor size contributes to hypoxic and metabolic gradients in the solid tumor and to an aggressive tumor phenotype. Thus, it is important to develop three-dimensional (3D) breast tumor models that recapitulate size-induced microenvironmental changes and, consequently, natural tumor progression in real time without the use of artificial culture conditions or gene manipulations. Here, we developed size-controlled multicellular aggregates (“microtumors”) of subtype-specific breast cancer cells by using non-adhesive polyethylene glycol dimethacrylate hydrogel microwells of defined sizes (150–600 μm). These 3D microtumor models faithfully represent size-induced microenvironmental changes, such as hypoxic gradients, cellular heterogeneity, and spatial distribution of necrotic/proliferating cells. These microtumors acquire hallmarks of tumor progression in the same cell lines within 6 days. Of note, large microtumors of hormone receptor–positive cells exhibited an aggressive phenotype characterized by collective cell migration and upregulation of mesenchymal markers at mRNA and protein level, which was not observed in small microtumors. Interestingly, triple-negative breast cancer (TNBC) cell lines did not show size-dependent upregulation of mesenchymal markers. In conclusion, size-controlled microtumor models successfully recapitulated clinically observed positive association between tumor size and aggressive phenotype in hormone receptor–positive breast cancer while maintaining clinically proven poor correlation of tumor size with aggressive phenotype in TNBC. Such clinically relevant 3D models generated under controlled experimental conditions can serve as precise preclinical models to study mechanisms involved in breast tumor progression as well as antitumor drug effects as a function of tumor progression. Cancer Res; 76(13); 3732–43. ©2016 AACR.
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When a tumor exceeds a critical diameter of 200 μm, hypoxia develops at its central core.
“When a tumor exceeds a critical diameter of 200 μm, hypoxia develops at its central core, and a complex biochemical cascade commands vascularization to start [126,184].”
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 [184]
The Results (Microtumors mimic size-dependent microenvironmental changes; page unavailable) report reduced oxygen availability in the cores of 600 μm breast microtumors compared with 150 μm microtumors. The Discussion likewise describes hypoxia in the centers of large microtumors, but the paper does not establish a critical diameter of 200 μm or show that hypoxia begins once a tumor exceeds it. (LLM, conf=0.88)
Experimental — accuracy not yet measuredA complex biochemical cascade commands vascularization to start when a tumor exceeds a critical diameter of 200 μm.
“When a tumor exceeds a critical diameter of 200 μm, hypoxia develops at its central core, and a complex biochemical cascade commands vascularization to start [126,184].”
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 [184]
The Results section (“Microtumors mimic size-dependent microenvironmental changes”; page unavailable) reports central oxygen limitation and increased Hif-1α and Vegf expression in 600 μm breast microtumors compared with 150 μm microtumors. It does not establish a critical diameter of 200 μm or show that vascularization starts at that threshold. (LLM, conf=0.86)
Experimental — accuracy not yet measured
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Self-citation
- Authors
- Singh, M., Mukundan, S., Jaramillo, M., Oesterreich, S., & Sant, S.
- Affiliations
- University of Pittsburgh (US)
- 1Department of Pharmaceutical Sciences, School of Pharmacy, University of Pittsburgh, Pittsburgh, Pennsylvania.
- Corresponding author
- Sant, Shilpa
- Venue
- Cancer Research
- Published
- 2016-06-30
- Volume
- 76
- Issue
- 13
- Pages
- 3732-3743
- ISSN
- 0008-5472 (ISSN-L)
- 1538-7445
- PMC
- PMC4947371
- OpenAlex
- W2403387548
- Cited by
- 68
- References
- 47
- Citations by year
- 2026: 1 · 2025: 3 · 2024: 3 · 2023: 5 · 2022: 9 · 2021: 6 · 2020: 9 · 2019: 10 · 2018: 9 · 2017: 9 · 2016: 4
- FWCI
- 5.75
- Type
- journal article
- Language
- en
- Open access
- green
- www.ncbi.nlm.nih.gov
- Locations
- Cancer Research (publishedVersion)
- PubMed (publishedVersion)
- PubMed Central (acceptedVersion)
- Funders
- NIH (EB018575)
- Department of Pharmaceutical Sciences, School of Pharmacy, University of Pittsburgh
- Breast Cancer Research Fund
- Topics
- Health Sciences › Medicine › Oncology › Cancer Cells and Metastasis
- Physical Sciences › Engineering › Biomedical Engineering › 3D Printing in Biomedical Research
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Cell Biology › Cellular Mechanics and Interactions
- Keywords
- breast cancer, tumor size, tumor progression, 3D tumor models, microtumors, tumor microenvironment, tumor heterogeneity, necrosis, collective cell migration, epithelial-mesenchymal transition, hormone receptor-positive breast cancer, triple-negative breast cancer, preclinical models
- MeSH terms
- Breast Neoplasms, Cell Movement, Female, Humans, Models, Biological, Tumor Cells, Cultured, Biomarkers, Tumor, Signal Transduction, Gene Expression Regulation, Neoplastic, Disease Progression, Hydrogel, Polyethylene Glycol Dimethacrylate, Tumor Burden, Cell Proliferation, Tumor Microenvironment, Mesenchymal Stem Cells
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