A microfluidic 3D in vitro model for specificity of breast cancer metastasis to bone
Open accessAbstract
Cancer metastases arise following extravasation of circulating tumor cells with certain tumors exhibiting high organ specificity. Here, we developed a 3D microfluidic model to analyze the specificity of human breast cancer metastases to bone, recreating a vascularized osteo-cell conditioned microenvironment with human osteo-differentiated bone marrow-derived mesenchymal stem cells and endothelial cells. The tri-culture system allowed us to study the transendothelial migration of highly metastatic breast cancer cells and to monitor their behavior within the bone-like matrix. Extravasation, quantified 24 h after cancer cell injection, was significantly higher in the osteo-cell conditioned microenvironment compared to collagen gel-only matrices (77.5 ± 3.7% vs. 37.6 ± 7.3%), and the migration distance was also significantly greater (50.8 ± 6.2 μm vs. 31.8 ± 5.0 μm). Extravasated cells proliferated to form micrometastases of various sizes containing 4 to more than 60 cells by day 5. We demonstrated that the breast cancer cell receptor CXCR2 and the bone-secreted chemokine CXCL5 play a major role in the extravasation process, influencing extravasation rate and traveled distance. Our study provides novel 3D in vitro quantitative data on extravasation and micrometastasis generation of breast cancer cells within a bone-like microenvironment and demonstrates the potential value of microfluidic systems to better understand cancer biology and screen for new therapeutics.
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These microfluidic systems enable continuous delivery of oxygen, nutrients, and therapeutic agents while introducing shear stress and directional mass transport, allowing investigation of flow-regulated processes within a tumor-relevant architecture.
“These systems enable continuous delivery of oxygen, nutrients, and therapeutic agents while introducing shear stress and directional mass transport, thereby allowing the investigation of flow-regulated processes within a tumor-relevant architecture [224,225,226,227,228].”
From Modeling Tumor Microenvironment Complexity In Vitro: Spheroids as Physiologically Relevant Tumor Models and Strategies for Their Analysis (2025) · cites this paper as [227]
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Experimental — accuracy not yet measuredDifferent cancer cells (lung, breast, melanoma) flowed through the vascular channel disrupted the integrity of the BBB and extravasated, with the exception of liver cancer cells.
“A compartmental channel model was used to establish a blood-brain barrier (BBB) [74]; different cancer cells (lung, breast, melanoma) flowed through the vascular channel and were found to disrupt the integrity of the BBB and extravasate, with the exception of liver cancer cells.”
From Cancer-on-chip models for metastasis: importance of the tumor microenvironment (2024) · cites this paper as [74]
Breast cancer cells introduced into the vascular channel transmigrated across an endothelial monolayer into the osteo-cell compartment in a vascularized osteo-cell environment.
“Breast cancer cells were introduced into the vascular channel, which led to cancer cell transmigration across an endothelial monolayer into the osteo-cell compartment.”
From Cancer-on-chip models for metastasis: importance of the tumor microenvironment (2024) · cites this paper as [74]
Regulation of the cancer cell surface receptor CXCR2 and bone-secreted chemokine CXCL5 significantly altered the extravasation rate.
“Regulation of the cancer cell surface receptor CXCR2 and bonesecreted chemokine CXCL5 significantly altered the extravasation rate.”
From Cancer-on-chip models for metastasis: importance of the tumor microenvironment (2024) · cites this paper as [74]
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- Authors
- Bersini, S., Jeon, J. S., Dubini, G., Arrigoni, C., Chung, S., Charest, J. L., Moretti, M., & Kamm, R. D.
- Affiliations
- IRCCS Ospedale Galeazzi - Sant'Ambrogio (IT)
- Massachusetts Institute of Technology (US)
- Politecnico di Milano (IT)
- Korea University (KR)
- Draper Laboratory (US)
- Corresponding author
- Moretti, Matteo
- Kamm, Roger D.
- ORCID
- Venue
- Biomaterials
- Publisher
- Elsevier BV
- Published
- 2014-03
- Volume
- 35
- Issue
- 8
- Pages
- 2454-2461
- ISSN
- 0142-9612 (ISSN-L)
- PMC
- PMC3905838
- OpenAlex
- W2051403546
- Cited by
- 534
- References
- 63
- Citations by year
- 2026: 26 · 2025: 33 · 2024: 33 · 2023: 42 · 2022: 52 · 2021: 51 · 2020: 55 · 2019: 46 · 2018: 57 · 2017: 49 · 2016: 44 · 2015: 32 · 2014: 14
- FWCI
- 22.34
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Locations
- Biomaterials (publishedVersion)
- PubMed (publishedVersion)
- Europe PMC (PubMed Central) (acceptedVersion)
- PubMed Central (acceptedVersion)
- DSpace@MIT (Massachusetts Institute of Technology) (submittedVersion, cc-by-nc-nd)
- Virtual Community of Pathological Anatomy (University of Castilla La Mancha) (submittedVersion)
- Funders
- National Cancer Institute (R33 CA174550-01, R21 CA140096)
- Fondazione Fratelli Agostino and Enrico Rocca
- Repligen Fellowship
- Cancer Research and Draper Fellowship
- 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 metastasis, bone metastasis, organ specificity, extravasation, transendothelial migration, micrometastases, CXCR2, CXCL5, bone marrow microenvironment, mesenchymal stem cells, endothelial cells, collagen gel
- MeSH terms
- Bone Marrow Cells, Bone Neoplasms, Breast Neoplasms, Cell Differentiation, Collagen, Female, Fluorescent Antibody Technique, Humans, Receptors, Interleukin-8B, Microfluidics, Cell Line, Tumor, Cell Proliferation, Chemokine CXCL5, Mesenchymal Stem Cells
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