Human 3D vascularized organotypic microfluidic assays to study breast cancer cell extravasation
Open accessAbstract
Significance: The cancer biology seed-and-soil paradigm recognizes the existence of organ-specific patterns of metastasization that drive the spread of selected primary tumors toward specific secondary loci. However, despite efforts to model the organotypic microenvironment, the organ specificity of cancer metastases needs to be elucidated. The relevance of this study lies in the generation of a human vascularized organ-specific microenvironment, which can be used to investigate and tune the extravasation process of metastatic tumor cells. Furthermore, beyond mimicking the pro- or antimetastatic signatures of different microenvironments, our microfluidic model provides insights into different properties of organ-specific endothelia. This study paves the way toward advanced in vitro models to screen for highly tailored organ-specific therapeutics and investigate key molecular pathways involved in organ-specific metastases.
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Adenosine played an important role in promoting tumor cell extravasation.
“Through this, it was shown that adenosine played an important role in promoting tumor cells extravasation.”
From Microfluidic modelling of the tumor microenvironment for anti-cancer drug development (2019) · cites this paper as [98]
The Results (p. 5) report that adding adenosine significantly reduced cancer cell extravasation, from 56.5% to 12.7%, rather than promoting it. The Fig. 3 caption (p. 6) confirms that extravasation decreased with adenosine. (LLM, conf=0.94)
Checked by a reasoning model — may be wrong.
Experimental — accuracy not yet measuredIn a model where MDA-MB-231 suspension was flowed into a vascular network to model extravasation, blocking A3 adenosine receptors reduced the extravasation rate of cancer cells.
“By blocking A3 adenosine receptors, cancer cells were observed to have a reduced extravasation rate.”
From Microfluidic modelling of the tumor microenvironment for anti-cancer drug development (2019) · cites this paper as [98]
The Results (p. 5) report the opposite effect: blocking A3 adenosine receptors with PSB-10 significantly increased cancer cell extravasation in C2C12-containing matrices, from 8.2 ± 2.3% to 32.4 ± 7.7%. The Fig. 3 caption (p. 6) also states that extravasation increased with receptor blockade. (LLM, conf=0.95)
Checked by a reasoning model — may be wrong.
Experimental — accuracy not yet measuredEndothelial cells in a 3D microvascular network displayed morphological features similar to in vivo conditions, contrasting with poorly aligned cells grown in 2D cultures or deprived of flow.
“Endothelial cells displayed morphological features similar to in vivo conditions, contrasting to poorly aligned cells grown in 2D cultures or deprived of fl ow.”
From 3D In Vitro Model (R)evolution: Unveiling Tumor–Stroma Interactions (2021) · cites this paper as [78]
The microfluidic device promoted perfusable culture of four different cell types and proved to be an appropriate platform for monitoring cancer cell extravasation in real time.
“This micro fl uidic device not only promoted the perfusable culture of four different cells types but also proved to be an appropriate platform for monitoring cancer cell extravasation in real time.”
From 3D In Vitro Model (R)evolution: Unveiling Tumor–Stroma Interactions (2021) · cites this paper as [78]
Adenosine inhibits extravasation, as blocking A3 adenosine receptors increased extravasation rates of breast cancer cells into myoblast-mimicking microenvironments compared with untreated cells.
“The results indicated inhibitory role of adenosine on extravasation as blocking A3 adenosine receptors increased extravasation rates of breast cancer cells into the myoblast, mimicking microenvironments compared with untreated cells [57].”
From Tumor microenvironment complexity and therapeutic implications at a glance (2020) · cites this paper as [57]
Microfluidic and 3D bioprinting technologies have been employed to create more in vivo-like perfusable 3D tumor models in the biomimetic matrix.
“Fortunately, with the development of biofabrication techniques, microfluidic and 3D bioprinting technologies have been employed to create more in vivo‐like perfusable 3D tumor models in the biomimetic matrix.[ 72 , 161 ]”
From 3D Biomimetic Models to Reconstitute Tumor Microenvironment In Vitro: Spheroids, Organoids, and Tumor‐on‐a‐Chip (2023) · cites this paper as [161]
CoC models can be applied to elucidate these effects, and researchers have developed vascularized CoC models to study extravasation to bone, brain, and other organs.
“CoC models can be applied to elucidate these effects, and researchers have developed vascularized CoC models to study extravasation to bone [74][75][76], brain [77,78], and other organs [79]”
From Cancer-on-chip models for metastasis: importance of the tumor microenvironment (2024) · cites this paper as [75]
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Engineering 3D Hydrogels for Personalized In Vitro Human Tissue Models
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Microfluidics Enabled Bottom-Up Engineering of 3D Vascularized Tumor for Drug Discovery
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Hydrogel Network Dynamics Regulate Vascular Morphogenesis
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The Mechanics of Single Cell and Collective Migration of Tumor Cells
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Vasculature-On-A-Chip for In Vitro Disease Models
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Self-citationA review of microfluidic approaches for investigating cancer extravasation during metastasis
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3D Bioprinting of Breast Cancer Models for Drug Resistance Study
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In Vitro Microfluidic Models for Neurodegenerative Disorders
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Self-citationCD47 Promotes Tumor Invasion and Metastasis in Non-small Cell Lung Cancer
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Mechanical properties of human tumour tissues and their implications for cancer development
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Microfluidic Organ/Body-on-a-Chip Devices at the Convergence of Biology and Microengineering
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Biochemical analysis on microfluidic chips
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Microfluidic Tumor–Vascular Model to Study Breast Cancer Cell Invasion and Intravasation
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Review: <i>in vitro</i> microvessel models
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Bone remodelling in vitro: Where are we headed?
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Tumor organoid models in precision medicine and investigating cancer-stromal interactions
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Evaluating natural killer cell cytotoxicity against solid tumors using a microfluidic model
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Vascularized microfluidic organ-chips for drug screening, disease models and tissue engineering
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Self-citationBone-on-a-chip: Microfluidic technologies and microphysiologic models of bone tissue
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Fabrication of 3D Biomimetic Microfluidic Networks in Hydrogels
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Designing Microgels for Cell Culture and Controlled Assembly of Tissue Microenvironments
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Self-citationTherapy response testing of breast cancer in a 3D high-throughput perfused microfluidic platform
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Breast Cancer Cell Invasion into a Three Dimensional Tumor-Stroma Microenvironment
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Self-citationMimicking tumor microenvironment by 3D bioprinting: 3D cancer modeling
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3D-printed fluidic networks as vasculature for engineered tissue
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Engineered models to parse apart the metastatic cascade
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Endothelial Regulation of Drug Transport in a 3D Vascularized Tumor Model
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Self-citationMetastasis of circulating tumor cells: Favorable soil or suitable biomechanics, or both?
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Microengineered cancer-on-a-chip platforms to study the metastatic microenvironment
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Tumor-on-chip modeling of organ-specific cancer and metastasis
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Engineering the pre-metastatic niche
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Metastasis in context: modeling the tumor microenvironment with cancer-on-a-chip approaches
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Hydrogel microfabrication technology toward three dimensional tissue engineering
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Tumor-on-a-chip for integrating a 3D tumor microenvironment: chemical and mechanical factors
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Three-dimensional microengineered vascularised endometrium-on-a-chip
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Microfluidic Platforms toward Rational Material Fabrication for Biomedical Applications
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Cancer Modeling‐on‐a‐Chip with Future Artificial Intelligence Integration
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Organ-on-a-chip engineering: Toward bridging the gap between lab and industry
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A Multi-Niche Microvascularized Human Bone-Marrow-on-a-Chip
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- Authors
- Jeon, J. S., Bersini, S., Gilardi, M., Dubini, G., Charest, J. L., Moretti, M., & Kamm, R. D.
- Affiliations
- Massachusetts Institute of Technology (US)
- IRCCS Ospedale Galeazzi - Sant'Ambrogio (IT)
- Politecnico di Milano (IT)
- Draper Laboratory (US)
- ORCID
- Venue
- Proceedings of the National Academy of Sciences
- Publisher
- National Academy of Sciences
- Published
- 2014-12-18
- Volume
- 112
- Issue
- 1
- Pages
- 214-219
- ISSN
- 0027-8424 (ISSN-L)
- 1091-6490
- PMC
- PMC4291627
- OpenAlex
- W2081560083
- Semantic Scholar
- f475569e9cefbccc34378d56e185a60e479f18b8
- Cited by
- 723
- References
- 44
- Citations by year
- 2026: 28 · 2025: 44 · 2024: 53 · 2023: 71 · 2022: 79 · 2021: 85 · 2020: 83 · 2019: 71 · 2018: 77 · 2017: 59 · 2016: 52 · 2015: 21
- FWCI
- 22.85
- Type
- journal article
- Language
- en
- Update notices
- correction (2015-02-02)
- Open access
- bronze
- doi.org
- Locations
- Proceedings of the National Academy of Sciences (publishedVersion)
- Europe PMC (PubMed Central) (publishedVersion)
- PubMed Central (publishedVersion)
- PubMed (publishedVersion)
- Virtual Community of Pathological Anatomy (University of Castilla La Mancha) (submittedVersion, other-oa)
- BOA (University of Milano-Bicocca) (submittedVersion)
- DSpace@MIT (Massachusetts Institute of Technology) (submittedVersion, cc-by-nc)
- Funders
- HHS | NIH | National Cancer Institute (R33 CA174550-01, R21 CA140096)
- Topics
- Physical Sciences › Engineering › Biomedical Engineering › 3D Printing in Biomedical Research
- Health Sciences › Medicine › Oncology › Cancer Cells and Metastasis
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Cell Biology › Cellular Mechanics and Interactions
- Keywords
- breast cancer, tumor cell extravasation, organ-specific metastasis, microvascular permeability, A3 adenosine receptor, drug screening, personalized medicine
- MeSH terms
- Adenosine, Animals, Breast Neoplasms, Capillary Permeability, Extravasation of Diagnostic and Therapeutic Materials, Female, Humans, Stress, Mechanical, Shear Strength, Microfluidics, Cell Line, Tumor, Mice, Microvessels, Cellular Microenvironment, Human Umbilical Vein Endothelial Cells
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