A 3D microvascular network model to study the impact of hypoxia on the extravasation potential of breast cell lines
Open accessAbstract
Hypoxia is a common feature of the tumor microenvironment. Accumulating evidence has demonstrated hypoxia to be an important trigger of tumor cell invasion or metastasizes via hypoxia-signaling cascades, including hypoxia-inducible factors (HIFs). Microfluidic model can be a reliable in vitro tool for systematically interrogating individual factors and their accompanying downstream effects, which may otherwise be difficult to study in complex tumor tissues. Here, we used an in vitro model of microvascular networks in a microfluidic chip to measure the extravasation potential of breast cell lines subjected to different oxygen conditions. Through the use of HIF-1α knock-down cell lines, we also validated the importance of HIF-1α in the transmigration ability of human breast cell lines. Three human breast cell lines derived from human breast tissues (MCF10A, MCF-7 and MDA-MB-231) were used in this study to evaluate the role of hypoxia in promoting metastasis at different stages of cancer progression. Under hypoxic conditions, HIF-1α protein level was increased, and coincided with changes in cell morphology, viability and an elevated metastatic potential. These changes were accompanied by an increase in the rate of extravasation compared to normoxia (21% O 2). siRNA knockdown of HIF-1α in hypoxic tumors significantly decreased the extravasation rates of all the cell lines tested and may have an effect on the function of metastatic and apoptotic-related cellular processes.
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Tumor size and associated hypoxia levels affect tumor aggressiveness.
“recently published literature discusses the role of the size of a tumor (and the associated hypoxia levels) on its aggressiveness [81,82,83,84,85] and on the efficacy of drug delivery to it [84,86,87].”
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 [85]
The Introduction and Discussion state that hypoxia is associated with an aggressive tumor phenotype and promotes invasion and metastasis. The Discussion explains that proliferating tumor cells can become farther from blood vessels and oxygen, but it does not establish that tumor size itself affects aggressiveness or quantify a size–hypoxia relationship. Page numbers are unavailable in our copy. (LLM, conf=0.82)
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- Authors
- Song, J., Miermont, A., Lim, C. T., & Kamm, R. D.
- Affiliations
- Singapore-MIT Alliance for Research and Technology (SG)
- National University of Singapore (SG)
- Corresponding author
- Kamm, Roger D.
- Venue
- Scientific Reports
- Published
- 2018-12-18
- Volume
- 8
- Issue
- 1
- Pages
- 17949-17949
- ISSN
- 2045-2322 (ISSN-L)
- PMC
- PMC6298998
- OpenAlex
- W2903694002
- Cited by
- 87
- References
- 87
- Citations by year
- 2026: 1 · 2025: 14 · 2024: 12 · 2023: 17 · 2022: 18 · 2021: 10 · 2020: 12 · 2019: 3
- FWCI
- 1.89
- Type
- journal article
- Language
- en
- Open access
- gold
- doi.org
- Locations
- Scientific Reports (publishedVersion, cc-by)
- Europe PMC (PubMed Central) (publishedVersion, other-oa)
- PubMed Central (publishedVersion, cc-by)
- PubMed (publishedVersion)
- National University of Singapore (submittedVersion, cc-by)
- DOAJ (DOAJ: Directory of Open Access Journals) (submittedVersion)
- DSpace@MIT (Massachusetts Institute of Technology) (submittedVersion, cc-by-nc)
- Funders
- National Research Foundation
- National Research Foundation Singapore
- National Cancer Institute (CA202177, U01CA202177)
- National Institute of Neurological Disorders and Stroke (R21NS105027)
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Cancer Research › Cancer, Hypoxia, and Metabolism
- Health Sciences › Medicine › Oncology › Cancer Cells and Metastasis
- Physical Sciences › Engineering › Biomedical Engineering › 3D Printing in Biomedical Research
- Keywords
- hypoxia, HIF-1α, breast cancer, tumor microenvironment, extravasation, metastasis, microvascular networks, microfluidics, transmigration, siRNA knockdown, MCF-7 cells, MDA-MB-231 cells, MCF10A, tumor invasion
- MeSH terms
- Angiography, Hypoxia, Breast Neoplasms, Cell Survival, Female, Humans, Neoplasm Invasiveness, Phenotype, Biomarkers, Tumor, Cell Hypoxia, Gene Expression, Imaging, Three-Dimensional, Cell Line, Tumor, Hypoxia-Inducible Factor 1, alpha Subunit, Microvessels, Tumor Microenvironment
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