Abstract
Introduction: In vivo, breast cancer cells spend on average 3–7 days adhered to the endothelial cells inside the vascular lumen before entering the brain. IL-1β is one of the highly upregulated molecules in brain-seeking triple negative breast cancer (TNBC) cells. In this study, the effect of IL-1β on the blood–brain barrier (BBB) and astrocytes and its role in transmigration of TNBC cells were evaluated. Methods: The effect of IL-1β on transendothelial electrical resistance, gene and protein expression of human induced pluripotent stem cell-derived brain-specific microvascular endothelial-like cells (iBMECs) was studied. Transport of IL-1β across the iBMEC layer was investigated and the effect of IL-1β treatment of astrocytes on their cytokine and chemokine secretome was evaluated with a cytokine membrane array. Using BBB-on-a-chip devices, transmigration of MDA-MB-231 cells and their brain-seeking variant (231BR) across the iBMECs was studied, and the effect of an IL-1β neutralizing antibody on TNBC cell transmigration was investigated. Results: We showed that IL-1β reduces BBB integrity and induces endothelial-to-mesenchymal transition in iBMECs. IL-1β crosses the iBMEC layer and induces secretion of multiple chemokines by astrocytes, which can enhance TNBC cell transmigration across the BBB. Transmigration assays in a BBB-on-a-chip device showed that 231BR cells have a higher rate of transmigration across the iBMECs compared to MDA-MB-231 cells, and IL-1β pretreatment of BBB-on-a-chip devices increases the number of transmigrated MDA-MB-231 cells. Finally, we demonstrated that neutralizing IL-1β reduces the rate of 231BR cell transmigration. Conclusion: IL-1β plays a significant role in transmigration of brain-seeking TNBC cells across the BBB.
Original language | English (US) |
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Pages (from-to) | 99-114 |
Number of pages | 16 |
Journal | Cellular and Molecular Bioengineering |
Volume | 15 |
Issue number | 1 |
DOIs | |
State | Published - Feb 2022 |
Externally published | Yes |
Bibliographical note
Publisher Copyright:© 2021, Biomedical Engineering Society.
Keywords
- Astrocytes
- BBB-on-a-chip
- Blood–brain barrier
- Brain metastasis
- Breast cancer
- Chemokines
- Endothelial-to-mesenchymal transition
- Pluripotent stem cells