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.
Bibliographical noteFunding Information:
Portions of this work were conducted in the Minnesota Nano Center, which is supported by the National Science Foundation through the National Nano Coordinated Infrastructure Network (NNCI) under Award Number ECCS-2025124. Confocal microscopy and image analysis was performed using the Nikon A1Rsi Confocal microscope and NIS-Elements software at the University Imaging Center, University of Minnesota.
This work was supported by the University of Minnesota.
© 2021, Biomedical Engineering Society.
- Blood–brain barrier
- Brain metastasis
- Breast cancer
- Endothelial-to-mesenchymal transition
- Pluripotent stem cells