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-1ß is one of the highly upregulated molecules in brain-seeking triple negative breast cancer (TNBC) cells. In this study, the effect of IL-1ß on the blood-brain barrier (BBB) and astrocytes and its role in transmigration of TNBC cells were evaluated. METHODS: The effect of IL-1ß 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-1ß across the iBMEC layer was investigated and the effect of IL-1ß 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-1ß neutralizing antibody on TNBC cell transmigration was investigated. RESULTS: We showed that IL-1ß reduces BBB integrity and induces endothelial-to-mesenchymal transition in iBMECs. IL-1ß 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-1ß pretreatment of BBB-on-a-chip devices increases the number of transmigrated MDA-MB-231 cells. Finally, we demonstrated that neutralizing IL-1ß reduces the rate of 231BR cell transmigration. CONCLUSION: IL-1ß plays a significant role in transmigration of brain-seeking TNBC cells across the BBB. SUPPLEMENTARY INFORMATION: The online version contains supplementary material available at 10.1007/s12195-021-00710-y.
