Human Brain Endothelial Cell-derived COX-2 Facilitates Extravasation of Breast Cancer Cells Across the Blood-brain Barrier

Abstract

With improvements in systemic control, metastasis to the brain has been more frequently found in patients with breast cancer. In order to gain access to the brain, breast cancer cells must overcome the blood-brain barrier (BBB), a highly selective filter against cellular and soluble substances. Human brain endothelial cells (HBECs) comprise a major element of the BBB, and breast cancer cells first encounter and pass through them for extravasation. To date, however, the precise role of HBECs in metastasis to the brain is unknown. In this study, we examined how HBECs take part in the extravasation process. In an established in vitro model of the BBB, unexpectedly, the transmigration of breast cancer cells was markedly enhanced in the presence of HBECs than in their absence, suggesting that HBECs facilitate the transmigration of breast cancer cells rather than acting as a barrier against them. We then showed that cyclooxygenase (COX-2) induced from HBECs rather than that from breast cancer cells plays a key role in the transmigration. Moreover, expression of matrix metalloproteinase (MMP-2) mediating the transmigration was induced in HBECs by COX-2 after co-culture with breast cancer cells. Taken together, our results suggest that COX-2 and MMP-2 produced from HBECs facilitate the extravasation of breast cancer cells across the BBB.