Small cell lung cancer is the most aggressive histologic subtype of
lung cancer, with a strong predilection for metastasizing to brain early. However, the cellular and molecular basis is poorly known. Here, we provided evidence to reveal the role of
annexin A1 in
small cell lung cancer metastasis to brain. Firstly, the elevated
annexin A1 serum levels in
small cell lung cancer patients were associated with brain
metastasis. The levels of
annexin A1 were also upregulated in NCI-H446 cells, a
small cell lung cancer cell line, upon migration into the mice brain. More interestingly,
annexin A1 was secreted by NCI-H446 cells in a time-dependent manner when co-culturing with human brain microvascular endothelial cells, which was identified with the detections of
annexin A1 in the co-cultured cellular supernatants by ELISA and western blot. Further results showed that blockage of
annexin A1 in the co-cultured cellular supernatants using a neutralized antibody significantly inhibited NCI-H446 cells adhesion to brain endothelium and its transendothelial migration. Conversely, the addition of Ac2-26, an
annexin A1 mimic
peptide, enhanced these effects. Furthermore, knockdown of
annexin A1 in NCI-H446 cells prevented its transendothelial migration in vitro and
metastasis to mice brain in vivo. Our data showed that
small cell lung cancer cell in brain microvasculature microenvironment could express much more
annexin A1 and release it outside, which facilitated
small cell lung cancer cell to gain malignant properties of entry into brain. These findings provided a potential target for the management of SCLC brain
metastasis.