title: Brain microvascular endothelium induced-annexin A1 secretion contributes to small cell lung cancer brain metastasis.
abstract: 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.
authors.affiliation: Department of Developmental Cell Biology, Key Laboratory of Cell Biology, Ministry of Public Health and Key Laboratory of Medical Cell Biology, Ministry of Education, China Medical University, China.
authors.forename: Yi
authors.initials: Y
authors.lastname: Liu
authors.affiliation: Department of Developmental Cell Biology, Key Laboratory of Cell Biology, Ministry of Public Health and Key Laboratory of Medical Cell Biology, Ministry of Education, China Medical University, China.
authors.forename: Yong-Shuo
authors.initials: YS
authors.lastname: Liu
authors.affiliation: Department of Neurosurgery, The First Hospital of China Medical University, China.
authors.forename: Peng-Fei
authors.initials: PF
authors.lastname: Wu
authors.affiliation: Department of Medical Examination, Shengjing Hospital of China Medical University, China.
authors.forename: Qiang
authors.initials: Q
authors.lastname: Li
authors.affiliation: Department of Developmental Cell Biology, Key Laboratory of Cell Biology, Ministry of Public Health and Key Laboratory of Medical Cell Biology, Ministry of Education, China Medical University, China.
authors.forename: Wu-Min
authors.initials: WM
authors.lastname: Dai
authors.affiliation: Department of Developmental Cell Biology, Key Laboratory of Cell Biology, Ministry of Public Health and Key Laboratory of Medical Cell Biology, Ministry of Education, China Medical University, China.
authors.forename: Shuai
authors.initials: S
authors.lastname: Yuan
authors.affiliation: Department of Developmental Cell Biology, Key Laboratory of Cell Biology, Ministry of Public Health and Key Laboratory of Medical Cell Biology, Ministry of Education, China Medical University, China.
authors.forename: Zhi-Hua
authors.initials: ZH
authors.lastname: Xu
authors.affiliation: Department of Developmental Cell Biology, Key Laboratory of Cell Biology, Ministry of Public Health and Key Laboratory of Medical Cell Biology, Ministry of Education, China Medical University, China.
authors.forename: Ting-Ting
authors.initials: TT
authors.lastname: Liu
authors.affiliation: Department of Developmental Cell Biology, Key Laboratory of Cell Biology, Ministry of Public Health and Key Laboratory of Medical Cell Biology, Ministry of Education, China Medical University, China.
authors.forename: Zi-Wei
authors.initials: ZW
authors.lastname: Miao
authors.affiliation: Department of Developmental Cell Biology, Key Laboratory of Cell Biology, Ministry of Public Health and Key Laboratory of Medical Cell Biology, Ministry of Education, China Medical University, China.
authors.forename: Wen-Gang
authors.initials: WG
authors.lastname: Fang
authors.affiliation: Department of Developmental Cell Biology, Key Laboratory of Cell Biology, Ministry of Public Health and Key Laboratory of Medical Cell Biology, Ministry of Education, China Medical University, China.
authors.forename: Yu-Hua
authors.initials: YH
authors.lastname: Chen
authors.affiliation: Department of Developmental Cell Biology, Key Laboratory of Cell Biology, Ministry of Public Health and Key Laboratory of Medical Cell Biology, Ministry of Education, China Medical University, China. Electronic address: bli@mail.cmu.edu.cn.
authors.forename: Bo
authors.initials: B
authors.lastname: Li
mesh_terms: D000818:Animals; D015153:Blotting, Western; D001921:Brain / Q000098:blood supply / Q000473:pathology; D001932:Brain Neoplasms / Q000235:genetics / Q000378:metabolism* / Q000556:secondary; D045744:Cell Line, Tumor; D002478:Cells, Cultured; D018920:Coculture Techniques; D042783:Endothelial Cells / Q000378:metabolism; D004730:Endothelium, Vascular / Q000378:metabolism*; D005260:Female; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D008175:Lung Neoplasms / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D008297:Male; D008807:Mice, Inbred BALB C; D008819:Mice, Nude; D018613:Microscopy, Confocal; D008875:Middle Aged; D034622:RNA Interference; D020133:Reverse Transcriptase Polymerase Chain Reaction; D055752:Small Cell Lung Carcinoma / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D057705:Transendothelial and Transepithelial Migration / Q000235:genetics; D014183:Transplantation, Heterologous
keywords: Annexin A1; Blood–brain barrier; Brain metastasis; Human brain microvascular endothelial cells; Small cell lung cancer