title: The endothelin-integrin axis is involved in macrophage-induced breast cancer cell chemotactic interactions with endothelial cells.
abstract: Elevated macrophage infiltration in tumor tissues is associated with breast cancer metastasis. Cancer cell migration/invasion toward angiogenic microvasculature is a key step in metastatic spread. We therefore studied how macrophages stimulated breast cancer cell interactions with endothelial cells. Macrophages produced cytokines, such as interleukin-8 and tumor necrosis factor-α, to stimulate endothelin (ET) and ET receptor (ETR) expression in breast cancer cells and human umbilical vascular endothelial cells (HUVECs). ET-1 was induced to a greater extent from HUVECs than from breast cancer cells, resulting in a density difference that facilitated cancer cell chemotaxis toward HUVECs. Macrophages also stimulated breast cancer cell adhesion to HUVECs and transendothelial migration, which were repressed by ET-1 antibody or ETR inhibitors. The ET axis induced integrins, such as αV and β1, and their counterligands, such as intercellular adhesion molecule-2 and P-selectin, in breast cancer cells and HUVECs, and antibodies against these integrins efficiently suppressed macrophage-stimulated breast cancer cell interactions with HUVECs. ET-1 induced Ets-like kinase-1 (Elk-1), signal transducer and activator of transcription-3 (STAT-3), and nuclear factor-κB (NF-κB) phosphorylation in breast cancer cells. The use of inhibitors to prevent their phosphorylation or ectopic overexpression of dominant-negative IκBα perturbed ET-1-induced integrin αV and integrin β1 expression. The physical associations of these three transcriptional factors with the gene promoters of the two integrins were furthermore evidenced by a chromatin immunoprecipitation assay. Finally, our mouse orthotopic tumor model revealed an ET axis-mediated lung metastasis of macrophage-stimulated breast cancer cells, suggesting that the ET axis was involved in macrophage-enhanced breast cancer cell endothelial interactions.
authors.affiliation: From the National Institute of Cancer Research, National Health Research Institutes, No. 35, Keyan Road, Zhunan Town, Miaoli 350, Taiwan.
authors.forename: Chia-Chi
authors.initials: CC
authors.lastname: Chen
authors.forename: Li-Li
authors.initials: LL
authors.lastname: Chen
authors.forename: Yu-Ting
authors.initials: YT
authors.lastname: Hsu
authors.forename: Ko-Jiunn
authors.initials: KJ
authors.lastname: Liu
authors.forename: Chi-Shuan
authors.initials: CS
authors.lastname: Fan
authors.forename: Tze-Sing
authors.initials: TS
authors.lastname: Huang
mesh_terms: D000818:Animals; D015703:Antigens, CD / Q000235:genetics / Q000378:metabolism; D001943:Breast Neoplasms / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D015815:Cell Adhesion Molecules / Q000235:genetics / Q000378:metabolism; D045744:Cell Line, Tumor; D002465:Cell Movement; D019332:Endothelin-1 / Q000235:genetics / Q000378:metabolism*; D005260:Female; D015972:Gene Expression Regulation, Neoplastic / Q000235:genetics; D064593:Heterografts; D061307:Human Umbilical Vein Endothelial Cells; D006801:Humans; D039564:Integrin alphaV / Q000096:biosynthesis* / Q000235:genetics; D019012:Integrin beta1 / Q000096:biosynthesis* / Q000235:genetics; D008264:Macrophages / Q000378:metabolism* / Q000473:pathology; D051379:Mice; D016688:Mice, Inbred NOD; D016513:Mice, SCID; D009368:Neoplasm Transplantation; D019007:P-Selectin / Q000235:genetics / Q000378:metabolism; D050807:ets-Domain Protein Elk-1 / Q000235:genetics / Q000378:metabolism
chemical_list: D015703:Antigens, CD; D015815:Cell Adhesion Molecules; C494112:ELK1 protein, human; D019332:Endothelin-1; C065289:ICAM2 protein, human; D039564:Integrin alphaV; D019012:Integrin beta1; D019007:P-Selectin; D050807:ets-Domain Protein Elk-1
keywords: Cell-Cell Interaction; Chemotaxis; Endothelin; Macrophages; Tumor Microenvironment