Galectin-1 induces vascular permeability through the neuropilin-1/vascular endothelial growth factor receptor-1 complex.
Galectin-1 (Gal-1) is a β-galactoside-binding lectin that regulates endothelial cell migration, proliferation, and adhesion. However, the effect of Gal-1 on vascular permeability and the underlying mechanisms are unclear. We found that high Gal-1 expression was associated with elevated tumor vascular permeability in specimens of oral squamous cell carcinoma. Using transendothelial passage of FITC-dextran and a Miles assay, we demonstrated that Gal-1 increased vascular permeability extracellularly through its carbohydrate recognition domain. Mechanism dissection revealed that the neuropilin (NRP)-1/vascular endothelial growth factor receptor- (VEGFR)-1 complex was required for Gal-1-regulated vascular permeability. Activation of VEGFR-1 triggered activation of Akt which led to a reduction in vascular endothelial-cadherin at cell-cell junctions and resulted in cytoskeletal rearrangement. Both inhibition of Gal-1 secreted from cancer cells and administration of an anti-Gal-1 antibody in the tumor microenvironment suppressed tumor growth and vascular permeability in xenograft models. In conclusion, our results demonstrate a novel function of Gal-1 of increasing vascular permeability through the NRP-1/VEGFR1 and Akt signaling pathway and indicate that targeting Gal-1 by an anti-Gal-1 antibody is a feasible therapy for vascular hyperpermeability and cancer.
Graduate Institute of Translational Medicine, College of Medical Sciences and Technology, Taipei Medical University, Taipei, Taiwan.
Ming-Heng
MH
Wu
Nien-Wen
NW
Ying
Tse-Ming
TM
Hong
Wei-Fan
WF
Chiang
Yueh-Te
YT
Lin
Yuh-Ling
YL
Chen
D000199:Actins / Q000737:chemistry; D002199:Capillary Permeability; D045744:Cell Line, Tumor; D002465:Cell Movement; D049109:Cell Proliferation; D037483:Galectin 1 / Q000378:metabolism*; D061307:Human Umbilical Vein Endothelial Cells; D006801:Humans; D007150:Immunohistochemistry; D016086:Lentivirus / Q000235:genetics; D039942:Neuropilin-1 / Q000378:metabolism*; D010539:Permeability; D010766:Phosphorylation; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism; D034741:RNA, Small Interfering / Q000378:metabolism; D040281:Vascular Endothelial Growth Factor Receptor-1 / Q000378:metabolism*; D020742:rhoA GTP-Binding Protein / Q000378:metabolism
D000199:Actins; D037483:Galectin 1; D034741:RNA, Small Interfering; C066737:RHOA protein, human; D039942:Neuropilin-1; D040281:Vascular Endothelial Growth Factor Receptor-1; D051057:Proto-Oncogene Proteins c-akt; D020742:rhoA GTP-Binding Protein