Abstract
The oligosaccharides in human milk have various biological functions. However, the molecular mechanism(s) underlying the anti-angiogenic action of sialylated human milk oligosaccharides (HMOs) are still unclear. Here, we show that siallylactose (SL) found in human milk can inhibit the activation of vascular endothelial growth factor (VEGF)-mediated VEGF receptor-2 (VEGFR-2) by binding to its VEGF binding site (second and third IgG-like domains), thus blocking downstream signal activation. SL also inhibits growth of VEGF-stimulated endothelial cells. In endothelial cells treated with VEGF, SL diminished tube formation, migration, and the arrangement of actin filament. In addition, SL clearly suppressed VEGF-induced neovascularization in an in vivo Matrigel plug assay. Notably, SL prevented the growth of tumor cells, and angiogenesis on tumor tissues in in vivo mice models allotransplanted with Lewis lung carcinoma, melanoma, and colon carcinoma cells. Taken together, we have demonstrated that the sialylated milk oligosaccharide sialyllactose functions as an inhibitor of angiogenesis through suppression of VEGF-mediated VEGFR-2 activation in endothelial cells, Accordingly, it could be a novel candidate for the development of anti-angiogenic drugs without any side effects.
Highlights
Human milk is composed of many bioactive ingredients, including milk oligosaccharides [1, 2]
We show that siallylactose (SL) found in human milk can inhibit the activation of vascular endothelial growth factor (VEGF)mediated VEGF receptor-2 (VEGFR-2) by binding to its VEGF binding site, blocking downstream signal activation
We have demonstrated that the sialylated milk oligosaccharide sialyllactose functions as an inhibitor of angiogenesis through suppression of VEGFmediated VEGFR-2 activation in endothelial cells, it could be a novel candidate for the development of anti-angiogenic drugs without any side effects
Summary
Human milk is composed of many bioactive ingredients, including milk oligosaccharides [1, 2]. It has been suggested that human milk oligosaccharides (HMOs) have diverse biological functions. They can function as including prebiotics, anti-microbials, modulators of intestinal epithelial cell, and regulators of the immune system [3, 4]. HMOs form a complex group of oligosaccharides composed of more than a hundred different glycans. They are constructed by five basic monosaccharide elements, including glucose (Glc), galactose (Gal), N-acetylglucosamine (GlcNAc), fucose (Fuc), and sialic acid (Sia) [4]. Especially sialic acid-containing oligosaccharides, play critical roles in the progression of tumorigenesis, including www.impactjournals.com/oncotarget neoplastic transformation, survival, tumor-induced immune modulation, and metastasis [9]. Acetamido GM3 (a-GM3 including lactose moiety with sialic acid) which forms the core glycan component of the gangliosides, interacts with human galectin-3 associated with diseases including cancer, inflammation, and angiogenesis [10]
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