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Role of sialylated human milk oligosaccharides in inhibiting angiogenesis

Angiogenesis is an important characteristic of tumors that aids tumor growth, progression and invasion. This is mediated by angiogenic factors such as VEGF, that act on VEGF receptors (VEGFRs) to promote the proliferation and migration of endothelial cells. 

The anti-tumorigenic activity of human milk oligosaccharides (HMOs), particularly the anti-angiogenic effect of sialylated HMOs, have been described in several studies, however with unexplained mechanism of action. Chung et al uncovered the composition of oligosaccharide in HMOs that is responsible for the anti-angiogenic effect of silalylated HMOs and investigated the mechanism of its anti-angiogenic function. 

A series of structural core units of oligosaccharides in HMOs were tested for their effect on VEGFR in human umbilical vein endothelial cells (HUVECs), including lactose, lacto N-biose, N-acetyllactosamine, 3′-sialyllactosamine, 6′-sialyllactosamine, 3′-sialyllactose (3SL), and 6′-sialyllactose (6SL) from Carbosynth. Of these, 3SL and 6SL demonstrated dose-dependent loss of VEGF-mediated VEGFR-2 phosphorylation and hence suppressed activation of downstream pathways – such as PI3K/Akt, ERK and p38. 

Further experiments using 3SL, demonstrated inhibition of HUVEC proliferation, migration and actin filament formation. Interaction studies, using immunoprecipitation and high performance thin layer chromatography (HPLC) revealed binding of 3SL to the third IgG-like domain in the extracellular domain of VEGFR, the binding site for VEGF.

Moreover, a 3D model for angiogenesis using a Matrigel plug assay, showed reduced vascularization in response to VEGF when treated with 3SL. Having no cytotoxic effect on allograft tumor cells, inhibition of angiogenesis by 3SL resulted in reduced growth of allograft tumors.

Overall, the anti-angiogenic activity of sialyllactose makes it a potential candidate for pharmacological inhibition of VEGF. Its low toxicity favors its use over current VEGF inhibitors. Further investigation of sialyllactose is required to determine its specificity and in vivo toxicity are suggested for future studies.

For further details, please refer to the original paper: Chung TW et al (2018).

 

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