Distant
metastasis account for about 90 % of
cancer associated deaths, and yet the oncology field is cruelly lacking tools to accurately predict and/or prevent
metastasis. Distant
metastasis occurs when
circulating tumor cells interact with the endothelium of distant organs and extravasate from the blood vessel into the surrounding tissue.
Selectins are a family of
carbohydrate receptors well depicted for their role in
tumor cells extravasation. They mediate primary interactions of
cancer cells with endothelial cells, as well as secondary interactions with leucocytes and platelets, which are also promoting
metastasis. The
cancer associated
carbohydrate antigen sialyl-Lewis x (
sLe(x)) has been repeatedly shown to be involved, as
selectin ligand, in these interactions. However, recent studies have highlighted that
glycosaminoglycans (GAGs), another class of
glycans, may also serve as
ligands for
selectins. We report herein that
cancer-associated GAGs are differentially recognized by
selectins according to their density of sulfation and the pH conditions of the binding. We also show that these parameters regulate platelets-
cancer cells heterotypic aggregation, supporting the idea that GAGs may have pro-metastatic function. Combining our experimental results with in depth analyses of molecular dockings, we propose a model of GAG/
selectin interactions robust enough to recapitulate the differential binding of
selectins to GAGs, the competition between GAGs and
sLe(x) for
selectin binding and the effect of sub-physiological pH on GAGs affinities towards
selectins. Altogether, our data suggest GAGs to be good
ligands for
selectins, potentially promoting distant
metastasis in a complementary way to
sLe(x).