Abstract
The tetrasaccharide structures Siaα2,3Galβ1,3(Fucα1,4)GlcNAc and Siaα2,3Galβ1,4(Fucα1,3)GlcNAc constitute the epitopes of the carbohydrate antigens sialyl-Lewis a (sLea) and sialyl-Lewis x (sLex), respectively, and are the minimal requirement for selectin binding to their counter-receptors. Interaction of sLex expressed on the cell surface of leucocytes with E-selectin on endothelial cells allows their arrest and promotes their extravasation. Similarly, the rolling of cancer cells ectopically expressing the selectin ligands on endothelial cells is potentially a crucial step favoring the metastatic process. In this review, we focus on the biosynthetic steps giving rise to selectin ligand expression in cell lines and native tissues of gastrointestinal origin, trying to understand whether and how they are deregulated in cancer. We also discuss the use of such molecules in the diagnosis of gastrointestinal cancers, particularly in light of recent data questioning the ability of colon cancers to express sLea and the possible use of circulating sLex in the early detection of pancreatic cancer. Finally, we reviewed the data dealing with the mechanisms that link selectin ligand expression in gastrointestinal cells to cancer malignancy. This promising research field seems to require additional data on native patient tissues to reach more definitive conclusions.
Highlights
The three members of the selectin family bind carbohydrate structures through a Ca++ -dependent domain
In a recent review [20], we have proposed that the right question to answer is not “why are sialyl-Lewis x (sLex) levels high in colon cancer?” but rather “why are sLex levels low in the normal colon?” Competition between FUT6 and enzymes synthesizing alternative structures, such as Siaα2,3(GalNAcβ1,4)Galβ1,3/4GlcNAc [21,22] or the sialyl 6-sulfo-Lewis x antigen [23] has been proposed
On the O-linked chains of glycoproteins, sLex /sialyl-Lewis a (sLea) expression is strongly dependent on Core 2 GlcNAc transferase (C2GnT) [44], while in glycolipids a pivotal role in their biosynthesis appears to be played by a β1,3GlcNAc transferase which synthesizes a common precursor of both type 1 and 2 chain Lewis structures [45]
Summary
The three members of the selectin family bind carbohydrate structures (and are referred to as lectins) through a Ca++ -dependent domain. The three selectins differ in their structure and pattern of cell type expression. P-selectin is expressed by platelets and endothelial cells and is stored in membranes of α granules of platelets and in Weibel-Palade bodies of endothelial cells It is involved in the earlier steps of the adhesion process since its mobilization to the cell surface of activated endothelial cells from the stores occurs within minutes upon the activation stimuli. Selectins were originally described in the context of inflammation and immunological response, their role in cancer progression soon became evident in consideration of the role played by cancer cell adhesion to endothelia in metastasis. We will highlight the still controversial points requiring further experimental studies
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