Regulation of the metastatic cell phenotype by sialylated glycans

Abstract

Tumor cells exhibit striking changes in cell surface glycosylation as a consequence of dysregulated glycosyltransferases and glycosidases. In particular, an increase in the expression of certain sialylated glycans is a prominent feature of many transformed cells. Altered sialylation has long been associated with metastatic cell behaviors including invasion and enhanced cell survival; however, there is limited information regarding the molecular details of how distinct sialylated structures or sialylated carrier proteins regulate cell signaling to control responses such as adhesion/migration or resistance to specific apoptotic pathways. The goal of this review is to highlight selected examples of sialylated glycans for which there is some knowledge of molecular mechanisms linking aberrant sialylation to critical processes involved in metastasis.

Fig. 1

Types of glycosylation. a Structure of the most common sialic acid, Neu5Ac. The negative charge is from the carboxylic acid group on carbon 1. b N-linked glycans (left) are attached to asparagine (N) residues on selected proteins containing the N-X-S/T consensus sequence, while O-linked glycans (center) are linked to serine (S) or threonine (T) residues. Glycolipids (right) are lipids which carry glycan structures

Fig. 2

Sialic acid linkages. Sialic acids are added to the termini of glycans in an α2-3, α2-6, or α2-8 linkage. In the top two panels, sialic acid linkage to galactose is depicted, however other sugars, such as GalNAc, can be modified with sialic acid, depending upon the type of linkage. Note that the structures shown in the figure have been simplified (e.g., hydroxyl and acetyl groups are not represented)

Fig. 3

α2-6 sialylation blocks galectin binding. Galectins require a free hydroxyl group on the 6 carbon of galactose for binding [37], therefore α2-6 sialylation at this site inhibits galectin binding. In contrast, α2-3-linked sialic acids have variable effects on binding, depending upon the specific galectin species

Fig. 4

Regulation of integrins by sialylation. α2-6 sialylation of N-linked glycans on the β1 integrin enhances cell adhesion to collagen I and stimulates migration and invasion

Fig. 5

Sialyl Thomsen-nouvelle antigen. The sialyl Tn antigen is formed by α2-6 sialylation of GalNAc bound to serine or threonine

Fig. 6

Sialyl Tn antigen expression correlates to increased invasion. Upregulation of the sialyltransferase, ST6GalNAc-I, or inactivation of the chaperone, Cosmc, contributes to an increase in sialyl Tn expression on O-linked glycans. Elevated levels of sialyl Tn antigen expressed on tumor cells is correlated to increased invasion; however, the mechanism remains unclear

Fig. 7

Sialyl Lewis structures promote tumor dissemination. Sialyl Lewis structures on tumor cell glycoproteins interact with selectins expressed by activated endothelial cells, thereby facilitating tumor cell extravasation

Fig. 8

Sialyl Lewis antigens. Sialyl Lewis (sLe) antigens are tetrasaccharide structures composed of a GlcNAc-Gal backbone with fucose linked to GlcNAc and sialic acid α2-3 linked to Gal. sLe^x and sLe^a are different isomers, both of which bind to endothelial selectins

Fig. 9

Inhibition of Fas-mediated apoptosis by α2-6 sialylation. α2-6 sialylation of the Fas receptor blocks apoptosis by preventing receptor internalization and formation of the death-inducing signaling complex (DISC)