Galectin-Binding O-Glycosylations as Regulators of Malignancy

Abstract

Cancer cells commonly display aberrant surface glycans and related glycoconjugate scaffolds. Compared with their normal counterparts, cancer cell glycans are variably produced and often structurally distinct, serving as biomarkers of cancer progression or as functional entities to malignancy. The glycan signature of a cancer cell is created by the collaborative activities of glycosyltransferases, glycosidases, nucleotide-sugar transporters, sulfotransferases, and glycan-bearing protein/lipid scaffolds. In a coordinated fashion, these factors regulate the synthesis of cancer cell glycans and thus are considered correlates of cancer cell behavior. Functionally, cancer cell glycans can serve as binding targets for endogenous lectin effectors, such as C-type selectins and S-type galectins. There has been a recent surge of important observations of the role of glycosytransferases, specifically α2,6 sialyltransferases, in regulating the length and lectin-binding features of serine/threonine (O)-glycans found on cancer cells. The capping activity of O-glycan-specific α2,6 sialyltransferases, in particular, has been found to regulate cancer growth and metastasis in a galectin-dependent manner. These findings highlight the functional importance of cancer cell O-glycans and related galectin-binding features in the virulent activity of cancer and raise the prospect of targeting cancer cell glycans as effective anticancer therapeutics.

Figure 1. ST6GalNAc1-4 enzyme activities help regulate Gal-1- and Gal-3-binding moieties on O-glycans

Data indicate that the virulent behavior of breast and lung cancer cells is regulated, in part, by ST6GalNAc2 and ST6GalNAc4 and related synthesis of Gal-3-binding moieties (47, 48). Results from other work indicate that O-glycan-bearing poly-N-acetyllactosamines are regulated by ST6GalNAc2 and help mediate Gal-1 ligand activity and related tumorigenic potential of melanoma cells (26).

Figure 2. Novel insights on ST6GalNAcs and Gal-1/Gal-3-binding O-glycans in cancer growth and metastasis

Results from recent studies indicate that: (A) Gal-3 facilitates intravascular aggregation and vascular adhesion of breast cancer cells expressing low levels of ST6GalNAc2 expression and related α2,6 sialyl-O-glycan moieties, increasing lung metastatic potential (48); (B) Gal-3 on liver-resident macrophages encourages binding activity to metastatic lung cancer cells expressing elevated levels of ST6GalNAc4 and low levels of GCNT3 (47); and (C) host Gal-1 encourages melanoma cell migration and in vivo growth, in part, by binding poly-N-acetyllactosaminyl O-glycans inhibited by ST6GalNAc2 (26).