Altered tumor-cell glycosylation promotes metastasis

Abstract

Malignant transformation of cells is associated with aberrant glycosylation presented on the cell-surface. Commonly observed changes in glycan structures during malignancy encompass aberrant expression and glycosylation of mucins; abnormal branching of N-glycans; and increased presence of sialic acid on proteins and glycolipids. Accumulating evidence supports the notion that the presence of certain glycan structures correlates with cancer progression by affecting tumor-cell invasiveness, ability to disseminate through the blood circulation and to metastasize in distant organs. During metastasis tumor-cell-derived glycans enable binding to cells in their microenvironment including endothelium and blood constituents through glycan-binding receptors - lectins. In this review, we will discuss current concepts how tumor-cell-derived glycans contribute to metastasis with the focus on three types of lectins: siglecs, galectins, and selectins. Siglecs are present on virtually all hematopoietic cells and usually negatively regulate immune responses. Galectins are mostly expressed by tumor cells and support tumor-cell survival. Selectins are vascular adhesion receptors that promote tumor-cell dissemination. All lectins facilitate interactions within the tumor microenvironment and thereby promote cancer progression. The identification of mechanisms how tumor glycans contribute to metastasis may help to improve diagnosis, prognosis, and aid to develop clinical strategies to prevent metastasis.

Keywords: cancer; galectins; glycan ligands; glycosylation; metastasis; mucins; selectins; siglecs.

Figure 1

Biosynthesis of O-glycans. O-glycan synthesis is initiated by linking of GalNAc to the protein at Ser or Thr residue. The simplest O-glycan Tn antigen can be further converted to core 1 structure (T antigen) by β1,3 galactose extension; core 3 structure by addition of β1,3-GlcNAc. During cancer increased expression (green arrow) of sialyltransferases with concomitant reduced expression (red arrow) of core 1 GalT and core 3 GlcNAcT leads to increased formation of sialyl-Tn and sialyl-T antigens. Core 1 structure is further branched by C2GnT1 to form core 2 that can be further modified to poly-N-acetyllactosamine structures carrying sialyl-Lewis^x/a [modified from Ref. (23)].

Figure 2

Formation of Lewis antigens. Terminal GlcNAc residues, particularly on core 2 structures, are further extended by addition of β1,4 galactose, for Lewis^x epitope, and β1,3 galactose, for Lewis^a epitope. This is further followed by the addition of α2,3-linked sialic acid to Gal by ST3Gal enzymes and finalized by the addition of α1,3-linked fucose for sLe^x and α1,4-linked fucose for the sLe^a antigen. FUT3 finalized the synthesis of Lea antigen, while FUT6 and FUT7 were shown to finalize Le^x epitopes.