Mucin-type O-glycans in human colon and breast cancer: glycodynamics and functions

Abstract

The glycoproteins of tumour cells are often abnormal, both in structure and in quantity. In particular, the mucin-type O-glycans have several cancer-associated structures, including the T and Tn antigens, and certain Lewis antigens. These structural changes can alter the function of the cell, and its antigenic and adhesive properties, as well as its potential to invade and metastasize. Cancer-associated mucin antigens can be exploited in diagnosis and prognosis, and in the development of cancer vaccines. The activities and Golgi localization of glycosyltransferases are the basis for the glycodynamics of cancer cells, and determine the ranges and amounts of specific O-glycans produced. This review focuses on the glycosyltransferases of colon and breast cancer cells that determine the pathways of mucin-type O-glycosylation, and the proposed functional and pathological consequences of altered O-glycans.

Figure 1

Biosynthesis of the sialyl-Tn antigen. In the biosynthetic pathway that forms the sialyl-Tn (STn) antigen, a family of polypeptide N-acetylgalactosamine (GalNAc)-transferases (ppGalNAcT) initially adds a GalNAc residue to Ser or Thr of the peptide. This is followed by the addition of sialic acid in α2-6 linkage to GalNAc, catalysed by a family of α6-sialyltransferases (ST6GalNAc), and produces the STn antigen. Although GalNAc can be further converted to core structures, STn can only be a substrate for an O-acetylation reaction to produce O-acetyl-STn that is not recognized by anti-STn antibodies. Bars across the arrows indicate a block in the biosynthetic pathway.

Figure 2

Biosynthesis of the T antigens. N-acetylgalactosamine (GalNAc; Tn antigen) can be converted to core 1 (T antigen) by core 1 β3-Gal-transferase (core 1 GalT) or to core 3 structures by core 3 β3-N-acetylglucosamine (GlcNAc)-transferase (core 3 GlcNAcT), which can be branched by C2GnT2 to form core 4. Colonic mucosum expresses the enzymes that synthesize cores 1–4. In mammary cells, cores 1 and 2, but not cores 3 and 4, are synthesized. Core 1 can be converted to sialyl-T antigens by α3-sialyltransferases (ST3Gal) or by α6-sialyltransferases (ST6GalNAc). Alternatively, core 1 can be elongated by a β3-GlcNAc-transferase (elong. GlcNAcT) or can be branched by C2GnT to form core 2. All core structures can be further extended to form complex O-glycans.

Figure 3

Assembly of Lewis antigens. Terminal N-acetylglucosamine (GlcNAc) residues, and especially those of core 2 structures, can be used as the basis for the attachment of Lewis antigens. The sialyl-Lewis^x (SLe^x) structure is synthesized by the addition of a β4Gal to GlcNAc (type 2 chain) by β4-Gal-transferase (β4-GalT), followed by the addition of α3-sialic acid to Gal by α3-sialyltransferase (ST3Gal) and of α3-Fuc to GlcNAc by α3-Fuc-transferase (α3-FucT). Type 1 chains are synthesized by β3-Gal-transferase (β3-GalT). ST3Gal and α4-Fuc-transferase (α4-FucT) then assemble the sialyl-Lewisa antigen.

Figure 4

Distribution of glycosyltransferases in the Golgi. The diagram shows the localization of several membrane-bound glycosyltransferases that assemble O-glycans in the Golgi, on the basis of studies of several different cell types. β4GalT, β4-Gal-transferase; C2GnT, core 2 β6-N-acetylglucosamine (GlcNAc)-transferase 1; Core 1GalT, core 1 β3-Gal-transferase synthesizing core 1, the T antigen; ppGalNAcT, polypeptide N-acetylgalactosamine (GalNAc)-transferase; ST3Gal, α3-sialyltransferase I acting on core 1; ST6GalNAc, α6-sialyltransferase I acting on GalNAc. Due to the broad localization of ppGalNAcT in HeLa cells, GalNAc can be added to Ser/Thr throughout the Golgi. Core 1 and 2 synthesis starts in the cis-Golgi, and chains are completed in the medial Golgi and trans-Golgi. C2GnT competes with ST3Gal for the core 1 substrate. Most of the elongation reactions involving Galβ1-4 residues (that is, the synthesis of type 2 chains and SLe^x) occur in the trans-Golgi. The arrow shows the transport of glycoproteins from the endoplasmic reticulum (ER) to the cell surface. Some of the glycosyltransferases might form protein complexes of as yet unknown composition. TGN, trans-Golgi network.

Inka Brockhausen