Protein glycosylation in cancer

Abstract

Neoplastic transformation results in a wide variety of cellular alterations that impact the growth, survival, and general behavior of affected tissue. Although genetic alterations underpin the development of neoplastic disease, epigenetic changes can exert an equally significant effect on neoplastic transformation. Among neoplasia-associated epigenetic alterations, changes in cellular glycosylation have recently received attention as a key component of neoplastic progression. Alterations in glycosylation appear to not only directly impact cell growth and survival but also facilitate tumor-induced immunomodulation and eventual metastasis. Many of these changes may support neoplastic progression, and unique alterations in tumor-associated glycosylation may also serve as a distinct feature of cancer cells and therefore provide novel diagnostic and even therapeutic targets.

Keywords: biomarkers; cancer; glycans; glycoprotein; glycosylation; immunohistochemistry; oligosaccharides; transformation.

Figure 1

Animal cells synthesize a wide assortment of glycoproteins in which different amino acids may be modified to contain specific glycan structures. Biosynthesis of such glycoproteins is initiated in the secretory pathway comprising the endoplasmic reticulum and Golgi apparatus of cells and can lead to membrane localization and secretion of glycoproteins. In addition, O-GlcNAc may be added to glycoproteins in the cytoplasm, nucleus, and mitochondria. This single GlcNAc residue is not extended but can be reversibly added and removed. The multiple other types of glycan linkages to proteins can be extended (R groups indicated) with many additional sugar molecules to form oligosaccharides or polysaccharides, all termed glycans. The 10 common monosaccharides that make up animal glycans are indicated: N-acetylglucosamine (GlcNAc), N-acetylgalactosamine (GalNAc), 5-N-acetylneuraminic acid (Neu5Ac, or sialic acid), fucose (Fuc), galactose (Gal), glucose (Glc), glucuronic acid (GlcA); iduronic acid (IdoA); mannose (Man), and xylose (Xyl). 5-N-Glycolylneuraminic acid (Neu5Gc), a non-natural sugar, is also shown. Other abbreviations: ER, endoplasmic reticulum; GPI, glycosylphosphatidylinositol; HyL, hydroxylated lysine.

Figure 2

Cellular transformation is typically accompanied by changes in protein glycosylation on multiple types of glycans; the most commonly studied are N-glycans and O-glycans. Changes in protein glycosylation can result in altered glycoprotein conformation, oligomerization, and turnover and can also be associated with altered cell signaling pathways. Frequently observed altered O-glycans include the Tn and STn antigens. Abbreviations: Fuc, fucose; Gal, galactose; GalNAc, N-acetylgalactosamine; Glc, glucose; GlcA, glucuronic acid; GlcNAc, N-acetylglucosamine; IdoA, iduronic acid; Man, mannose; Neu5Ac, 5-N-acetylneuraminic acid (sialic acid); Neu5Gc, 5-N-glycolylneuraminic acid; STn, sialyl Tn; Xyl, xylose.

Figure 3

During cellular transformation, changes in protein glycosylation on membrane and soluble glycoproteins, such as mucins, are typical and may occur early and/or late in cancer progression, but this phenomenon is not well understood. Different types of changes are shown in the pink-boxed areas, highlighting changes in O-glycans (T, Tn, and STn antigens) and altered expression of branched and fucosylated N- and O-glycans, including changes in Lewis antigens (SLe^x and SLe^a). Abbreviations: Fuc, fucose; Gal, galactose; GalNAc, N-acetylgalactosamine; GlcNAc, N-acetylglucosamine; Man, mannose; Neu5Ac, 5-N-acetylneuraminic acid (sialic acid); Neu5Gc, 5-N-glycolylneuraminic acid; SLe, sialyl Lewis; STn, sialyl Tn.

Figure 4

Specific structures of N- and O-glycans and Lewis antigens along with enzymes responsible for addition of specific sugar residues. Each glycosyltransferase indicated requires a nucleotide sugar donor and acts to add a sugar in a specific anomeric linkage (α or β) to a specific acceptor glycan. Antigens indicated in blue boxes represent the major determinants recognized by monoclonal antibodies. Abbreviations: Fuc, fucose; Gal, galactose; GalNAc, N-acetylgalactosamine; Glc, glucose; GlcA, glucuronic acid; GlcNAc, N-acetylglucosamine; IdoA, iduronic acid; Le, Lewis; Man, mannose; Neu5Ac, 5-N-acetylneuraminic acid (sialic acid); Neu5Gc, 5-N-glycolylneuraminic acid; SLe, sialyl Lewis; STn, sialyl Tn; Xyl, xylose. The Lewis gene encodes the fucosyltransferase responsible for Lewis antigen synthesis.

Figure 5

The expression of the Tn and/or STn antigens can occur in cells lacking the molecular chaperone Cosmc. Cosmc is present in the ER of animal cells and has a single client protein, the T-synthase, to which it binds cotranslationally in the ER to prevent oligomerization and destruction in the proteasome. Successful binding of Cosmc to the T-synthase requires the presence of a novel CBRT (297), which is exposed in non-native T-synthase but becomes buried and inaccessible in the folded T-synthase. Once folded properly, the T-synthase moves to the Golgi apparatus, where it acts quantitatively on the products of the ppGalNAcTs to generate normal O-glycans (102). Abbreviations: CBRT, Cosmc-binding region within T-synthase; ER, endoplasmic reticulum; Gal, galactose; GalNAc, N-acetylgalactosamine; Neu5Ac, 5-N-acetylneuraminic acid (sialic acid); ppGalNAcT, polypeptide GalNAc transferase; STn, sialyl Tn.