**2. Chondroitin sulfate biosynthesis and presentation**

A relative variation in the composition of CS/DS has been reported in neoplastic tissues (Chiarugi and Dietrich, 1979; Bumol et al., 1982; Reisfeld and Cheresh, 1987; Olsen et al., 1988; Alini and Losa, 1991; Vijayagopal et al., 1998; Vynios et al., 2008).

Fig. 1. **A)** Proteoglycans consist of a core protein and covalently attached GAG chains. **B)** Biosynthesis of chondroitin and heparan sulfate building blocks initiates by the formation of a linkage tetrasaccharide attached to serine residue on the core protein. GlcA: Glucuronic acid; GlcNAc: N-acetyl-D-glucosamine; GalNAc: N-acetyl-D-galactosamine; Gal: Galactose; Xyl: xylose.

Chondroitin sulfate (CS)/ dermatan sulfate (DS) polysaccharides are widely distributed in extracellular matrices and at cell surfaces as PGs, in which glycosaminoglycan (GAG) chains are covalently attached to a variety of core proteins (**Figure 1A**) (Esko et al., 1999). Chondroitin or heparan backbone is synthesized on the common GAG-protein linkage region tetrasaccharide (GlcUA-Galactose-Galactose-Xlylose) (**Figure 1B**), which is attached to specific serine residues in the respective core protein (Silbert and Sugumaran, 2002; Sugahara et al., 2003).

Large variation exists in CS-GAG sequences and in proteoglycans (PGs) presenting them. The prevalence of a presenting core protein may predict the functional outcomes of Pselectin-mediated adhesion of tumor cells. To use these molecules as targets for diagnostic or therapeutic purposes, a thorough understanding of their presentation and expression is necessary. This chapter reviews the biological roles of chondroitin sulfates (CS) in tumor development and metastasis and the role of different types of CS and the core protein

A relative variation in the composition of CS/DS has been reported in neoplastic tissues (Chiarugi and Dietrich, 1979; Bumol et al., 1982; Reisfeld and Cheresh, 1987; Olsen et al.,

Fig. 1. **A)** Proteoglycans consist of a core protein and covalently attached GAG chains. **B)** Biosynthesis of chondroitin and heparan sulfate building blocks initiates by the formation of a linkage tetrasaccharide attached to serine residue on the core protein. GlcA: Glucuronic acid; GlcNAc: N-acetyl-D-glucosamine; GalNAc: N-acetyl-D-galactosamine; Gal: Galactose;

Chondroitin sulfate (CS)/ dermatan sulfate (DS) polysaccharides are widely distributed in extracellular matrices and at cell surfaces as PGs, in which glycosaminoglycan (GAG) chains are covalently attached to a variety of core proteins (**Figure 1A**) (Esko et al., 1999). Chondroitin or heparan backbone is synthesized on the common GAG-protein linkage region tetrasaccharide (GlcUA-Galactose-Galactose-Xlylose) (**Figure 1B**), which is attached to specific serine residues in the respective core protein (Silbert and Sugumaran, 2002;

carrying these polysaccharides.

Xyl: xylose.

Sugahara et al., 2003).

**2. Chondroitin sulfate biosynthesis and presentation** 

1988; Alini and Losa, 1991; Vijayagopal et al., 1998; Vynios et al., 2008).

The Chondroitin chain backbone consists of repetitive disaccharide units containing Dglucuronic acid (GlcUA) and *N*-acetyl-D-galactosamine (GalNAc) residues. They further differentiate into variable chains with distinct structures and functions after various modifications. Sulfation and epimerization will further generate CS/DS isomers (**Table 1**). DS or CS-B is a stereoisomeric variant of CS with varying proportions of L-iduronic acid (IdoUA) in place of GlcUA, which forms by epimerization of GlcUA to IdoUA (**Table 1**).


Table 1. Chondroitin sulfate types

The monosulfated disaccharide A-unit [GlcUA-GalNAc(4S)] and C-unit [GlcUA-GalNAc(6S)] are common and major components of mammalian CS chains. Disulfated disaccharide D-unit [GlcUA(2S)-GalNAc(6S)] and E-unit [GlcUA-GalNAc(4S,6S)] also exist that are based on further sulfation of monosulfated C and A units, respectively.

CS/DS chains that often found as CS/DS hybrid structures have the potential to display an enormous structural diversity by embedding multiple overlapping sequences constructed with distinct disaccharide blocks modified by different patterns of sulfation (Kusche-Gullberg and Kjellen, 2003; Sugahara et al., 2003). Given the complexity of these structures, the expression of modifying enzymes may correlate better with an aggressive tumor phenotype. Therefore, linking the expression of these enzymes with a functional role of cell surface CS glycans is highly significant
