Ingrid 't Hart

76 Chapter 4 4 Introduc�on Cancer cells o�en express aberrant glycans, such as truncated structures, or having altered fucosyla�on or increased sialyla�on. 1 Over the years, many tumor associated carbohydrate an�gens (TACAs) have been discovered. 2 Glycoprotein TACAs, such as (sialyl-)Thomson-nouveau (sTn), (sialyl-)Thomsen-Friedenreich (sT) and (sialyl-)Lewis (sLe) an�gens 3,4 have received considerable a�en�on. Furthermore, glycosphingolipid and sulfoglycolipid an�gens have been found to be key players in various cancers. Examples include ganglio-series GM3, SM3, GM2, GD3, GD2 and SB1a and globo-series Gb3, Gb4, Gb5, Globo-H, MSGb5 and DSGb5. 5,6,7 An�bodies against these carbohydrate an�gens are a�rac�ve candidates for cancer cell detec�on and vaccine development. 2,8,9 Epiglycanin is a mucin-type glycoprotein that was first isolated from mouse mammary carcinoma cells. 10,11 The an�-epiglycanin an�body (AE3, later named HAE3) was raised against epiglycanin. HAE3 cross-reacts with human epithelial carcinoma-associated an�gen (HCA) in serum samples of pa�ents with epithelial carcinomas such as; lung, bladder, prostate, esophagus, ovarian and breast cancer. 12,13 However, li�le is known about the specific glycoan�gen that HAE3 recognizes. A carbohydrate microarray study revealed that HAE3 binds similar structures as the lec�n PNA (specific to Galβ1,3GalNAc), but did not show any binding to blood group or Lewis an�gens. Surprisingly, the sulfated glycolipid SM1a showed strong binding to HAE3. 14 SM1a is the sulfoglycolipid (SGL) analog of ganglio-series glycosphingolipid GM1a (Fig 1A). GM1a has a sialic acid (α2,3-)linked to the inner galactose residue, while SM1a has a (3- O -)sulfate group on the C-3 of this galactose. SM1a was first isolated from rat and green monkey in kidney cells and is proposed to be a precursor of SB1a (Fig 1A). 15,16 Li�le is known about the role of SM1a and its analogs in healthy or cancerous cells. Nevertheless, other SGLs have been associated with different types of cancer. In breast cancer, upregulated 3- O -sulfotransferase ac�vity was detected towards core 3 O -glycans, lactosamine and globo-sequences. 17 Furthermore, SM3 (sulfated analog of GM3) and disulfated SB1a have been reported to be upregulated in liver carcinoma. 18,19 Figure 1. ( A ) SM1a : R 1 = SO 3 - , R 2 = H, SB1a, SB1a : R 1 = R 2 : SO 3 - and GM1a : R 1 = α2,3Neu5Ac, R 2 = H | ( B ) Proposed SM1-core3 glycan 14 (R = Ser or Thr). Target of this chapter: 1 , R = (CH 2 ) 5 NH 2 . O OH O HO HO OCer O OH O R 1 O OH O HO OH O AcHN O HO OH R 2 O HO A SM1a residue O NHAc O HO HO O AcHN OR O OH HO O OH O NaO 3 SO OH O HO OH O AcHN O HO OH HO HO core3 B 1