Ingrid 't Hart

28 Chapter 2 2 Introduc�on Glycosphingolipids (GSPs) are a diverse group of biomolecules that are composed of ceramide modified by a glycan. They decorate the cell surface of all vertebrate cells and play important roles in a variety of cellular processes such as cell signalling, trafficking, adhesion, prolifera�on, and immune modula�on. 1 GSPs are also cri�cally involved in embryogenesis and are expressed in stage dependent manner. For example, globopentaosyl ceramide ( 1 , Gb5Cer or SSEA-3, Fig. 1) and monosialyl Gb5Cer ( 2 , MSGb5Cer or SSEA-4), which belong to the globo-series of GSPs, are well established markers of pluripotent stem cells and their expression is o�en used for embryonic stem cell (ES) characteriza�on. Recently, a number of other GSPs, including Gb4, Lc4, fucosyl Lc4Cer, Globo H, and disialyl Gb5 ( 3 , DSGb5), were iden�fied in undifferen�ated human ES and iPS cells. 2 It was found that during ES differen�a�on, the biosynthesis of globo- and lacto-series GSPs declines and switches to the forma�on of ganglioside type GSPs. 3 A number of GSPs that are expressed during early embryogenesis reoccur during oncogenesis. For example, Gb5 and MSGb5 are highly expressed in breast cancer, 4 tes�cular germ cell tumors, 5 and aggressive human renal cell carcinomas. 6 Furthermore, GSLs such as Globo-H are overexpressed by many epithelial cell cancers and occur on cancer stem cells. The overexpression of these glycolipids appears to promote tumorigenicity, 7 immune suppression, 8 and enhances cancer cell mo�lity and invasiveness. 9 The chemical synthesis of the oligosaccharide moie�es of these glycolipids has received considerable a�en�on, 10 which has made it possible to examine biological proper�es of individual GSPs and opened the way to develop immune-therapeu�c strategies such as experimental cancer vaccines. 11 Figure 1. Chemical structures of Gb5 ( 1 ), MSGb5 ( 2 ) and DSGb5 ( 3 ) where the fa�y acid chain length can vary between n = 14 – 22. O HO O O AcHN O HO OH O OH O HO OH O HO O O OH HO OH O O OH HO OH O HO OH HO HO AcHN COOH O HO OH HO HO AcHN COOH O HN O (CH 2 ) n CH 3 OH (CH 2 ) 12 CH 3 O HO OH O AcHN O HO OH O OH O HO OH O HO O O OH HO OH O O OH HO OH O HO OH HO HO AcHN COOH O HN O (CH 2 ) n CH 3 OH (CH 2 ) 12 CH 3 O HO OH O AcHN O HO OH HO OH O HO OH O HO O O OH HO OH O O OH HO OH O HN O (CH 2 ) n CH 3 OH (CH 2 ) 12 CH 3 1 Gb5 3 DSGb5 2 MSGb5