Ingrid 't Hart

13 Introduc�on 1 1.2 GSLs and SGLs in cancer Carcinogenesis is the transforma�on of normal cells into tumor cells and is characterized by changes in biological processes such as increased prolifera�on, resistance of cell death, evasion of growth suppression and increased migra�on. 44 Most of these biological processes involve glycans and during cellular transforma�on, altera�ons in the glycosyla�on have been observed. In early stages of cancer a decrease in glycosyla�on is commonly seen, leading to truncated structures such as sialyl Tn (STn). The forma�on of neo-epitopes, such as sialyl Lewis a (SLe a ) and sialyl Lewis x (SLe x ), has been correlated with more advanced stages of cancer. Overall, an increase in sialyla�on is highly associated with carcinogenesis. 45 Furthermore, higher Gal-3-O-sulfotransferase ac�vity was seen in breast and colon cancer cells compared to healthy cells. 17 Both neutral and nega�vely charged GSLs (gangliosides or SGLs) are up- or downregulated in different types of cancer: a selec�on of globo- and ganglio-series glycans are listed in Table 1. 46,47 Table 1. Globo- and ganglio-series GSLs and SGLs and their prevalence in different types of cancer. Adapted from Zhuo et al., 2018. 16,18,46,47,48,49 GSLs form a great pool of tumor markers, however their exact roles in cancer remains to be elucidated. Some pathways and interac�ons have been proposed in literature, mainly focusing on cell-cell interac�ons, cell adhesion, growth factor regula�on and immune cell func�on. For convenience, GSL abbrevia�ons in the discussion on GSLs in cancer and autoimmune diseases will be used without descrip�on of the lipid moiety: e.g. “Gb3” instead of “Gb3-Cer”. GSL Structure Cancer type Gb3 Galα1,4Lac -Cer lung↑, colorectal↑, gastric↑ Gb4 GalNAcβ1,3Galα1,4Lac -Cer colorectal↑ Gb5 Galβ1,3GalNAcβ1,3Galα1,4Lac -Cer breast↑ Globo-H Fucα1,2Galβ1,3GalNAcβ1,3Galα1,4Lac -Cer breast↑, prostate↑, MSGb5 Neu5Acα2,3Galβ1,3GalNAcβ1,3Galα1,4Lac -Cer breast↑, renal↑, prostate↑, DSGb5 Neu5Acα2,3Galβ1,3[Neu5Acα2,6]GalNAcβ1,3Galα1,4Lac - Cer renal↑, prostate↓ GM3 Neu5Acα2,3Lac -Cer colorectal↓, leukemia↑↓, ovarian↓, renal↑, bladder↓ SM3 3-O-SO 3 -Lac-Cer renal↑, liver↑ GM2 GalNAcβ1,4[Neu5Acα2,3]Lac -Cer lung↑ SM2 GalNAcβ1,4[3 -O-SO 3 ]Lac -Cer renal↑ GM1 Galβ1,3GalNAcβ1,4[Neu5Acα2,3]Lac -Cer colorectal↓ GD3 Neu5Acα2,8Neu5Acα2,3Lac -Cer breast↑, melanoma↑, ovarian↑ GD2 GalNAcβ1,4[Neu5Acα2,8Neu5Acα2,3]Lac -Cer breast↑, melanoma↑ GD1a Neu5Acα2,3Galβ1,3GalNAcβ1,4[Neu5Acα2,3]Lac -Cer colorectal↓, prostate↑ SB1a 3-O-SO 3 - Galβ1,3GalNAcβ1,4[3 -O-SO 3 ]Lac -Cer renal↑ GD1α Neu5Acα2,3Galβ1,3[Neu5Acα2,6]GalNAcβ1,4Lac -Cer breast↑ GD1b Galβ1,3GalNAcβ1,4[Neu5Acα2,8Neu5Acα2,3]Lac -Cer breast↓