Mixed-Up Sugars: Glycosyltransferase Cross-Reactivity in Cancerous Tissues and Their Therapeutic Targeting

The main categories of glycan changes in cancer are: (1) decreased expression of histo-blood group A and/or B antigens and increased Lewis-related antigens, (2) appearance of cryptic antigens, such as Tn and T, (3) emergence of genetically incompatible glycans, such as A antigen expressed in tumors of individuals of group B or O and heterophilic expression of Forssman antigen (FORS1), and (4) appearance of neoglycans. This review focuses on the expression of genetically incompatible A/B/FORS1 antigens in cancer. Several possible molecular mechanisms are exemplified, including missense mutations that alter the sugar specificity of A and B glycosyltransferases (AT and BT, respectively), restoration of the correct codon reading frame of O alleles, and modification of acceptor specificity of AT to synthesize the FORS1 antigen by missense mutations and/or altered splicing. Taking advantage of pre-existing natural immunity, the potential uses of these glycans for immunotherapeutic targeting will also be discussed.