Incomplete synthesis and neo-synthesis are two major concepts for
cancer-associated alterations of cell surface
carbohydrate determinants, formulated by Hakomori and collaborators almost 25 years ago. These concepts are still as relevant and useful as ever for
cancer-associated alteration of
carbohydrate determinants. Incomplete synthesis of
carbohydrate determinants occurs through the epigenetic silencing of glycogenes through DNA methylation and/or
histone modification in the early stage
cancers. The natural selection of more malignant
cancer cells occurs through acquisition of
hypoxia resistance by constitutively activated
hypoxia inducible factors (HIFs) in the advanced stages of
cancers. HIFs induce transcription of several important glycogenes, and lead to neo-synthesis of
carbohydrate determinants. For instance, expression of
sialyl Lewis A/X is induced by epigenetic silencing of glycogenes in the early stages, and is further accelerated in the advanced stages by
hypoxia-induced transcription of several glycogenes. Expression of
GM2 ganglioside is induced in
cancers by altered
glycosyltransferase activities, and its N-glycolyl
sialic acid content increases by
hypoxia-induced transcription of a
sialic acid transporter gene. N-glycolyl GM2 thus reflects two
cancer-associated genetic abnormalities in a single determinant, and has high
cancer specificity. Every
carbohydrate determinant is synthesized through multiple steps, each of which is affected by
cancer-associated genetic abnormality. Superiority of
carbohydrate determinants as
cancer-specific molecules over
protein determinants is demonstrated in that a single
carbohydrate determinant can reflect multiple
cancer-associated genetic abnormalities.