Glycosylation defining cancer malignancy: New wine in an old bottle

Aberrant glycosylation occurs in essentially all types of experimental and human cancers, as has been observed for over 35 years, and many glycosyl epitopes constitute tumor-associated antigens. A long-standing debate is whether aberrant glycosylation is a result or a cause of cancer. Many recent studies indicate that some, if not all, aberrant glycosylation is a result of initial oncogenic transformation, as well as a key event in induction of invasion and metastasis. Glycosylation promoting or inhibiting tumor cell invasion and metastasis is of crucial importance in current cancer research. Nevertheless, this area of study has received little attention from most cell biologists involved in cancer research, mainly because structural and functional concepts of glycosylation in cancer are more difficult to understand than the functional role of certain proteins and their genes in defining cancer cell phenotypes. Glycosylation appears to be considered “in the shade” of more popular topics such as oncogenes and antioncogenes, apoptosis, angiogenesis, growth factor receptors, integrin and caderin function, etc., despite the fact that aberrant glycosylation profoundly affects all of these processes. The apoptotic signaling triggered by glycosylation presents an immense challenge for future study. The concept of glycosylation-dependent promotion or inhibition of tumor progression has developed in conjunction with clinicopathological studies. High expression of some glycosyl epitopes promotes invasion and metastasis, leading to shorter 5–10 year survival rates of patients, whereas expression of some other glycosyl epitopes suppresses tumor progression, leading to higher postoperative survival rates (for review see refs. 1 and 38). The former category of epitopes includes β6GlcNAc branching in N -linked structure; sialyl-Tn in O -linked structure; sialyl-Lex, sialyl-Lea, and Ley in either N -linked, O -linked, or lipid-linked structure; GM2, GD3, and sialyl-Gb5 in lipid-linked structure. The latter category includes β4GlcNAc competitive with β6GlcNAc; histo-blood group A …