Carbohydrate antigen sialyl Lewis a (CA19-9) is the most frequently applied serum
tumor marker for diagnosis of
cancers in the digestive organs. Recent progress disclosed the presence of a normal counterpart of the determinant, namely disialyl Lewis a, which is predominantly expressed in non-malignant epithelial cells of the digestive organs, while
sialyl Lewis a is preferentially expressed in
cancers. The disialyl Lewis a determinant carries one extra sialic residue attached through a 2 --> 6 linkage to the GlcNAc moiety compared to
cancer-associated
sialyl Lewis a, which carries only one 2 --> 3 linked
sialic acid residue (monosialyl Lewis a). Disialyl Lewis a in normal epithelial cells serves as a
ligand for immunosuppressive receptors such as
sialic acid binding
immunoglobulin (Ig)-like
lectins (siglec-7) and -9 expressed on resident monocytes/macrophages and maintains immunological homeostasis of mucosal membranes in digestive organs. Epigenetic silencing of a gene for a 2 --> 6 sialyl-
transferase in the early stages of
carcinogenesis results in an impairment of 2 --> 6 sialylation, leading to incomplete synthesis and accumulation of
sialyl Lewis a, which lacks the 2 --> 6 linked
sialic acid residue, in
cancer cells. Simultaneous determination of serum levels of sialyl- and disialyl Lewis a, and calculation of the monosialyl/disialyl Lewis a ratio provide information useful for excluding a false-positive serum diagnosis, and also for averting the undesired influence of the Lewis
blood group of patients on serum
antigen levels. During the course of
cancer progression in locally advanced
cancers, tumor hypoxia induces transcription of several glycogenes involved in
sialyl Lewis a synthesis. Expression of the determinant, consequently, is further accelerated in more malignant
hypoxia-resistant
cancer cell clones, which become predominant clones in advanced stage
cancers and frequently develop hematogenous
metastasis.
Sialyl Lewis a, as well as its positional isomer
sialyl Lewis x, serves as a
ligand for
vascular cell adhesion molecule E-selectin and facilitates hematogenous
metastasis through mediating adhesion of circulating
cancer cells to vascular endothelium. Patients having both strong
sialyl Lewis a expression on
cancer cells and enhanced
E-selectin expression on vascular beds are at a greater risk of developing distant hematogenous
metastasis.