Carbohydrate antigen sialyl Lewis a--its pathophysiological significance and induction mechanism in cancer progression

Abstract

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.