SA-Le a and Tumor Metastasis: The Old Prediction and Recent Findings

Abstract

Several in vivo studies demonstrated that tumor metastasis depend on the expression of carbohydrate Lewis structures. Lewis antigens and their derivatives such as Lewis b (Le^b), Lewis X (LeX), sialyl Lewis X (SA-LeX), sialyl Lewis a (SA-Le^a), and Lewis Y (LeY) were identified as tumor-associated structures approximately 20 years ago by Koprowski et al. using hybridoma technology and showed that upregulation and/or de novo expression of these determinants on the tumor cell surface is associated with a poor prognosis. LeX and SA-LeX are ligands for selectin adhesion molecules; E- and P-selectins are vascular receptors expressed on activated endothelial cells (ECs) and L-selectin is expressed on leukocytes. Leukocytes also express on their surface LeX and SA-LeX determinants, which are involved in the initial steps of extravasation, that is, rolling, which is α step mediated by interaction with E-selectin on ECs. We hypothesized that the tumor cells transmigration from the bloodstream to metastatic sites is similar to lymphocyte extravasation and that adhesion of cancer cells in analogy with the lymphocyte rolling is mediated by interaction of carbohydrate determinants on tumor cells with selectins on ECs. To assess the role of interaction of carbohydrate structures with E-selectin in metastatic process in vivo, we demonstrated that the peptides mimicking SA-Le^a blocked colonization of tumor cells in experimental model of lung metastasis in vivo. Furthermore, the metastases formation was completely attenuated in E-selectin-knock out (KO) mice demonstrating the importance of selectin-mediated interaction in this process. We also showed that a peptide mimicking SA-Le^a E-selectin ligand has an ability to significantly reduce neutrophil recruitment into peritoneal cavity in acute inflammatory conditions. These studies support the hypothesis that the interaction of tumor cells via the carbohydrate SA-Le^a determinant and E-selectin constitutes the important step in the metastatic process in analogy with lymphocyte extravasation and that carbohydrate antigen mimics have a potential as anti-inflammatories and anti-adhesive tumor therapeutics.