Ameliorating Skin-Homing Receptors on Malignant T Cells with a Fluorosugar Analog of N-acetylglucosamine: P-Selectin Ligand Is a More Sensitive Target than E-Selectin Ligand

Expression of E- and P-selectin ligands is required for T cell entry into skin. Sialyl Lewis X moieties are critical for ligand activity and are elevated on malignant skin-homing T cells. We hypothesize that these glycosylations are selectable targets for treating the dermal tropism associated with cutaneous lymphomas. In this study, we analyzed the efficacy of a novel 4-fluorinated analog of N-acetylglucosamine (GlcNAc) on E- and P-selectin ligands expressed by malignant skin-homing T cells. We also examined the specificity of 4-F-GlcNAc (2-acetamido-1,3,6-tri-O-acetyl-4-deoxy-4-fluoro-d-glucopyranose) action by contrasting the effects on sialyl Lewis X expression displayed by P-selectin glycoprotein ligand-1 (PSGL-1) with sialylated O-glycans expressed by CD43. Using parallel-plate flow analysis, we found that 4-F-GlcNAc elicited 5-fold more potent inhibition on P-selectin ligand activity than on E-selectin ligand activity. To determine whether glycosylations conferring E- and P-selectin ligand activities were inhibited, we analyzed the expression of sialyl Lewis X and sialyl-fucosylated core 2 O-glycan (CHO-131 antigen), respectively. We found that 4-F-GlcNAc treatment resulted in dose-dependent ablation of sialyl Lewis X and CHO-131 antigen expression on PSGL-1, whereas sialylated O-glycans on CD43 were minimally affected. These results indicate that 4-F-GlcNAc treatment can selectively downregulate the P-selectin ligand activity and potentially prevent dermal dissemination of cutaneous lymphomas

Alpha 1,3 fucosyltransferases are master regulators of prostate cancer cell trafficking

How cancer cells bind to vascular surfaces and extravasate into target organs is an underappreciated, yet essential step in metastasis. We postulate that the metastatic process involves discrete adhesive interactions between circulating cancer cells and microvascular endothelial cells. Sialyl Lewis X (sLeX) on prostate cancer (PCa) cells is thought to promote metastasis by mediating PCa cell binding to microvascular endothelial (E)-selectin. Yet, regulation of sLeX and related E-selectin ligand expression in PCa cells is a poorly understood factor in PCa metastasis. Here, we describe a glycobiological mechanism regulating E-selectin-mediated adhesion and metastatic potential of PCa cells. We demonstrate that α1,3 fucosyltransferases (FT) 3, 6, and 7 are markedly elevated in bone- and liver-metastatic PCa and dictate synthesis of sLeX and E-selectin ligands on metastatic PCa cells. Upregulated FT3, FT6, or FT7 expression induced robust PCa PC-3 cell adhesion to bone marrow (BM) endothelium and to inflamed postcapillary venules in an E-selectin-dependent manner. Membrane proteins, CD44, carcinoembryonic antigen (CEA), podocalyxin-like protein (PCLP), and melanoma cell adhesion molecule (MCAM) were major scaffolds presenting E-selectin-binding determinants on FT-upregulated PC-3 cells. Furthermore, elevated FT7 expression promoted PC-3 cell trafficking to and retention in BM through an E-selectin dependent event. These results indicate that α1,3 FTs could enhance metastatic efficiency of PCa by triggering an E-selectin-dependent trafficking mechanism