Fucosylated Antigens in Cancer: An Alliance toward Tumor Progression, Metastasis, and Resistance to Chemotherapy

Abstract

Aberrant glycosylation of tumor cells is recognized as a universal hallmark of cancer pathogenesis. Overexpression of fucosylated epitopes, such as type I (H1, Lewis^a, Lewis^b, and sialyl Lewis^a) and type II (H2, Lewis^x, Lewis^y, and sialyl Lewis^x) Lewis antigens, frequently occurs on the cancer cell surface and is mainly attributed to upregulated expression of pertinent fucosyltransferases (FUTs). Nevertheless, the impact of fucose-containing moieties on tumor cell biology is not fully elucidated yet. Here, we review the relevance of tumor-overexpressed FUTs and their respective synthesized Lewis determinants in critical aspects associated with cancer progression, such as increased cell survival and proliferation, tissue invasion and metastasis, epithelial [corrected] to mesenchymal transition, endothelial and immune cell interaction, angiogenesis, multidrug resistance, and cancer stemness. Furthermore, we discuss the potential use of enhanced levels of fucosylation as glycan biomarkers for early prognosis, diagnosis, and disease monitoring in cancer patients.

Keywords: Lewis antigens; cancer; fucosylation; fucosyltransferases; glycosylation.

Figure 1

Cell-surface fucosylated antigens. Type I (H1, Lewis^a, Lewis^b, and sialyl Lewis^a) and type II (H2, Lewis^x, Lewis^y, and sialyl Lewis^x) Lewis antigens are terminal fucosylated carbohydrate motifs decorating cell surface glycoproteins or glycolipids. In the case of glycoproteins, N- and O-linked glycans containing Lewis antigens are covalently attached to the protein at Asparagine (Asn), or Serine and Threonine (Ser/Thr) residues, respectively. Expression of Lewis antigens is attributed to the expression of key enzymes, named fucosyltransferases (FUTs). The substrate specificity of different FUTs determines the site-specific transfer of fucose to oligosaccharides and the synthesis of the respective Lewis determinants.

Figure 2

Involvement of fucosylated antigens in different aspects of cancer progression. Due to genetic or epigenetic alterations, overexpression of certain fucosyltransferases (FUTs) by cancer cells leads to increased cell-surface expression of fucosylated Lewis antigens. Aberrant regulation of the fucosylation machinery in cancer cells is causally associated with the acquisition of various tumorigenic properties, such as increased cell survival and proliferation, epithelial to mesenchymal transition, metastasis, resistance to chemotherapy, and cancer stemness. In parallel, interaction of cancer cells overexpressing Lewis antigens with endothelial or immune cells bearing Lewis antigen-specific receptors might also play a critical role during cancer-induced angiogenesis and immunosuppression, respectively.