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, Lewisa, Lewisb, and sialyl Lewisa) and type II (H2, Lewisx, Lewisy, and sialyl Lewisx) 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 to mesenchymal transition, epithelial 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.

Fucosyltransferase 4 shapes oncogenic glycoproteome to drive metastasis of lung adenocarcinoma

“…Aberrant expression of fucosylated epitopes such as Lewis antigens have been widely reported in various types of cancer 4 . These Lewis antigens are mainly synthesized by α1-3/ α1-4 fucosyltransferases in a tissue-specific manner.…”

“…Abundant evidence indicates that aberrant glycosylation plays critical roles in fundamental steps of tumor development and progression, including cell-cell/cell-matrix interactions, metastasis, cancer metabolism as well as immune surveillance [1][2][3] . In particular, patterns of fucosylation, which adds a fucose (6-deoxy-L-galactose) residue to surface oligosaccharides/proteins catalyzed by the fucosyltransferase (FUT) gene family, are frequently altered in various types of cancer 4,5 . Depending on the site of oligosaccharide chain to which the fucose is added, two types of fucosylation-core and terminal fucosylation-were defined 4 .…”

“…In particular, patterns of fucosylation, which adds a fucose (6-deoxy-L-galactose) residue to surface oligosaccharides/proteins catalyzed by the fucosyltransferase (FUT) gene family, are frequently altered in various types of cancer 4,5 . Depending on the site of oligosaccharide chain to which the fucose is added, two types of fucosylation-core and terminal fucosylation-were defined 4 . So far, there are 13 FUTs identified in human, each of which catalyzes the synthesis of fucosylated glycans with designated glycosidic linkages and targets different substrate proteins/glycans in a tissue-specific manner.…”

“…On the other hand, clinical significance of fucosyltransferases involved in terminal fucosylation (α1,3-or α1,4-linkage) in lung cancer remains controversial. Past studies 4 have demonstrated aberrant expression of terminal fucosylated epitopes such as Lewis antigens in non-small cell lung cancer tissues [8][9][10] . Nevertheless, the prognostic values of various Lewis antigens appeared to differ.…”

Don’t sugarcoat it: How glycocalyx composition influences cancer progression

“…The sialyl Lewis antigens, especially sLe x and sLe a , form the binding epitopes to the endothelial selectins on immune cells (Buffone et al, 2013; Mondal et al, 2015) and circulating tumor cells (Burdick et al, 2012; Li and King, 2012). These tetrasaccharide structures, consisting of sialic acid bound to a lactosamine (Gal-GlcNAc) in a 2,3 linkage and a fucose bound in either a 1,3 or 1,4 linkage (Trinchera et al, 2017), are highly implicated in the metastasis of tumors to secondary sites through the bloodstream (Blanas et al, 2018; Mondal et al, 2018). They are strongly up-regulated in a variety of tumors, and sLe a (CA19.9) and sLe x (NCC-ST-439) are prognostic markers for both colon and pancreatic cancer (Shiozaki et al, 2011).…”