Lewis antigens are fucosylated carbohydrates linked to lipids or to proteins and thus present as glycolipids or glycoproteins.
Characteristics
G protein-coupled receptors Lewis antigens are expressed in normal tissues on two major carbohydrate-type chains, type 1 and type 2, according to the linkage type between the galactose (Gal) residue and the N-acetyl-glucosamine residue (GlcNAc), β1,3 and β1,4, respectively (Fig. 1). Type 1 Lewis structures are widely expressed in endodermally derived tissues, such as glandular epithelia, in body fluids and saliva and are adsorbed from plasma-circulating glycolipids onto the surface of erythrocytes and lymphocytes. The presence or absence of type 1 antigens in a particular individual depends upon the presence of active enzymes responsible for the addition of the fucose monosaccharide. The α1,2 fucosyltransferase, the product of the secretor gene (Se) (secretor (Se) enzyme), acts on the terminal galactose and produces the H type 1 structure that forms the substrate for the α1,4 fucosyltransferase, the product of the Lewis gene (Le) (Lewis (Le) enzyme), that synthesizes the difucosylated Leb antigen. Individuals that have inactivating mutations of the Se gene and are unable to synthesize the H type 1 structure and the Leb antigen are called nonsecretors and constitute 20% of human populations. Type 2 Lewis antigens are expressed in ecto- and mesodermally derived tissues, including skin and erythrocytes, and in a more restricted manner in endodermally derived epithelia like stomach glands. The α1,2 fucosyltransferase that acts on the terminal galactose and produces the H type 2 structure is the product of the H gene, the H enzyme, that forms the substrate for the α1,3 fucosyltransferase, the product of the Lewis gene (Le), that synthesizes the difucosylated Ley antigen. Other fucosyltransferases may be involved, in a tissue-specific manner, in the synthesis of Lewis antigens: an α1,3 fucosyltransferase activity has been described for FUT3, FUT4, FUT5, FUT6, FUT7, and FUT9, and an α1,4 activity was described for FUT3 and FUT5. The secretor and Lewis status of individuals are implicated in susceptibility to several diseases, mostly human infections, with the most dramatic example being the virtual absence of gastrointestinal infections by calicivirus in nonsecretors.
Schematic representation of type 1 and type 2 ABH and Lewis antigens. Histo-blood group A is defined by the α1,3 terminal GalNAc, histo-blood group B is defined by the α1,3 terminal Gal, and the absence of further elongation of the H structure is characteristic of histo-blood group O individuals. Synthesis of type 1 Lewis antigens (Lea and Leb) and type 2 Lewis antigens (Lex and Ley) depends upon the activity of fucosyltransferases (see text for details). GlcNAc N-acetyl-glucosamine, Gal galactose, GalNAc N-acetyl-galactosamine, Fuc fucose; A antigen, histo-blood group antigen A; B antigen, histo-blood group antigen B
Lewis Antigens in Cancer
Malignant cells frequently have abnormal glycosylation with expression of modified carbohydrate antigens, among which stand sialylated forms of the Lewis antigens – sialyl-Lea and sialyl-Lex (Fig. 2). Sialyl-Lea/x cell-surface molecules, linked to lipids and proteins, when tumor cells become invasive and depolarized, gain access to circulation, either linked to the cell surface or shed into the serum. The relevance of these sialylated structures in cancer was first revealed, in the 1980s, when monoclonal antibodies raised against cancer cells were shown to recognize sialyl-Lea/x. They are widely used as tumor markers (CA19-9 for sialyl-Lea and SLX for sialyl-Lex) for initial serum diagnosis of cancer and for detection of cancer recurrence after surgery or treatment with radio- and chemotherapy. Later, in the 1990s, sialyl-Lea/x were identified as cancer cell-surface molecules involved in adhesion to endothelial cells, through E-selectin-mediated adhesion (and P-selectin). Binding of tumor cells to endothelial cells, in a model that mimics leukocyte extravasation, contributes to the establishment of tumor growth at distant sites by hematogenous metastization. Several studies, analyzing cancers from different organ origins, showed that expression of these sialylated Lewis antigens correlated to the prognosis of the patients, reinforcing their role on metastatic behavior. They are more frequently overexpressed in carcinomas, mainly adenocarcinomas, but also in leukemia. Mechanisms underlying overexpression of sialyl-Lea/x in cancer cells have been clarified in some cancer models and essentially result from altered expression of α2,3 sialyltransferases and/or of α 1,3/4 fucosyltransferases, responsible for their synthesis (Fig. 2). A viral gene product that induces HTLV-1 viral-associated leukemias was shown to transactivate fucosyltransferase VII, an α1,3 fucosyltransferase with rate-limiting activity for the synthesis of sialyl-Lex in leukocytes, and therefore induces a strong constitutive expression of sialyl-Lex in leukemic cells. Other mechanisms controlling gene expression, including methylation and identification of transcription factors, are under investigation.
Schematic representation of sialylated Lewis antigens – sialyl-Lea and sialyl-Lex. NeuAc, sialic acid (neuraminic acid)
The role of sialylated Lewis antigens in the metastatic process led to the development of several new candidate therapeutic approaches. Therapeutic strategies have been attempted to reduce the biosynthesis of sialylated Lewis antigens. Specifically, the synthesis of sialyl-Lex was successfully inhibited in colon carcinoma cell lines by using a disaccharide competitive substrate as a decoy. An alternative approach is to use monoclonal antibodies directed to sialyl-Lea/x or analogs of the sialyl-Lea/x to block adhesion of tumor cells to endothelial cells and prevent metastization.
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