J. Le Pendu

Detection of a potential receptor for the H-blood-group antigen on rat colon-carcinoma cells and normal tissues.

Up‐regulation of the synthesis of carbohydrate tumor‐associated antigens terminated by the disaccharide Fucα1‐2Gal is frequent in colon carcinoma and associated with poor prognosis. There is evidence that Fucα1‐2Gal (H‐disaccharide) structures increase cancer‐cell motility and tumorigenicity by as‐yet unknown mechanisms. Using polyacrylamide‐based neoglycoconjugates, we looked for a potential receptor for this disaccharide, and observed that a neoglycoconjugate probe containing the H‐disaccharide could bind rat colon‐carcinoma cells in a dose‐dependent manner, whereas very little binding was evidenced when a probe containing glucose was used. Binding of the H‐disaccharide probe could be inhibited by the free H‐disaccharide as well as by unlabeled neoglycoconjugates containing a terminal H‐disaccharide. The best inhibitor was the H‐type‐1 trisaccharide neoglycoconjugate. Histochemical detection of the potential H‐receptor was performed on rat normal tissues and in situ 1,2‐dimethylhydrazine‐induced colon carcinomas. A strong binding of the H‐disaccharide probe was evidenced on most tumors that could be partly inhibited by the trisaccharide Fucα1‐2Galβ1‐4Glc and by the unlabeled H‐disaccharide neoglycoconjugate, indicating carbohydrate specificity of the binding. Staining of normal colonic mucosa was much weaker. Strong staining was also observed on some normal tissues, such as the spleen or lymph nodes, while others, such as lungs or liver, were negative. Probes containing glucose or the Lewis‐a trisaccharide did not stain tumors or normal tissues. These results provide preliminary evidence for the existence of H‐specific binding sites, the number of which increases in colon carcinoma. Int. J. Cancer 76:136–140, 1998.© 1998 Wiley‐Liss, Inc.

A HYPOTHESIS ON THE DUAL SIGNIFICANCE OF ABH, LEWIS AND RELATED ANTIGENS

ABH and related antigens appeared a long time ago in the evolution of vertebrates on tissues in contact with the external environment, which suggests that the polymorphism given by these antigens might play a role in the relationships of the species with pathogens. However, they are also oncodevelopmental markers and some recent experimental data suggest that they might play a role in cell‐cell recognition at some stages of development. This type of function is difficult to reconcile with the polymorphic nature of these markers unless one considers that the glycosyltransferases necessary for the synthesis of the active structures are encoded by various members of multigene families. Some non‐polymorphic members of the families would have their expression limited in time and space during development, leading to the same antigenic patterns in every individual, and these could reappear in some tumours, while the expression of other polymorphic members (A/B/O, H/h, Se/se, Le/le), leading to a variety of antigenic phenotypes, would be expressed at later stages and remain so during the whole life of the individual. The corresponding antigens could disappear from some cancer cells. It is argued that the ABH and related antigens would have primarily been involved in cell‐cell recognition phenomena. The polymorphism would have evolved later from gene duplication under environmental pressure, the expression on erythrocytes which occurred very late in evolutionary time probably being of very little biological significance.

Human Norovirus Receptors

Due to the lack of cell culture methods, studies of human norovirus receptors have been limited to virus challenge and outbreak studies and in vitro binding studies of virus-like particles (VLPs). Norovirus VLPs recognize glycans from the ABO(H) and Lewis histo-blood group family on glycoproteins and glycosphingolipids in a strain-dependent manner. Host genetic studies have shown that for the clinically dominating strains the binding pattern correlates with susceptibility to infection. Particularly, the so-called nonsecretors, characterized by their lack of expression of ABO(H) structures in the gastrointestinal tract, have been identified as resistant to infections by many strains. In support of a receptor status, norovirus VLPs have been shown to bind to intestinal epithelium expressing ABO(H) epitopes, to intestinal glycosphingolipids carrying ABO(H) epitopes and to induce membrane invaginations, resembling endocytosis intermediates, on model membranes carrying such glycosphingolipids. However, in addition to the ABO(H) structures, the VLPs also recognizes other glycans that could play an important role in virus entry into the host cells.