Lewis blood group biosynthesis

The same two oligosaccharides (Type 1 and Type 2) used to determine ABO blood types are also utilised by the Lewis system. Fucosyltransferase 3 (FUT3, Le) adds fucose to Type 1 chains to form the Lewis A antigen (LeA). IF the individual is a non-secretor (lacks the Se gene, homozygous sese), LeA is adsorbed onto the red cell, and that individual is LeA type. Approximately 80% of the population has the Se gene. Functional fucosyltransferase 2 (FUT2, Se) adds a fucose to LeA to form LeB. Both LeA and LeB present in the plasma of secretors but LeA preferentially adsorbs onto the RBC and therefore, the individual types as LeB. Other FUTs, especially FUT4, can add a fucose to Type 2 chains to form the Lewis X antigen (LeX). Further fucosylation of LeX by FUT2 produces the Lewis Y antigen (LeY). LeX and LeY are structural isomers of LeA and LeB. The formation of LeY is controlled by Se/se as in the case for LeB. LeA and LeX antigens can also undergo sialation to produce sialated forms of these antigens.

Aberrant glycosylation of tumour cells is recognised as a feature of cancer pathogenesis. Overexpression of fucosylated and sialated Lewis antigens frequently occurs on the surfaces of cancer cells and is mainly attributed to upregulated expression of the relevant fucosyltransferases (FUTs). The sialyl-Lewis A antigen (sLeA), also known as the CA19-9 antigen, is the most common tumour marker used primarily in the management of pancreatic and gastrointestinal cancers worldwide.

Selectins (L-, E- and P-selectin) are type I membrane proteins composed of long N-terminus C-type lectin domains protruding into the extracellular space and with a short cytoplasmic tail. They bind carbohydrate structures through a Ca2+-dependent domain, the minimal sugar structure recognised fulfilled by sLeA and sLeX. Selectins are found on endothelial cells, platelets and leukocytes and are involved in trafficking of cells of the innate immune system, T lymphocytes and platelets, thereby playing important roles in chronic and acute inflammation and haemostasis. Selectins also play a role in cancer progression. Metastasis is facilitated by cell-cell interactions between cancer cells and endothelial cells in distant tissues. In addition, cancer cell interactions with platelets and leukocytes contribute to cancer cell adhesion, extravasation, and the establishment of metastatic lesions. Targeting selectins and their ligands as well as the enzymes involved in their generation, in particular sialyl transferases, could be a useful strategy in cancer treatment.