Toward Cancer Biomarker Discovery using the Glycomics Approach

Following on from genomics and proteomics, glycomics has become one of the most important research fields in recent years. The techniques for glycomics are rather complicated as compared to those for genomics and proteomics because glycans are very heterogeneous and there are no amplifying or cloning techniques such as those for PCR or molecular cloning, nor are there any synthesizers or sequencers such as those for DNA and proteins. As a result scientists in the other research fields feel it is difficult to become involved in this field and they have not paid attention to the significance of glycans. However, in the postgenomic era, the significance of posttranslational modification of proteins is gaining significance as more than 50% of proteins are glycosylated and it is impossible for us to understand the protein functions without knowing the glycan functions. Owing to the development of mass spectrometry, NMR, and HPLC/CE, although expensive, scientists are finding it easier to analyze glycan structures. Moreover, glycoscience including glycobiology and glycotechnology is expanding enormously these days. I would like to mention some examples in medical science. Influenza drugs are neuraminidase inhibitors which inhibit growth of the influenza virus, and at the early stage of infectious diseases some bacteria, bacterial toxins and viruses bind firstly to glycans of infected cells. There are more than 30 congenital disorders of glycosylation (CDG), and more than 60 glycosyltransferase gene KO mice have been developed. Interesting phenotypic changes in the mice have been reported in relation to human diseases. Under inflammatory conditions and/or in the process of cancer metastasis, specific glycans of leukocytes, platelets and cancer cells bind specific adhesion molecules, such as selectin with a lectin motif in the endothelial cells which accelerate rolling of cells and cancer metastasis. Antibody therapies against various cancers, such as breast cancer and non-Hodgkin’s lymphoma, are being widely used at present and most of them involve antibodies raised against cell surface receptors such as growth factor receptors. If fucoyslation (a1,6-fucosylation of innermost GlcNAc residues in glycoproteins) is absent in the IgG1 molecules of the above antibodies, the antibodies will facilitate the binding of the FcgIIIa receptor of NK cells or mononuclear cells to their Fc portion of IgG1, and activate those cells and destroy the tumor cells. This is called antibody-dependent cellular cytotoxity (ADCC). The ADCC of antibodies without core fucose is increased up to 50–100-fold as compared to that of ones with core fucose. In August 2002 we launched the HGPI (Human Glycome/Proteomics Initiative) under HUPO (Taniguchi, N., Mol Cell Proteomics 2008, 7, 626–627) and so far two pilot studies involving N-glycan analysis headed by Wada (Wada, EDITORIAL