The sweet and sour of cancer: glycans as novel therapeutic targets

Tumours aberrantly express various glycans. Glycans regulate many different aspects of tumour progression, including proliferation, invasion, angiogenesis and metastasis.The proliferation of tumour cells is potentiated by the ability of glycoproteins and glycosphingolipids to directly activate growth-factor receptor tyrosine kinases and by the ability of proteoglycans to function as co-receptors for soluble tumour growth factors.The overexpression of specific glycosyltransferases by tumour cells promotes the formation of tumour glycans that facilitate invasion.Carcinomas commonly overexpress O-linked glycans in the form of cell-surface and secreted mucins that present ligands for adhesion receptors, such as the selectins, which promote the ability of tumour cells to interact with host platelets, leukocytes and endothelial cells. These interactions facilitate haematogenous metastasis of tumour cells.Glycosphingolipids, in the form of gangliosides, are overexpressed by a range of tumours, and their shedding into the bloodstream might impair host immunity to some tumours.During tumour proliferation and invasion, heparan-sulphate proteoglycans (HSPGs) that are present on the surface of tumour cells function as co-receptors to stabilize growth-factor receptor signalling complexes. Secreted HSPGs that are present in the extracellular matrix store growth factors that can be mobilized by the action of tumour heparanases. A similar mechanism that involves endothelial-associated HSPGs and endothelial growth factors facilitates vascular sprouting during tumour angiogenesis.Some glycans can be measured in the bloodstream, and their use as markers of disease burden can be used to screen for specific cancers as well as track response to therapy.Experiments in which glycan function is genetically altered in cell-culture systems or mouse tumour models validate their potential as targets for anticancer therapy.A few glycan-based targeting strategies are currently being tested in clinical trials. As we learn more about the roles of glycans in tumour progression, new targets will continue to emerge for drug design.