The Sweet and Sour of Cancer: Glycan as Novel Therapeutic Targets Mark M. Fuster; Jeffrey D. Esko Abegail Rasco Jenneli Espolita Allen Espinosa Glycan and Cancer Glycans regulate tumour proliferation, invasion, haematogenous metastasis and angiogenesis, and increased understanding of these roles sets the stage for developing pharmaceutical agents that target these molecules. Glycan and Cancer Tumor Progression Unique alterations in intracellular and intercellular signalling Main Stages of Tumour Progression Proliferation Invasion angiogenesis Metastasis Immunity Proliferation of Tumour Cells Glycans as Co-Receptors For Soluble Tumour Growth Factors Glycosaminoglycan (GAG) Facilitate formation of ligandreceptor complexes Facilitate storage of ligands for future mobilization Facilitate protection of ligands from degradation Heparan-sulphate proteoglycan (HSPG’s) Pancreatic cancer cells overproduced glypican 1 Mediates mitogenic responses by tumour cells to Basic fibroblast growth factor Heparin-binding EGFlike growth factor Tumour Invasion Tumour cells detach from one another and from ECM Migrate through neighbouring tissue Matrix Degradation and the Release of Sequestered Growth Factor HSPG’s Bind and sequester large amounts of important heparin-binding growth factor Release and use glycan-bound factors during matrix invasion Tumour Angiogenesis Create and edotheliallined neovascular network from nearby host endothelial cells HSPG 10-15 times higher level of HSPG found in macrovascular endothelial The endothelial growth and migration are stimulated by several pro-angiogenic factors Pro-angiogenic factors binding Heparan sulphate FGF2, VEGF, hepatocyte growth factor (HGF) etc Tumour Immunity Glycosphingolipids role in immune silencing Very high levels of immnogenic gangliosides in mammary carcinomas Inhibition of co-stimulatory molecule synthesis Arrest of dendritic-cell maturation Resulting in the inability of dendritic cells to generate effective anti-tumour T-cell immune responses Therapeutic Role of Glycan Affecting Tumour Progression Tumour Proliferation Interference with the co-receptor activity of HSPGs Inhibition of sulphotransferases responsible for sulphating heparan-sulphate chains during biosynthesis Design competitive blocking agents such as heparan sulphate mimetics Tumour Invasion and Angiogenesis Clinical heparin Inhibits tumour heparanase activity and invasion Ability of heparin to compete with matrix heparan sulphate as a substrate for tumour heparanase Ability to interfere with formation of growth factorheparan sulphate-receptor complexes Tumour Immunity Certain glycosphingolipids might be manipulated to generate both passive immunity and active immunity against tumours. Implications and Future Directions A given glycan might act at different stages of tumour progression, so targeting that glycan might have broad effect. At any given stage of progression, a specific glycan-targeting strategy might alter several glycan-dependent interactions. Implications and Future Directions Some therapeutic strategies can target more than one class of glycan-protein interaction. The choice and timing of any future glycanbased therapy against cancer should be guided by both serological assays for glycan markers as well as novel biopsy information. References Esko, Jefferey and Mark Fuster (2005). The Sweet and Sour of Cancer: Glycans as Novel Therapeutic Targets. Nature Publishing Group. Mc Kallip, Robert, et. al. Tumor Ganglioside Inhibit the Tumour Specific Immune Response. Vlodavsly, Friedrann, et. al. Mammalian Heparanase: Molecular Properties Inhibition and Involvement in Tumour Metastasis and Angiogenesis. Tang, Weihua, et. al. (2002). Heparanase: A Key Enzyme in Invasion and Metastasis of Gastric Carcinoma. Journal of Human Genetics. Sasisekharan, Ram and James Myette (2003). The Sweet Science of Glycobiology. American Scientist Volume 91.
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