Glycan as Novel Therapeutic Targets

Abegail Rasco

Jenneli Espolita

Allen Espinosa

The Sweet and Sour of Cancer:

Mark M. Fuster; Jeffrey D. Esko

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

Proliferation Invasion angiogenesis Metastasis Immunity

Main Stages of Tumour Progression

Proliferation of Tumour Cells Glycans as Co-Receptors For

Soluble Tumour Growth Factors Glycosaminoglycan (GAG)

Facilitate formation of ligand-receptor 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 EGF-like growth factor

Tumour Invasion Tumour cells detach

from one another and from ECM

Migrate through neighbouring tissue

HSPG’s Bind and sequester large amounts of

important heparin-binding growth factor

Release and use glycan-bound factors during matrix invasion

Matrix Degradation and the Release of Sequestered Growth Factor

Tumour Angiogenesis Create and edothelial-

lined 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 factor-

heparan 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 glycan-based 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.