Heparan-sulphate glycosaminoglycans (HSGAGs) act at the cell–extracellular-matrix (ECM) interface to modulate cell signalling, thereby regulating how a cell perceives its environment.
HSGAGs interact with various extracellular signalling molecules: growth factors, morphogens, enzymes and chemokines. The specificity of these interactions is dependent on HSGAG sequence, spacing of binding sites and the three-dimensional structure of the HSGAG chain.
HSGAGs, depending on location and sequence, impinge on tumour onset and progression in various ways, some of which are pro-tumorigenic and others of which are anti-tumorigenic.
HSGAGs at the tumour-cell surface actively modulate the tumorigenic process by regulating autocrine signalling loops that lead to unregulated cell growth.
HSGAGs impinge on how an organism responds to a growing tumour, including the recruitment of cells of the immune system to the tumour site, formation of a fibrin shell around the tumour that acts as a protective barrier and development of new blood vessels to the site of the growing tumour.
Compelling clinical evidence indicates that pharmacological doses of heparin, a highly sulphated HSGAG, can have a marked effect on tumour metastasis. Clinical trials have been designed to determine the exact benefits of heparin therapy in cancer.
In addition, the low-molecular-weight heparins (LMWHs) — a series of heparin fragments that share many of heparin's activities, including its anticoagulant effect, but lack several of its side effects — might show even greater antitumour activity.
The advent of HSGAG sequencing technologies promises to usher in a new generation of LMWHs with potent antitumour activity.
Cell-surface/extracellular-matrix heparan-sulphate glycosaminoglycans (HSGAGs) are complex polysaccharides that are ubiquitous in nature, and that regulate several aspects of cancer biology, including tumorigenesis, tumour progression and metastasis. Recently gained insights into the structure of HSGAGs have extended our understanding of their role in the oncogenic process. At present, clinical trials are examining the anticancer properties of exogenous highly sulphated HSGAGs, including heparin and low-molecular-weight heparins, in addition to small oligosaccharide heparin mimetics. Combined with our more intricate understanding of HSGAG structure, this emerging structure–activity approach opens exciting avenues for the generation of polysaccharide-based anticancer therapeutics.
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The authors would like to acknowledge financial assistance from the Burroughs Wellcome Foundation, the Arnold and Mabel Beckman Foundation, the CapCure Foundation and the National Institutes of Health.
A glycoprotein that consists of a core protein sequence and glycosaminoglycan extensions. Proteoglycans that contain heparan-sulphate glycosaminoglycan side chains are called heparan-sulphate proteoglycans.
A membrane-bound proteoglycan that contains a large extracellular domain with attached heparan-sulphate glycosaminoglycan chains, a conserved transmembrane domain and a small cytoplasmic domain.
A heparan-sulphate proteoglycan that is tethered to the membrane by a glycosylphosphatidylinositol anchor. The core protein contains a conserved cysteine-rich globular region and several glycosaminoglycan attachment sites.
A proteoglycan that is typically extruded into the extracellular space.
A highly sulphated member of the heparan-sulphate glycosaminoglycan family. Typically present in mast cells, where it acts as a storage depot for proteases, heparin is used pharmacologically as an anticoagulant.
- PROPERTY-ENCODED NOMENCLATURE
(PEN). A rational system for defining a polymer that is based on the properties of its monomeric units. This system forms the basis for a computationally aided sequencing approach for heparan-sulphate glycosaminoglycan complex oligosaccharides.
- ANTITHROMBIN III
(AT-III). An inhibitor of the coagulation cascade, specifically Factor Xa and Factor IIa (thrombin). Binding of AT-III to a specific pentasaccharide sequence in heparan sulphate results in a conformational change in AT-III, increasing its anticoagulant activity by orders of magnitude. Factor Xa is a serine protease of the coagulation cascade. Factor Xa activates thrombin — the penultimate step of the coagulation cascade.
Tongue enlargement, leading to functional and cosmetic problems.
Atypically large body size.
- SULPHATION PATTERN
Each HSGAG disaccharide unit can be differentially sulphated at four possible positions. On the uronic acid, the 2-O position might be sulphated or unsulphated. For the glucosamine, the 6-O and 3-O positions might also be sulphated or unsulphated. Finally, the N-position of the glucosamine can be N-sulphated, acetylated or unsubstituted.
- LOW-MOLECULAR-WEIGHT HEPARIN
(LMWH). Developed to maintain the potent anticoagulant affect of heparin but to reduce the number of side effects. LMWHs are generated by enzymatic or chemical means.
Also known as Factor IIa, it is the penultimate factor of the coagulation cascade. Thrombin converts fibrinogen into fibrin, which is ultimately responsible for clot formation.
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Sasisekharan, R., Shriver, Z., Venkataraman, G. et al. Roles of heparan-sulphate glycosaminoglycans in cancer. Nat Rev Cancer 2, 521–528 (2002). https://doi.org/10.1038/nrc842
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