Journal
BIOCHEMICAL SOCIETY TRANSACTIONS
Volume 42, Issue -, Pages 1596-1600Publisher
PORTLAND PRESS LTD
DOI: 10.1042/BST20140229
Keywords
angiogenesis; heparan sulfate; oligosaccharide
Categories
Funding
- Cancer Research UK [C2075/A9106]
- Medical Research Council [G0601746, G902173]
- MRC [G0601746, G0902173] Funding Source: UKRI
- Medical Research Council [G0601746, G0902173] Funding Source: researchfish
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Angiogenesis has emerged as a novel target for anti-cancer therapies through randomized clinical trials that tested the benefit of adding vascular endothelial growth factor (VEGF) inhibitors to conventional cytotoxic therapies. However, despite improvements in the progression-free survival, the benefit in overall survival is modest. Tumour angiogenesis is regulated by a number of angiogenic cytokines. Thus innate or acquired resistance to VEGF inhibitors can be caused, at least in part, through expression of other angiogenic cytokines, including fibroblast growth factor 2 (FGF2), interleukin 8 (IL-8) and stromal-cell-derived factor 1 alpha (SDF-1 alpha), which make tumours insensitive to VEGF signalling pathway inhibition. The majority of angiogenic cytokines, including VEGF-A, FGF2, IL-8 and SDF-1 alpha, manifest an obligate dependence on heparan sulfate (HS) for their biological activity. This mandatory requirement of angiogenic cytokines for HS identifies HS as a potential target for novel anti-angiogenic therapy. Targeting multiple angiogenic cytokines with HS mimetics may represent an opportunity to inhibit tumour angiogenesis more efficiently. Our published studies and unpublished work have demonstrated the feasibility of generating synthetic HS fragments of defined structure with biological activity against a number of angiogenic cytokines.
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