More to “heparin” than anticoagulation

Lindahl, Ulf; Lidholt, Kerstin; Spillmann, Dorothe; Kjellén, Lena

doi:10.1016/0049-3848(94)90136-8

Cited by 349 publications

(284 citation statements)

References 171 publications

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“…However, FGFs are more likely to interact with the heparan sulfate glycosaminoglycan chains attached to HSPG core proteins. HSPGs are expressed on the surface of almost all the cell types, including the endothelium, where they can be found as membrane-associated receptors, as ECM components, or released as free molecules [119]. HSPGs modulate angiogenesis by interacting with pro and negative regulators [120].…”

Section: Heparin and Hspgsmentioning

confidence: 99%

Fibroblast growth factor/fibroblast growth factor receptor system in angiogenesis

Presta

Dell’Era

Mitola

et al. 2005

Cytokine & Growth Factor Reviews

1,129

870

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Fibroblast growth factors (FGFs) are a family of heparin-binding growth factors. FGFs exert their pro-angiogenic activity by interacting with various endothelial cell surface receptors, including tyrosine kinase receptors, heparan-sulfate proteoglycans, and integrins. Their activity is modulated by a variety of free and extracellular matrix-associated molecules. Also, the cross-talk among FGFs, vascular endothelial growth factors (VEGFs), and inflammatory cytokines/chemokines may play a role in the modulation of blood vessel growth in different pathological conditions, including cancer. Indeed, several experimental evidences point to a role for FGFs in tumor growth and angiogenesis. This review will focus on the relevance of the FGF/FGF receptor system in adult angiogenesis and its contribution to tumor vascularization. #

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Section: Heparin and Hspgsmentioning

confidence: 99%

Fibroblast growth factor/fibroblast growth factor receptor system in angiogenesis

Presta

Dell’Era

Mitola

et al. 2005

Cytokine & Growth Factor Reviews

1,129

870

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“…Furthermore, these cells bound a reduced amount of IFN-g and were relatively refractory to class II MHC antigen induction. It is known that 582 M. S. Douglas et al chlorate reversibly inhibits ATP sulphurylase [29], thereby preventing the production of 3 0 -phosphoadenosine 5 0 -phosphosulphate, the active sulphate donor for the N-sulphotransferase enzyme which initiates GAG sulphation in endothelial cells [9]. Primary sulphation by this enzyme is a necessary prerequisite for epimerization of glucuronic acid to iduronic acid and for a series of subsequent sulphation steps [30].…”

Section: Discussionmentioning

confidence: 99%

“…HS is structurally related to heparin, arising from the same biosynthetic pathway, but the latter is more heavily sulphated, contains a greater proportion of iduronic acid [8], and is localized mainly in mast cell granules [9].…”

Section: Introductionmentioning

confidence: 99%

Examination of the mechanism by which heparin antagonizes activation of a model endothelium by interferon-gamma (IFN-γ)

Douglas

Rix

Dark

et al. 1997

Clinical and Experimental Immunology

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SUMMARYIFN-g increases the potential immunogenicity of vascular endothelial cells by up-regulation of intercellular adhesion molecule-1 (ICAM-1) and class I MHC antigen expression and by induction of class II MHC antigens and certain chemokines. In this study the mechanism by which the glycosaminoglycan (GAG) heparin antagonizes the activation of a model endothelium by IFN-g was investigated. Radioligand binding assays demonstrated that total binding of 125 I-IFN-g to the EAhy.926 endothelial hybridoma cell line was reduced in the presence of heparin or heparan sulphate (HS); the structurally dissimilar GAG chondroitin sulphate had no effect. Treatment of the cells with chlorate, a metabolic inhibitor of GAG sulphation, was found to reduce both the subsequent binding of IFN-g and its ability to induce expression of class II MHC antigens. Treatment with heparinase II dramatically reduced the binding of IFN-g, while chondroitin ABC lyase had no effect. A cationic peptide from the C-terminal region of IFN-g was also found to reduce binding of intact IFN-g to the cells. These results appear to demonstrate that IFN-g is sequestered at the surface of endothelial cells by electrostatic interaction between specific basic amino acid residues and sulphated domains on HS, the most abundant endothelial GAG. This interaction is competitively inhibited by heparin, which is structurally related to HS. These observations are consistent with the model that IFN-g is bound by membrane-associated HS before engagement with the high-affinity receptor and signal transduction. Inhibition of the interaction between proinflammatory cytokines and membrane-associated GAG molecules may provide a mechanism for inducing clinically useful immunosuppression.

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“…The biological role of Hep/HS is highly diverse. Aside from its well-known anti-coagulant action, the molecules are found to be associated with growth factors and cytokines in various biological processes, as well as being involved in cell adhesion, recognition, migration, and regulation of various enzymatic activities (Lindahl et al, 1994;Kjellen and Lindahl, 1991).…”

mentioning

confidence: 99%

“…Besides the anticoagulant function, Hep binds to various growth factors, cytokines, and extracellular matrix (ECM) proteins and consequently is able to affect proliferation and migration of cancer cells and angiogenesis in tumours (Lindahl et al, 1994). Furthermore, Heps have been found to inhibit expression of oncogenes and to affect the immune system (Smorenburg and Van Noorden, 2001).…”

mentioning

confidence: 99%

Periodate-treated, non-anticoagulant heparin-carrying polystyrene (NAC-HCPS) affects angiogenesis and inhibits subcutaneous induced tumour growth and metastasis to the lung

et al. 2002

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Periodate-treated, non-anticoagulant heparin-carrying polystyrene consists of about ten periodate-oxidized, alkaline-degraded low molecular weight-heparin chains linked to a polystyrene core and has a markedly lower anti-coagulant activity than heparin. In this study, we evaluated the effect of non-anticoagulant heparin-carrying polystyrene on tumour growth and metastasis. Non-anticoagulant heparin-carrying polystyrene has a higher activity to inhibit vascular endothelial growth factor-165-, fibroblast growth factor-2-or hepatocyte growth factor-induced human microvascular endothelial cell growth than heparin, ten periodate-oxidized-heparin and ten periodate-oxidized-low molecular weight-heparin, which is probably due to the heparin-clustering effect of non-anticoagulant heparin-carrying polystyrene. Non-anticoagulant heparin-carrying polystyrene inhibited human microvascular endothelial cell, B16 melanoma and Lewis lung cancer cell adhesion to Matrigel-coated plates. Non-anticoagulant heparin-carrying polystyrene also showed strong inhibitory activities in the tubular formation of endothelial cells on Matrigel and B16-melanoma and Lewis lung cancer cell invasion in a Matrigel-coated chamber assay. In vivo studies showed that growth of subcutaneous induced tumours and lung metastasis of B16-melanoma and Lewis lung cancer cells were more effectively inhibited by non-anticoagulant heparin-carrying polystyrene than ten periodate-oxidized-heparin and ten periodate-oxidized-low molecular weight-heparin. Furthermore, non-anticoagulant heparin-carrying polystyrene markedly reduced the number of CD34-positive vessels in subcutaneous Lewis lung cancer tumours, indicating a strong inhibition of angiogenesis. These results suggest that non-anticoagulant heparin-carrying polystyrene has an inhibitory activity on angiogenesis and tumour invasion and may be very useful in cancer therapy.

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More to “heparin” than anticoagulation

Cited by 349 publications

References 171 publications

Fibroblast growth factor/fibroblast growth factor receptor system in angiogenesis

Fibroblast growth factor/fibroblast growth factor receptor system in angiogenesis

Examination of the mechanism by which heparin antagonizes activation of a model endothelium by interferon-gamma (IFN-γ)

Periodate-treated, non-anticoagulant heparin-carrying polystyrene (NAC-HCPS) affects angiogenesis and inhibits subcutaneous induced tumour growth and metastasis to the lung

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