The Interaction of the Transforming Growth Factor-βs with Heparin/Heparan Sulfate Is Isoform-specific

Lyon, Malcolm; Rushton, Graham; Gallagher, John T.

doi:10.1074/jbc.272.29.18000

Cited by 250 publications

(191 citation statements)

References 58 publications

(50 reference statements)

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“…Indeed, LPS-induced production of IL-1␤ was inhibited to a lesser extent by TGF-␤1 or TGF-␤1 and IL-10 in combination in Synd4(Ϫ/Ϫ) macrophages than in Synd4(ϩ/ϩ) controls. Previous studies have demonstrated that TGF-␤1 binds to heparin/heparan sulfate (31,32). Our experiments showed that syndecan-4 deficiency reduced the amount of 125 I-labeled TGF-␤1 bound to macrophages and that syndecan-4 in the proteoglycan fraction from livers obtained 3 h after LPS injection bound to TGF-␤1 via its heparan sulfate chains.…”

Section: Discussionsupporting

confidence: 49%

Syndecan-4 Deficiency Leads to High Mortality of Lipopolysaccharide-injected Mice

Ishiguro¹,

Kadomatsu²,

Kojima³

et al. 2001

Journal of Biological Chemistry

118

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Syndecan-4 is a transmembrane heparan sulfate proteoglycan belonging to the syndecan family. Following intraperitoneal injection of lipopolysaccharide (LPS), syndecan-4-deficient mice exhibited high mortality compared with wild-type controls. Severe endotoxin shock was observed in the deficient mice: systolic blood pressure and left ventricular fractional shortening were lower in the deficient mice than in the wild-type controls 9 h after LPS injection. Although histological examinations revealed no apparent differences between two groups, the plasma level of interleukin (IL)-1␤ was higher in the deficient mice than in the wild-type controls 9 h after LPS injection. Consistent with the regulatory roles of syndecan-4, its expression in monocytes and endothelial cells of microvasculature increased in the wild-type mice after LPS administration. Although IL-1␤ was produced to the same extent by macrophages from syndecan-4-deficient and wild-type mice after LPS stimulation, inhibition of its production by transforming growth factor-␤1 was impaired in the syndecan-4-deficient macrophages. These results indicate that syndecan-4 could be involved in prevention of endotoxin shock, at least partly through the inhibitory action of transforming growth factor-␤1 on IL-1␤ production.

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Section: Discussionsupporting

confidence: 49%

Syndecan-4 Deficiency Leads to High Mortality of Lipopolysaccharide-injected Mice

Ishiguro¹,

Kadomatsu²,

Kojima³

et al. 2001

Journal of Biological Chemistry

118

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“…by preventing the formation of inactive complexes with a2-macroglobulin (15,16). We found that silencing of enzymes that attach sulfate groups to C-6 of glucosamine residues, HS6ST1 and HS6ST2, inhibited TGF-b induction of IL-11.…”

Section: Discussionmentioning

confidence: 84%

“…It has been shown that TGF-b1 binds to heparin and highly sulfated liver heparan sulfate, and this potentiates the biologic activity of TGF-b1 (15)(16)(17). It is also well established that heparan sulfate-protein interactions critically depend on the amount and the positions of the sulfate groups (18).…”

Section: Heparin and A Hlgag K5-nsos Inhibit Tgfb-induced Il-11 Produmentioning

confidence: 99%

Heparin-like Polysaccharides Reduce Osteolytic Bone Destruction and Tumor Growth in a Mouse Model of Breast Cancer Bone Metastasis

Pollari

Käkönen

Mohammad

et al. 2012

Molecular Cancer Research

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TGF-b regulates several steps in cancer metastasis, including the establishment of bone metastatic lesions. TGF-b is released from bone during osteoclastic bone resorption and it stimulates breast cancer cells to produce osteolytic factors such as interleukin 11 (IL-11). We conducted a cell-based siRNA screen and identified heparan sulfate 6-Osulfotransferase 2 (HS6ST2) as a critical gene for TGF-b-induced IL-11 production in highly bone metastatic MDA-MB-231(SA) breast cancer cells. HS6ST2 attaches sulfate groups to glucosamine residues in heparan sulfate glycosaminoglycans. We subsequently showed how heparin and a high-molecular-weight Escherichia coli K5-derived heparin-like polysaccharide (K5-NSOS) inhibited TGF-b-induced IL-11 production in MDA-MB-231 (SA) cells. In addition, K5-NSOS inhibited bone resorption activity of human osteoclasts in vitro. We evaluated the therapeutic potential of K5-NSOS and fragmin in a mouse model of breast cancer bone metastasis. MDA-MB-231 (SA) cells were inoculated into the left cardiac ventricle of athymic nude mice which were treated with fragmin, K5-NSOS, or vehicle once a day for four weeks. Both heparin-like glycosaminoglycans inhibited weight reduction, decreased osteolytic lesion area, and reduced tumor burden in bone. In conclusion, our data imply novel mechanisms involved in TGF-b induction and support the critical role of heparan sulfate glycosaminoglycans in cancer metastasis as well as indicate that K5-NSOS is a potential antimetastatic and antiresorptive agent for cancer therapy. This study illustrates the potential to translate in vitro siRNA screening results toward in vivo therapeutic concepts. Mol Cancer Res; 10(5); 597-604. Ó2012 AACR.

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“…The relationship between heparin and TGF is explained by Lyon et al in a recent paper. 74 The authors undertook a comparative study of the interaction of the three mammalian transforming growth factors (TGF-b) with heparin and heparan sulphate. They concluded that TGF-b 1 and -b 2 , but not -b 3 , bind to heparin and the highly sulphated liver heparan sulphate.…”

Section: Heparins and Angiogenic Growth Factorsmentioning

confidence: 99%

The heparins and cancer: review of clinical trials and biological properties

2004

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Abstract:The association between cancer and thromboembolic disease is a well-known phenomenon and can contribute significantly to the morbidity and mortality of cancer patients. The spectrum of thromboembolic manifestations in cancer patients includes deep vein thrombosis, pulmonary embolism, but also intravascular disseminated coagulation and abnormalities in the clotting system in the absence of clinical manifestations. Unfractioned heparin (UFH) and particularly low molecular weight heparins (LMWHs) are widely used for the prevention and treatment of thromboembolic manifestations that commonly accompany malignancies. Malignant growth has also been linked to the activity of heparin-like glycosoaminoglycans, to neoangiogenesis, to protease activity, to immune function and gene expression. All these factors contribute in the proliferation and dissemination of malignancies. Heparins may play a role in tumour cell growth and in cancer dissemination. The aims of the study are to review the efficiency of heparins in the prevention and treatment of cancer-related thromboembolic complications, and review the biological effects of heparins. Heparins are effective in reducing the frequency of thromboembolic complications in cancer patients. Meta-analyses comparing unfractioned heparins and LMWHs for the treatment of deep vein thrombosis have shown better outcome with a reduction of major bleeding complications in patients treated with LMWHs. LMWH have antitumour effects in animal models of malignancy: heparin oligosaccharides containing less than 10 saccharide residues have been found to inhibit the biological activity of basic fibroblast growth factor (bFGF), whereas heparin fragments with less than 18 saccharide residues have been reported to inhibit the binding of vascular endothelial growth factor (VEGF) to its receptors on endothelial cells. It has been shown that LMWH, in contrast with UFH, can hinder the binding of growth factors to their high-affinity receptors as a result of its smaller size. In vitro heparin fragments of less than 18 saccharide residues reduce the activity of VEGF, and fragments of less than 10 saccharide residues inhibit the activity of bFGF. Small molecular heparin fractions have also been shown to inhibit VEGF-and bFGF-mediated angiogenesis in vivo, in contrast with UFH. Moreover, heparin may influence malignant cell growth through other different interrelated mechanisms: inhibition of (1) heparin-binding growth factors that drive malignant cell growth; (2) tumour cell heparinases that mediate tumour cell invasion and metastasis; (3) cell surface selectin-mediated tumour cell metastasis and blood coagulation. The above evidence, together with favourable pharmaco-properties and with a reduction in major bleeding complications, suggests an important role for LMWHs in thromboprophylaxis and in the therapy of venous thromboembolism in cancer patients. There is sufficient experimental data to suggest that heparins may interfere with various aspects of cancer proliferation, angiogenesis, and meta...

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The Interaction of the Transforming Growth Factor-βs with Heparin/Heparan Sulfate Is Isoform-specific

Cited by 250 publications

References 58 publications

Syndecan-4 Deficiency Leads to High Mortality of Lipopolysaccharide-injected Mice

Syndecan-4 Deficiency Leads to High Mortality of Lipopolysaccharide-injected Mice

Heparin-like Polysaccharides Reduce Osteolytic Bone Destruction and Tumor Growth in a Mouse Model of Breast Cancer Bone Metastasis

The heparins and cancer: review of clinical trials and biological properties

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