Basic-Fibroblast-Growth-Factor-Mediated de novo Angiogenesis Is More Effectively Suppressed by Low-Molecular-Weight than by High-Molecular-Weight Heparin

Norrby, Klas; Østergaard, Per

doi:10.1159/000179145

Cited by 62 publications

(52 citation statements)

References 34 publications

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“…10,19 Under some circumstances, LMWH appears to be a relatively potent angiogenesis inhibitor. 20 In the present experiment, the angiogenic effect of LMWH tended to be slightly less than with UFH, but the difference was not statistically significant. It is possible that some of the angiogenic components of UFH are not present in the low molecular weight fraction, but their overall importance in terms of lung maturation appears to be minimal.…”

Section: Discussioncontrasting

confidence: 63%

Low Molecular Weight Heparin and Unfractionated Heparin Are Both Effective at Accelerating Pulmonary Vascular Maturation in Neonatal Rabbits

et al. 2003

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Background-Creation of a bi-directional cavopulmonary shunt after the Norwood procedure for hypoplastic left heart syndrome is delayed to allow pulmonary vascular resistance to fall with maturation of the pulmonary vascular bed. We hypothesized that unfractionated heparin (UFH) and low molecular weight heparin (LMWH), which promote angiogenesis and inhibit smooth muscle cell growth, could accelerate this process. Methods and Results-Fifty-six newborn rabbits were randomly selected to receive UFH 225U/kg (nϭ12), LMWH 1 mg/kg (nϭ14), LMWH 10 mg/kg (nϭ16), or saline (nϭ14) Reduced PA medial wall thickness and muscularization, two additional features of pulmonary vascular maturation, were also more evident in heparin treated animals. Mean PA pressures in 14-day-old rabbits treated with heparin were lower than those measured in control rabbits less than 7 weeks of age suggesting that heparin shortens the pulmonary vascular maturation process by over 60%. Conclusions-These results indicate that both UFH and LMWH are effective at accelerating pulmonary vascular maturation in newborn rabbits. This raises the possibility that administration of heparin to children after the Norwood procedure might allow for earlier conversion to a bi-directional cavopulmonary shunt.

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Section: Discussioncontrasting

confidence: 63%

Low Molecular Weight Heparin and Unfractionated Heparin Are Both Effective at Accelerating Pulmonary Vascular Maturation in Neonatal Rabbits

et al. 2003

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“…These include the inhibition of the adhesion and migration of breast cancer cells by heparin-mediated inhibition of selectin binding and proteases These processes are influenced to a greater degree by heparin than LMWHs and may potentially explain the differences seen between heparin and dp12 Koenig et al, 1998;Borsig, 2004). In addition, if dp12 does function by inhibiting the action of growth factors on the breast cancer cells it is unlikely that heparin will be functioning in a similar manner with studies demonstrating a promotional role for heparin in the presentation of growth factor receptors, in contrast to shorter length oligosaccharides (Soker et al, 1994;Norrby and Ostergaard, 1996).…”

Section: Discussionmentioning

confidence: 99%

Modulatory effects of heparin and short-length oligosaccharides of heparin on the metastasis and growth of LMD MDA-MB 231 breast cancer cells in vivo

et al. 2007

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Expression of the chemokine receptor CXCR4 allows breast cancer cells to migrate towards specific metastatic target sites which constitutively express CXCL12. In this study, we determined whether this interaction could be disrupted using short-chain length heparin oligosaccharides. Radioligand competition binding assays were performed using a range of heparin oligosaccharides to compete with polymeric heparin or heparan sulphate binding to I 125 CXCL12. Heparin dodecasaccharides were found to be the minimal chain length required to efficiently bind CXCL12 (71% inhibition; Po0.001). These oligosaccharides also significantly inhibited CXCL12-induced migration of CXCR4-expressing LMD MDA-MB 231 breast cancer cells. In addition, heparin dodecasaccharides were found to have less anticoagulant activity than either a smaller quantity of polymeric heparin or a similar amount of the low molecular weight heparin pharmaceutical product, Tinzaparin. When given subcutaneously in a SCID mouse model of human breast cancer, heparin dodecasaccharides had no effect on the number of lung metastases, but did however inhibit (Po0.05) tumour growth (lesion area) compared to control groups. In contrast, polymeric heparin significantly inhibited both the number (Po0.001) and area of metastases, suggesting a differing mechanism for the action of polymeric and heparin-derived oligosaccharides in the inhibition of tumour growth and metastases. Breast cancer is the most common malignancy in women and a major cause of morbidity and mortality in many parts of the world. The main cause of these deaths is metastatic spread of the disease (Dowsland et al, 2003). Breast cancer cells metastasise to specific anatomical sites, which include the brain, liver, lung and regional lymph nodes (Woodhouse et al, 1997). It appears that the metastatic spread of breast cancer cells to specific organs is dependant on the ability of these organs to express factor(s) that mediate specific cancer cell extravasation and recruitment from the blood, across the vascular endothelium and into the subendothelial tissue compartment. This process has clear parallels with the normal mechanism of leukocyte trafficking which is driven by chemokines (Muller et al, 2001).Chemokines are small structurally related chemo-attractant cytokines that exert their effects locally in a paracrine or autocrine manner. Chemokines signal through G-protein-coupled receptors on cells inducing cytoskeletal rearrangement, firm adhesion to endothelial cells and directional migration (Zlotnik and Yoshie, 2000). These secreted proteins act in a co-ordinated fashion with cell-surface proteins, including integrins, to direct specific homing of various subsets of haematopoietic cells to specific anatomical sites (Moser et al, 2004).There is increasing evidence that cancer cells express both chemokines and their receptors allowing both autocrine and paracrine responses, leading to migration, enhanced proliferation and cell survival (Azenshtein et al, 2002;Chen et al, 2006;Zlotnik, 2006). Indeed, meta...

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“…Norrby and Ostergaard 9 showed that FGF-2-mediated angiogenesis in a rat mesentery model was more effectively suppressed by a 2.6-kDa fraction compared with 4 higher M r fractions varying in charge density and anticoagulant activity. 9 More recently, Collen et al 23 evaluated the effect of unfractionated heparin and LMWHs on vessel development in vitro in a fibrin matrix. They demonstrated similar inhibition of endothelial cell proliferation by both unfractionated heparin and LMWH and observed that the formation of tubular structures was inhibited by LMWH but stimulated by unfractionated heparin.…”

Section: Discussionmentioning

confidence: 99%

“…8 The mechanism of this effect remains unknown but appears to be independent of the anticoagulant action of LMWH and may be related to effects on the vasculature. Prior studies have shown the effects of heparin on angiogenesis in rat mesentery 9 and cornea 10 models and have suggested a differential effect of fractions varying in M r without defining a relationship between M r and specific vascular cell functions.…”

Section: See Page 1954mentioning

confidence: 99%

Heparin Inhibition of Endothelial Cell Proliferation and Organization Is Dependent on Molecular Weight

Khorana

Sahni

Altland

et al. 2003

ATVB

132

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Objective-Studies have shown improved survival in cancer patients treated with low molecular weight heparins (LMWHs). Tumors depend on an expanding vasculature, and heparins may affect vessel growth and function. We investigated the effect of heparins differing in M r on selected endothelial cell properties. Methods and Results-Human umbilical vein endothelial cells were cultured with fibroblast growth factor-2 and heparins differing in M r . Cell proliferation was assessed by [ 3 H]thymidine incorporation, and vascular organization was assessed by in vitro assays. Maximum inhibition of 94Ϯ2% was observed with 6-kDa LMWH, greater than the inhibition seen with unfractionated heparin (58Ϯ8%) or 3-kDa LMWH (60Ϯ9%, Pϭ0.02 for both). No inhibition of proliferation was observed with heparin tetrasaccharide, octasaccharide, or pentasaccharide (fondaparinux). Three-and 6-kDa fractions decreased endothelial tube formation in Matrigel to 58Ϯ15% and 67Ϯ9% (PϽ0.05), respectively, of that with fibroblast growth factor-2, whereas no inhibition was observed with unfractionated heparin, tetrasaccharide, pentasaccharide, or octasaccharide. LMWH (6 kDa) also inhibited vessel formation in a placental explant. Conclusions-Heparin inhibition of endothelial cell proliferation and organization requires a chain length of Ͼ8 saccharide units, with maximal inhibition at M r of 6 kDa. This M r dependence differs from that required for anticoagulant activity. Key Words: low molecular weight heparins Ⅲ cancer Ⅲ angiogenesis Ⅲ endothelium Ⅲ thrombosis U nfractionated heparin is a heterogeneous mixture of polysaccharide molecules with a mean M r between 12 and 15 kDa containing glycosaminoglycan chains from 200 to 300 saccharide units. 1 Low molecular weight heparins (LMWHs) are fragments of unfractionated heparin produced by controlled enzymatic or chemical depolymerization with lower mean M r between 3 and 6 kDa and chain lengths of 12 to 18 saccharide units. 2 These structural differences result in important functional and pharmacokinetic differences, inasmuch as LMWHs have an increased anti-Xa/anti-IIa activity ratio, reduced plasma protein binding, decreased interaction with platelets and platelet factor 4, a prolonged half-life, and increased bioavailability after subcutaneous administration. 2,3 These changes give LMWHs an improved therapeutic profile compared with unfractionated heparin and have led to their increasing use in the treatment of venous and arterial thrombosis. See page 1954Individual studies 4,5 and meta-analyses 6,7 have found significant improvements in 3-and 6-month mortality in patients with cancer who were treated with LMWHs compared with unfractionated heparin. This survival advantage was found in subgroups differing in age, sex, and primary site of malignancy and could not be attributed to differences in thrombosis or bleeding complications. 8 The mechanism of this effect remains unknown but appears to be independent of the anticoagulant action of LMWH and may be related to effects on the vasculature. Prior studie...

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Basic-Fibroblast-Growth-Factor-Mediated de novo Angiogenesis Is More Effectively Suppressed by Low-Molecular-Weight than by High-Molecular-Weight Heparin

Cited by 62 publications

References 34 publications

Low Molecular Weight Heparin and Unfractionated Heparin Are Both Effective at Accelerating Pulmonary Vascular Maturation in Neonatal Rabbits

Low Molecular Weight Heparin and Unfractionated Heparin Are Both Effective at Accelerating Pulmonary Vascular Maturation in Neonatal Rabbits

Modulatory effects of heparin and short-length oligosaccharides of heparin on the metastasis and growth of LMD MDA-MB 231 breast cancer cells in vivo

Heparin Inhibition of Endothelial Cell Proliferation and Organization Is Dependent on Molecular Weight

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