Heparin as an Inhibitor of Cancer Progression

Borsig, Lubor

doi:10.1016/s1877-1173(10)93014-7

Cited by 62 publications

(47 citation statements)

References 84 publications

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“…Previously, it has been shown that anticoagulants including heparin can have an impact on endothelial cell growth and migration independently. 49 In our experiments, however, the anticoagulant exposure occurred for a designated period of time (referred to as preincubation), after which the platelets were extensively washed to remove exogenous anticoagulant prior to platelet stimulation and releasate collection. This suggests that the anticoagulants directly affected the platelets themselves and were not responsible for a more general effect.…”

Section: Discussionmentioning

confidence: 99%

Anticoagulation inhibits tumor cell–mediated release of platelet angiogenic proteins and diminishes platelet angiogenic response

Battinelli

Markens

Kulenthirarajan

et al. 2014

Blood

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• Anticoagulants inhibit release of angiogenic proteins from platelets.Platelets are a reservoir for angiogenic proteins that are secreted in a differentially regulated process. Because of the propensity for clotting, patients with malignancy are often anticoagulated with heparin products, which paradoxically offer a survival benefit by an unknown mechanism. We hypothesized that antithrombotic agents alter the release of angiogenesis regulatory proteins from platelets. Our data revealed that platelets exposed to heparins released significantly decreased vascular endothelial growth factor (VEGF) in response to adenosine 59-diphosphate or tumor cells (MCF-7 cells) and exhibited a decreased angiogenic potential. The releasate from these platelets contained decreased proangiogenic proteins. The novel anticoagulant fondaparinux (Xa inhibitor) demonstrated a similar impact on the platelet angiogenic potential. Because these anticoagulants decrease thrombin generation, we hypothesized that they disrupt signaling through the platelet protease-activated receptor 1 (PAR1) receptor. Addition of PAR1 antagonists to platelets decreased VEGF release and angiogenic potential. Exposure to a PAR1 agonist in the presence of anticoagulants rescued the angiogenic potential. In vivo studies demonstrated that platelets from anticoagulated patients had decreased VEGF release and angiogenic potential. Our data suggest that the mechanism by which antithrombotic agents increase survival and decrease metastasis in cancer patients is through attenuation of platelet angiogenic potential. (Blood. 2014;123(1):101-112) IntroductionCancer cells are surrounded by and interact with a complex milieu consisting of but not limited to endothelial cells, mast cells, macrophages, stromal cells, and lymphocytes. In fact, tumor cells live in intimate symbiosis with the rest of the body and appear to hijack normal physiological processes to aid their progression and growth. The recognition that tumor growth and metastasis is not exclusively an independent process for tumor cells suggests that disrupting the tumor microenvironment might provide a novel treatment modality for malignancy.Although platelets are best known for their role in hemostasis and thrombosis, a substantial amount of data supports the idea that platelets play important roles in tumorigenesis, contributing to inflammation, angiogenesis, and metastatic dissemination of tumor cells.1 Platelet count can be a prognostic factor in cancer, patients presenting with thrombocytosis having a poor survival in a variety of cancers including breast cancer.2-5 Conversely, the presence of thrombocytopenia is associated with a survival benefit and decreased metastasis.6-9 For tumors to grow beyond 1 to 2 mm 3 , they must establish their own blood supply through angiogenesis, and there is substantial evidence that angiogenesis is regulated by platelets. [10][11][12] In malignancy, platelets are the major serum source of many potent proangiogenic proteins, including more than 80% of circulating vascul...

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Section: Discussionmentioning

confidence: 99%

Anticoagulation inhibits tumor cell–mediated release of platelet angiogenic proteins and diminishes platelet angiogenic response

Battinelli

Markens

Kulenthirarajan

et al. 2014

Blood

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“…Clinical evidence indicates that patients with cancer treated with heparin survived longer, and data from various animal models demonstrate the ability of heparin to attenuate metastasis. 40 In cancer research, heparin is viewed as an inhibitor of angiogenesis and of the protumorigenic heparanase. 40 Additionally, increased systemic levels of sFlt-1 were associated with improved ventricular function of patients with myocardial infarction.…”

Section: Discussionmentioning

confidence: 99%

“…40 In cancer research, heparin is viewed as an inhibitor of angiogenesis and of the protumorigenic heparanase. 40 Additionally, increased systemic levels of sFlt-1 were associated with improved ventricular function of patients with myocardial infarction. 41 Hence, during pregnancy, heparin may augment the maternal systemic levels of sFlt-1 to actually protect against abruption, fetal growth restriction, and stillbirth through mechanisms that remain to be further investigated.…”

Section: Discussionmentioning

confidence: 99%

Heparin Elevates Circulating Soluble fms-Like Tyrosine Kinase-1 Immunoreactivity in Pregnant Women Receiving Anticoagulation Therapy

et al. 2011

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Background-Alterations in circulating levels of pro-and antiangiogenic factors have been associated with adverse pregnancy outcomes. Heparin is routinely administered to pregnant women, but without clear knowledge of its impact on these factors. Methods and Results-We conducted a longitudinal study of 42 pregnant women. Twenty-one women received prophylactic heparin anticoagulation, and 21 healthy pregnant women served as controls. Compared with gestational age-matched controls, heparin treatment was associated with increased circulating levels of soluble fms-like tyrosine kinase-1 (sFlt-1) in the third trimester (PϽ0.05), in the absence of preeclampsia, placental abruption, or fetal growth restriction. Heparin had no effect on circulating levels of vascular endothelial growth factor, placenta growth factor, or soluble endoglin as assessed by ELISA. In vitro, low-molecular weight and unfractionated heparins stimulated sFlt-1 release from placental villous explants, in a dose-and time-dependent manner. This effect was not due to placental apoptosis, necrosis, alteration in protein secretion, or increased transcription. Western blot analysis demonstrated that heparin induced shedding of the N-terminus of Flt-1 both in vivo and in vitro as indicated by a predominant band of 100 -112 kDa. By using an in vitro angiogenesis assay, we demonstrated that serum of heparin-treated cases inhibited both basal and vascular endothelial growth factor-induced capillary-like tube formation. Conclusions-Heparin likely increases the maternal sFlt-1 through shedding of the extracellular domain of Flt-1 receptor.Our results imply that upregulation of circulating sFlt-1 immunoreactivity in pregnancy is not always associated with adverse outcomes, and that heparin's protective effects, if any, cannot be explained by promotion of angiogenesis. (Circulation. 2011;124:2543-2553.)Key Words: anticoagulation Ⅲ angiogenesis Ⅲ sFlt-1 Ⅲ heparin Ⅲ pregnancy A successful pregnancy outcome requires the proper functioning of the molecular mechanisms responsible for regulating vascular endothelial homeostasis at both the systemic and local decidual/placental levels. 1 Derangements of these mechanisms can lead to major pregnancy-related complications. Recent studies have focused on how alterations in placental trophoblast production of angiogenic proteins may help to explain the pathogenesis of preeclampsia, 2,3 placental abruption, 4 intrauterine growth restriction, and stillbirth. 5 A unifying theory is that excessive release of antiangiogenic factors, such as soluble fms-like tyrosine kinase-1 (sFlt-1) and soluble endoglin (sEng) by hypoxic trophoblasts, antagonize proangiogenic factors such as vascular endothelial growth factor (VEGF) and placenta growth factor (PlGF). 3 This phenomenon causes aberrant placental angiogenesis and vasculogenesis. 6 The end result is an increasingly dysfunctional placenta with local and systemic vascular endothelial damage, activation of inflammatory pathways, and enhanced platelet turnover, which result in the...

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“…8 This antitumour activity of heparin, mechanistically, includes the inhibition of cell-cell interaction by blocking cell-adhesion molecules (selectins), the inhibition of extracellularmatrix protease heparanase and the inhibition of angiogenesis. 9 In a 1992 clinical trial comparing nadroparin, a LMWH, to unfractionated heparin (UFH) in patients with proven deep venous thrombosis (DVT), nadroparin unexpectedly reduced mortality in the subgroup of patients with cancer. 10 However, anticoagulants may increase the risk for bleeding and is likely higher in patients with cancer.…”

Section: Introductionmentioning

confidence: 99%

Randomized Phase III Trial of Standard Therapy Plus Low Molecular Weight Heparin in Patients With Lung Cancer: FRAGMATIC Trial

Macbeth

Noble

Evans

et al. 2016

JCO

148

110

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Purpose Venous thromboembolism (VTE) is common in cancer patients. Evidence has suggested that low molecular weight heparin (LMWH) might improve survival in patients with cancer by preventing both VTE and the progression of metastases. No trial in a single cancer type has been powered to demonstrate a clinically significant survival difference. The aim of this trial was to investigate this question in patients with lung cancer. Patients and Methods We conducted a multicenter, open-label, randomized trial to evaluate the addition of a primary prophylactic dose of LMWH for 24 weeks to standard treatment in patients with newly diagnosed lung cancer of any stage and histology. The primary outcome was 1-year survival. Secondary outcomes included metastasis-free survival, VTE-free survival, toxicity, and quality of life. Results For this trial, 2,202 patients were randomly assigned to the two treatment arms over 4 years. The trial did not reach its intended number of events for the primary analysis (2,047 deaths), and data were analyzed after 2,013 deaths after discussion with the independent data monitoring committee. There was no evidence of a difference in overall or metastasis-free survival between the two arms (hazard ratio [HR], 1.01; 95% CI, 0.93 to 1.10; P = .814; and HR, 0.99; 95% CI, 0.91 to 1.08; P = .864, respectively). There was a reduction in the risk of VTE from 9.7% to 5.5% (HR, 0.57; 95% CI, 0.42 to 0.79; P = .001) in the LMWH arm and no difference in major bleeding events but evidence of an increase in the composite of major and clinically relevant nonmajor bleeding in the LMWH arm. Conclusion LMWH did not improve overall survival in the patients with lung cancer in this trial. A significant reduction in VTE is associated with an increase in clinically relevant nonmajor bleeding. Strategies to target those at greatest risk of VTE are warranted.

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Heparin as an Inhibitor of Cancer Progression

Cited by 62 publications

References 84 publications

Anticoagulation inhibits tumor cell–mediated release of platelet angiogenic proteins and diminishes platelet angiogenic response

Anticoagulation inhibits tumor cell–mediated release of platelet angiogenic proteins and diminishes platelet angiogenic response

Heparin Elevates Circulating Soluble fms-Like Tyrosine Kinase-1 Immunoreactivity in Pregnant Women Receiving Anticoagulation Therapy

Randomized Phase III Trial of Standard Therapy Plus Low Molecular Weight Heparin in Patients With Lung Cancer: FRAGMATIC Trial

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