The Effect of Low Molecular Weight Heparin on Survival in Patients With Advanced Malignancy

Klerk, Clara P.W.; Smorenburg, Susanne M.; Otten, Hans Martin; Lensing, Anthonie W. A.; Prins, Martin H.; Piovella, Franco; Prandoni, Paolo; Bos, Monique M.E.M.; Richel, Dick J.; Tienhoven, Geertjan van; Büller, Harry R.

doi:10.1200/jco.2005.03.134

Cited by 565 publications

(407 citation statements)

References 16 publications

(11 reference statements)

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“…These data extend previous observations that have implicated antimetastatic effects for heparin and HLGAGs in animal model systems (21)(22)(23)(24)(25)(26). Clinical studies have also indicated that heparin and HLGAGs may prolong survival of patients with cancer with solid tumors (3)(4)(5).…”

Section: Discussionsupporting

confidence: 76%

“…Highly sulfated heparan sulfate glycosaminoglycans, such as heparin, are commonly used to prevent venous thromboembolism, which is a common complication in patients with cancer as well. Heparin and heparin-like glycosaminoglycans (HLGAGs) have also been shown to prolong survival of patients with cancer, suggesting an antimetastatic effect for these compounds (3)(4)(5). The applicability of heparin in cancer therapy is limited because of its strong anticoagulant activity, but HLGAGs with less undesired effects on blood coagulation have been developed.…”

Section: Introductionmentioning

confidence: 99%

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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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Section: Discussionsupporting

confidence: 76%

Section: Introductionmentioning

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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“…Low molecular weight heparin (LMWH) may attenuate these events through multiple mechanisms, including 1) by directly inhibiting thrombin or other coagulation proteins by catalyzing antithrombin, 3 2) by indirectly inhibiting thrombin formation by stimulating the release of tissue factor pathway inhibitor, an effective inhibitor of TF-mediated coagulation, 3 and 3) by inhibiting VEGF-A. 3 growth in several cancers in early, 32,33 but not advanced disease. 21 We show that LMWH significantly reduced tumor cell proliferation and thrombin generation in vitro and in vivo.…”

Section: Discussionmentioning

confidence: 99%

Thrombin induces osteosarcoma growth, a function inhibited by low molecular weight heparin in vitro and in vivo

Ichikawa

Cole

Magnussen

et al. 2011

Cancer

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BACKGROUND: Procoagulant states, leading to activation of the coagulation protease thrombin, are common in cancer and portend a poor clinical outcome. Although procoagulant states in osteosarcoma patients have been described, studies exploring osteosarcoma cells' ability to directly contribute to procoagulant activity have not been reported. This study explores the hypothesis that osteosarcoma can regulate thrombin generation and proliferate in response to thrombin, and that attenuating thrombin generation with anticoagulants can slow tumor growth. METHODS: Pathologic analysis of osteosarcoma with adjacent venous thrombus was performed. In vitro proliferation assays, cell-based coagulant activity assays, and quantification of coagulation cofactor expression were performed on human and murine osteosarcoma cell lines with varying aggressiveness. The efficacy of low molecular weight heparin (LMWH) attenuation of tumor-dependent thrombin generation and growth in vitro and in vivo was determined. RESULTS: Venous thrombi adjacent to osteosarcoma were found to harbor tumor surrounded by fibrin expressing coagulation cofactors, a finding associated with poor clinical outcome. More aggressive osteosarcoma cell lines had greater surface expression of procoagulant factors and generated more thrombin than less aggressive cell lines and were found to proliferate in response to thrombin. Treatment with LMWH reduced in vitro osteosarcoma proliferation and procoagulant activity as well as tumor growth in vivo. CONCLUSIONS: These findings suggest that elements of the coagulation cascade may play a role in and represent a pharmaceutical target to disrupt osteosarcoma growth. They also have broader implications, as they suggest that, to be effective, dosing of anticoagulants must take into account an individual tumor's capacity to generate thrombin. Cancer 2012;118:2494

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“…Of note, the HB-EGF-induced proliferation of myeloma cells was inhibited by 46% with 0.1 IU/ml of heparin, which is in the range of therapeutic concentrations. One recent study has reported that a short-term treatment with heparin could improve the survival of patients with metastatic epithelial cancers (Klerk et al, 2005). One possible mechanism might be that heparin competes with HS for the binding of growth factors preventing their stimulatory effect on tumor cells.…”

Section: Discussionmentioning

confidence: 99%

Heparan sulphate proteoglycans are essential for the myeloma cell growth activity of EGF-family ligands in multiple myeloma

et al. 2006

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The epidermal growth factor (EGF)/EGF-receptor (ErbB1-4) family is involved in the biology of multiple myeloma (MM). In particular, ErbB-specific inhibitors induce strong apoptosis of myeloma cells (MMC) in vitro.To delineate the contribution of the 10 EGF-family ligands to the pathogenesis of MM, we have assessed their expression and biological activity. Comparing Affymetrix DNA-microarray-expression-profiles of CD138-purified plasma-cells from 65 MM-patients and 7 normal individuals to those of plasmablasts and B-cells, we found 5/10 EGF-family genes to be expressed in MMC. Neuregulin-2 and neuregulin-3 were expressed by MMC only, while neuregulin-1, amphiregulin and transforming growth factor-a were expressed by both MMC and normal plasma-cells. Using real-time polymerase chain reaction, we found HB-EGF, amphiregulin, neuregulin-1 and epiregulin to be expressed by cells from the bone marrow-environment. Only the EGF-members able to bind heparan-sulphate proteoglycans (HSPGs) -neuregulin-1, amphiregulin, HB-EGF -promote the growth of MMC. Those ligands strongly bind MMC through HSPGs. The binding and the MMC growth activity was abrogated by heparitinase, heparin or deletion of the HS-binding domain. The number of HS-binding EGF ligand molecules bound to MMC was higher than 10 5 molecules/cell and paralleled that of syndecan-1. Syndecan-1, the main HSPG present on MM cells, likely concentrates high levels of HS-binding-EGF-ligands at the cell membrane and facilitates ErbB-activation. Altogether, our data further identify EGF-signalling as promising target for MM-therapy.

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The Effect of Low Molecular Weight Heparin on Survival in Patients With Advanced Malignancy

Abstract: A brief course of subcutaneous low molecular weight heparin favorably influences the survival in patients with advanced malignancy and deserves additional clinical evaluation.

Cited by 565 publications

References 16 publications

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

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

Thrombin induces osteosarcoma growth, a function inhibited by low molecular weight heparin in vitro and in vivo

Heparan sulphate proteoglycans are essential for the myeloma cell growth activity of EGF-family ligands in multiple myeloma

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