Download PDF
Thromb Haemost 2006; 95(03): 535-540
DOI: 10.1160/TH05-07-0515
Cellular Proteolysis and Oncology
Schattauer GmbH

The ability of different forms of heparins to suppress P-selectin function in vitro correlates to their inhibitory capacity on bloodborne metastasis in vivo

Ralf J. Ludwig
1   Department of Dermatology, Johann Wolfgang Goethe-University, Frankfurt am Main, Germany
,
Susanne Alban
2   Pharmaceutical Institute, Christian-Albrechts-University, Kiel, Germany
,
Roxana Bistrian
3   Institute for Transfusion Medicine and Immune Hematology, German Red Cross Blood Donor Service, Johann Wolfgang Goethe-University, Frankfurt am Main, Germany
,
Wolf-Henning Boehncke
1   Department of Dermatology, Johann Wolfgang Goethe-University, Frankfurt am Main, Germany
,
Roland Kaufmann
1   Department of Dermatology, Johann Wolfgang Goethe-University, Frankfurt am Main, Germany
,
Reinhard Henschler
3   Institute for Transfusion Medicine and Immune Hematology, German Red Cross Blood Donor Service, Johann Wolfgang Goethe-University, Frankfurt am Main, Germany
,
Jens Gille
1   Department of Dermatology, Johann Wolfgang Goethe-University, Frankfurt am Main, Germany
› Author AffiliationsFinancial support: This work was supported by Deutsche Forschungsgemeinschaft grants Lu 877/1–1 (R. Ludwig) and Gi 229/5–1 (J. Gille), and by grants from the Paul und Ursula Klein-Stiftung (R. Ludwig) and from the Adolf-Messer-Stiftung (J. Gille).
Further Information

Publication History

Received 24 July 2005

Accepted after resubmission 22 February 2005

Publication Date:
29 November 2017 (online)

Also available at
    Permissions and Reprints

Summary

Ample evidence suggests that many of the in vivo anti-metastatic effects by heparins reflect their actions on P-selectin-mediated binding. We hypothesized that the ability of widely used heparins and derivatives to interfere with P-selectin-dependent tumour cell interactions under flow in vitro could be used to identify anticoagulants with advanced inhibitory functions on experimental blood-borne metastasis in vivo. To test this assumption, the impact of unfractionated heparin, the low-molecular-weight heparins (LMWH) nadroparin and enoxaparin, and the synthetic pentasaccharide fondaparinux on P-selectin-dependent tumour interactions in vitro and metastasis formation in vivo were evaluated. Our data revealed that these commonly used anticoagulants widely differ in their potential to interfere with P-selectinmediated cell binding. Importantly, the superior inhibitory capacity on P-selectin function of unfractionated heparin and LMWH nadroparin as opposed to LMWH enoxaparin and synthetic heparin pentasaccharide fondaparinux strongly correlated to the inhibitory potency of each in inhibiting experimental lung metastasis in vivo. Hence, P-selectin inhibition may constitute a valuable feature to identify anticoagulants that are suitable for anticancer therapy.

Keywords

Anticoagulants - heparin - P-selectin - neoplasm metastasis - melanoma
 

  • References

  • 1 Chambers AF, Groom AC, MacDonald IC. Dissemination and growth of cancer cells in metastatic sites. Nat Rev Cancer 2002; 02: 563-72.
    CrossrefPubMedGoogle Scholar
  • 2 Smorenburg SM, Van Noorden CJ. The complex effects of heparins on cancer progression and metastasis in experimental studies. Pharmacol Rev 2001; 53: 93-105.
    PubMedGoogle Scholar
  • 3 Borsig L, Wong R, Feramisco J. et al. Heparin and cancer revisited: mechanistic connections involving platelets, P-selectin, carcinoma mucins, and tumour metastasis. Proc NatlAcad Sci USA 2001; 98: 3352-7.
    CrossrefPubMedGoogle Scholar
  • 4 Nelson RM, Cecconi O, Roberts WG. et al. Heparin oligosaccharides bind Land P-selectin and inhibit acute inflammation. Blood 1993; 82: 3253-8.
    PubMedGoogle Scholar
  • 5 Koenig A, Norgard-Sumnicht K, Linhardt R. et al. Differential interactions of heparin and heparan sulfate glycosaminoglycans with the selectins. Implications for the use of unfractionated and low molecular weight heparins as therapeutic agents. J Clin Invest 1998; 101: 877-89.
    CrossrefPubMedGoogle Scholar
  • 6 Ludwig RJ, Boehme B, Podda M. et al. Endothelial P-selectin as a target of heparin action in experimental melanoma lung metastasis. Cancer Res 2004; 64: 2743-50.
    CrossrefPubMedGoogle Scholar
  • 7 Pineo GF, Hull RD. Unfractionated and low-molecular-weight heparin. Comparisons and current recommendations. Med Clin North Am 1998; 82: 587-99.
    CrossrefPubMedGoogle Scholar
  • 8 Gould MK, Dembitzer AD, Doyle RL. et al. Lowmolecular-weight heparins compared with unfractionated heparin for treatment of acute deep venous thrombosis. A meta-analysis of randomized, controlled trials. Ann Intern Med 1999; 130: 800-9.
    CrossrefPubMedGoogle Scholar
  • 9 Turpie AG, Eriksson BI, Lassen MR. et al. Fondaparinux, the first selective factor Xa inhibitor. Curr Opin Hematol 2003; 10: 327-32.
    CrossrefPubMedGoogle Scholar
  • 10 Alban S. From heparins to factor Xa inhibitors and beyond. Eur J Clin Invest 2005; (35) (Suppl. 01) 12-20.
    PubMedGoogle Scholar
  • 11 Lee AY, Rickles FR, Julian JA. et al. Randomized comparison of low molecular weight heparin and coumarin derivatives on the survival of patients with cancer and venous thromboembolism. J Clin Oncol 2005; 23: 2123-9.
    CrossrefPubMedGoogle Scholar
  • 12 Klerk CP, Smorenburg SM, Otten HM. et al. The effect of low molecular weight heparin on survival in patients with advanced malignancy. J Clin Oncol 2005; 23: 2130-5.
    CrossrefPubMedGoogle Scholar
  • 13 Casu B, Gennaro U. A conductimetric method for the determination of sulphate and carboxyl groups in heparin and other mucopolysaccharides. Carbohydr Res 1975; 39: 168-76.
    CrossrefPubMedGoogle Scholar
  • 14 Jager E, Karbach J, Gnjatic S. et al. Identification of a naturally processed NY-ESO-1 peptide recognized by CD8+ T cells in the context of HLA-B51. Cancer Immunity 2002; 02: 12.
    PubMedGoogle Scholar
  • 15 Hopfner M, Alban S, Schumacher G. et al. Selectinblocking semisynthetic sulfated polysaccharides as promising anti-inflammatory agents. J Pharm Pharmacol 2003; 55: 697-706.
    CrossrefPubMedGoogle Scholar
  • 16 Richter R, Bistrian R, Escher S. et al. Quantum proteolytic activation of chemokine CCL15 by neutrophil granulocytes modulates mononuclear cell adhesiveness. J Immunol 2005; 175: 1599-608.
    CrossrefPubMedGoogle Scholar
  • 17 Kaur J, Woodman RC, Ostrovsky L. et al. Selective recruitment of neutrophils and lymphocytes by thrombin: a role for NF-kappaB. Am J Physiol Heart Circ Physiol 2001; 281: H784-95.
    CrossrefPubMedGoogle Scholar
  • 18 Gill V, Doig C, Knight D. et al. Targeting adhesion molecules as a potential mechanism of action for intravenous immunoglobulin. Circulation 2005; 112: 2031-9.
    CrossrefPubMedGoogle Scholar
  • 19 Mannori G, Crottet P, Cecconi O. et al. Differential colon cancer cell adhesion to E-, P-, and L-selectin: role of mucin-type glycoproteins. Cancer Res 1995; 55: 4425-31.
    PubMedGoogle Scholar
  • 20 Borsig L, Wong R, Hynes RO. et al. Synergistic effects of L-and P-selectin in facilitating tumour metastasis can involve non-mucin ligands and implicate leukocytes as enhancers of metastasis. Proc Natl Acad Sci USA 2002; 99: 2193-8.
    CrossrefPubMedGoogle Scholar
  • 21 Nakamori S, Kameyama M, Imaoka S. et al. Increased expression of sialyl Lewisx antigen correlates with poor survival in patients with colorectal carcinoma: clinicopathological and immunohistochemical study. Cancer Res 1993; 53: 3632-7.
    PubMedGoogle Scholar
  • 22 Nakayama T, Watanabe M, Katsumata T. et al. Expression of sialyl Lewis(a) as a new prognostic factor for patients with advanced colorectal carcinoma. Cancer 1995; 75: 2051-6.
    CrossrefPubMedGoogle Scholar
  • 23 Jorgensen T, Berner A, Kaalhus O. et al. Up-regulation of the oligosaccharide sialyl LewisX: a new prognostic parameter in metastatic prostate cancer. Cancer Res 1995; 55: 1817-9.
    PubMedGoogle Scholar
  • 24 Numahata K, Satoh M, Handa K. et al. Sialosyl- Le(x) expression defines invasive and metastatic properties of bladder carcinoma. Cancer 2002; 94: 673-85.
    CrossrefPubMedGoogle Scholar
  • 25 Kim YJ, Borsig L, Varki NM. et al. P-selectin deficiency attenuates tumour growth and metastasis. Proc Natl Acad Sci USA 1998; 95: 9325-30.
    CrossrefPubMedGoogle Scholar
  • 26 Zacharski LR, Ornstein DL. Heparin and cancer. Thromb Haemost 1998; 80: 10-23.
    Article in Thieme ConnectPubMedGoogle Scholar
  • 27 Sciumbata T, Caretto P, Pirovano P. et al. Treatment with modified heparins inhibits experimental metastasis formation and leads, in some animals, to long-term survival. Invasion Metastasis 1996; 16: 132-43.
    PubMedGoogle Scholar
  • 28 Wang L, Brown JR, Varki A. et al. Heparin’s anti-inflammatory effects require glucosamine 6-O-sulfation and are mediated by blockade of L- and P-selectins. J Clin Invest 2002; 110: 127-36.
    CrossrefPubMedGoogle Scholar
  • 29 Esko JD, Lindahl U. Molecular diversity of heparan sulfate. J Clin Invest 2001; 108: 169-73.
    CrossrefPubMedGoogle Scholar