Heparanase Expression Upregulates Platelet Adhesion Activity and Thrombogenicity

Overview

Journal Oncotarget

Specialty Oncology

Date 2016 Apr 30

PMID 27129145

Citations 22

Authors

Hao Cui

Ying-Xia Tan

Cecilia Osterholm

Xiao Zhang

Ulf Hedin

Israel Vlodavsky

Jin-Ping Li

Affiliations

Soon will be listed here.

Abstract

Heparanase is an endo-glucuronidase that specifically cleaves heparan sulfate (HS) and heparin polysaccharides. The enzyme is expressed at low levels in normal tissues, but is often upregulated under pathological conditions such as cancer and inflammation. Normal human platelets express exceptionally high levels of heparanase, but the functional consequences of this feature remain unknown. We investigated functional roles of heparanase by comparing the properties of platelets expressing high (Hpa-tg) or low (Ctr) levels of heparanase. Upon activation, Hpa-tg platelets exhibited a much stronger adhesion activity as compared to Ctr platelets, likely contributing to a higher thrombotic activity in a carotid thrombosis model. Furthermore, we found concomitant upregulated expression of both heparanase and CD62P (P-selectin) upon activation of mouse and human platelets. As platelets play important roles in tumor metastasis, these findings indicate contribution of the platelet heparanase to hyper-thrombotic conditions often seen in patients with metastatic cancer.

Citing Articles

Analysis of Expression Pattern and Prognostic Value of the Heparanase in Breast Cancer Through CD274/CTLA-4 Immune Checkpoint Proteins.

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Role of heparanase in pulmonary hypertension.

Wang L, Feng F, Li J, Chen T, Liu L Front Pharmacol. 2023; 14:1202676.

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Heparanase-A single protein with multiple enzymatic and nonenzymatic functions.

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References

Yahalom J, Eldor A, Fuks Z, Vlodavsky I . Degradation of sulfated proteoglycans in the subendothelial extracellular matrix by human platelet heparitinase. J Clin Invest. 1984; 74(5):1842-9. PMC: 425364. DOI: 10.1172/JCI111603. View

Vlodavsky I, Elkin M, Abboud-Jarrous G, Levi-Adam F, Fuks L, Shafat I . Heparanase: one molecule with multiple functions in cancer progression. Connect Tissue Res. 2008; 49(3):207-10. DOI: 10.1080/03008200802143281. View

Escobar Galvis M, Jia J, Zhang X, Jastrebova N, Spillmann D, Gottfridsson E . Transgenic or tumor-induced expression of heparanase upregulates sulfation of heparan sulfate. Nat Chem Biol. 2007; 3(12):773-8. DOI: 10.1038/nchembio.2007.41. View

Franchini M, Mannucci P . Venous and arterial thrombosis: different sides of the same coin?. Eur J Intern Med. 2008; 19(7):476-81. DOI: 10.1016/j.ejim.2007.10.019. View

Rossaint J, Herter J, Van Aken H, Napirei M, Doring Y, Weber C . Synchronized integrin engagement and chemokine activation is crucial in neutrophil extracellular trap-mediated sterile inflammation. Blood. 2013; 123(16):2573-84. DOI: 10.1182/blood-2013-07-516484. View

Woulfe D, Lilliendahl J, August S, Rauova L, Kowalska M, Abrink M . Serglycin proteoglycan deletion induces defects in platelet aggregation and thrombus formation in mice. Blood. 2007; 111(7):3458-67. PMC: 2275015. DOI: 10.1182/blood-2007-07-104703. View

Koenig A, Linhardt R, Varki A . 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(4):877-89. PMC: 508636. DOI: 10.1172/JCI1509. View

Petzold T, Ruppert R, Pandey D, Barocke V, Meyer H, Lorenz M . β1 integrin-mediated signals are required for platelet granule secretion and hemostasis in mouse. Blood. 2013; 122(15):2723-31. DOI: 10.1182/blood-2013-06-508721. View

Pisano C, Vlodavsky I, Ilan N, Zunino F . The potential of heparanase as a therapeutic target in cancer. Biochem Pharmacol. 2014; 89(1):12-9. PMC: 4709407. DOI: 10.1016/j.bcp.2014.02.010. View

10.

Zcharia E, Metzger S, Chajek-Shaul T, Aingorn H, Elkin M, Friedmann Y . Transgenic expression of mammalian heparanase uncovers physiological functions of heparan sulfate in tissue morphogenesis, vascularization, and feeding behavior. FASEB J. 2004; 18(2):252-63. DOI: 10.1096/fj.03-0572com. View

11.

Reed G, Fitzgerald M, Polgar J . Molecular mechanisms of platelet exocytosis: insights into the "secrete" life of thrombocytes. Blood. 2000; 96(10):3334-42. View

12.

Vlodavsky I, Eldor A, Haimovitz-Friedman A, Matzner Y, Lider O, Naparstek Y . Expression of heparanase by platelets and circulating cells of the immune system: possible involvement in diapedesis and extravasation. Invasion Metastasis. 1992; 12(2):112-27. View

13.

Zhang X, Wang B, OCallaghan P, Hjertstrom E, Jia J, Gong F . Heparanase overexpression impairs inflammatory response and macrophage-mediated clearance of amyloid-β in murine brain. Acta Neuropathol. 2012; 124(4):465-78. PMC: 3444710. DOI: 10.1007/s00401-012-0997-1. View

14.

Bombeli T, Schwartz B, Harlan J . Adhesion of activated platelets to endothelial cells: evidence for a GPIIbIIIa-dependent bridging mechanism and novel roles for endothelial intercellular adhesion molecule 1 (ICAM-1), alphavbeta3 integrin, and GPIbalpha. J Exp Med. 1998; 187(3):329-39. PMC: 2212123. DOI: 10.1084/jem.187.3.329. View

15.

Qi C, Wei B, Zhou W, Yang Y, Li B, Guo S . P-selectin-mediated platelet adhesion promotes tumor growth. Oncotarget. 2015; 6(9):6584-96. PMC: 4466636. DOI: 10.18632/oncotarget.3164. View

16.

Vlodavsky I, Beckhove P, Lerner I, Pisano C, Meirovitz A, Ilan N . Significance of heparanase in cancer and inflammation. Cancer Microenviron. 2011; 5(2):115-32. PMC: 3399068. DOI: 10.1007/s12307-011-0082-7. View

17.

Borsig L, Vlodavsky I, Ishai-Michaeli R, Torri G, Vismara E . Sulfated hexasaccharides attenuate metastasis by inhibition of P-selectin and heparanase. Neoplasia. 2011; 13(5):445-52. PMC: 3084621. DOI: 10.1593/neo.101734. View

18.

Nadir Y, Brenner B . Heparanase procoagulant activity. Thromb Res. 2012; 129 Suppl 1:S76-9. DOI: 10.1016/S0049-3848(12)70021-X. View

19.

Jackson S . The growing complexity of platelet aggregation. Blood. 2007; 109(12):5087-95. DOI: 10.1182/blood-2006-12-027698. View

20.

Goubran H, Stakiw J, Radosevic M, Burnouf T . Platelet-cancer interactions. Semin Thromb Hemost. 2014; 40(3):296-305. DOI: 10.1055/s-0034-1370767. View