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.
Highlights
Platelets are primary mediators of blood coagulation
Proteoglycans purified from human and mouse platelets were analyzed by electrophoresis (Figure 1D)
Alcian blue staining following PAGE separation revealed that glycosaminoglycans (GAG) from platelets were resistant to bacterial heparinases, but susceptible to chondroitinase, indicating that both human and mouse platelets express chondroitin sulfate (CS), but are devoid of heparan sulfate (HS)
Summary
Platelets are primary mediators of blood coagulation. Platelets are activated and aggregated at the site of injury[1]. Apart from forming a primary hemostatic plug, activated platelets degranulate and release a spectrum of active molecules from the granules. Dense granules release active ligands including ADP/ATP to propagate platelet aggregation. Alphagranules release, in addition to pro-coagulant proteins, anti-coagulation molecules such as antithrombin and fibrinolytic proteins, e.g. plasminogen. Emerging information points to additional biological roles of platelets, attributed to active molecules secreted upon their activation and to the release of microparticles that mediate cellular crosstalk[2]. Platelets directly and indirectly promote tumor growth and protect metastasizing cells to escape T-cell-mediated immunity and natural killer cell surveillance[3, 4]
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