The Low Molecular Weight Heparin Tinzaparin Attenuates Platelet Activation in Terms of Metastatic Niche Formation by Coagulation-Dependent and Independent Pathways

Abstract

An intimate interplay with platelets is an initial key issue for tumor cells in terms of hematogenous metastasis. Tumor cells activate platelets by different pathways and receive, upon forming a platelet cloak, protection from immune surveillance and support in metastatic niche creation. Therapeutic intervention with this early interaction is promising to antagonize the whole metastatic cascade. Here we aimed to investigate the capability of low molecular weight heparin (LMWH), unfractionated heparin (UFH), and a non-anticoagulant heparin derivative or FXa inhibitor fondaparinux to interfere with platelet activation by tumor cells. Coagulation-dependent and independent pathways of platelet activation by three tumor cell lines, and interference therewith were analyzed by fluorigenic thrombin formation assay, platelet aggregometry, ATP and VEGF release and endothelial tube formation assay. LMWH and UFH were found to repress various routes of platelet activation, reflected by attenuated endothelial tube formation. This confirms the duality of anti-coagulative and anti-adhesive properties of heparin. While non-anticoagulative heparin (RO-heparin) depressed platelets’ ATP and VEGF release by contact inhibition sufficiently, fondaparinux just attenuated tissue factor mediated thrombin generation. Concluding, these data suggest that LMWH as a guideline-based drug for anticoagulative strategies in oncology is promising to provide additional benefit for interference with metastatic activities.

Inhibition of Tumor–Host Cell Interactions Using Synthetic Heparin Mimetics

“…One of the key events in the metastatic dissemination of cancer cells in the blood is the activation of and interaction with platelets. Meanwhile, multiple pathways of tumor cell-induced platelet activation (TCIPA) have been identified. , LMWH was shown to interfere with TCIPA to prevent the formation of cancer cell/platelet heteroaggregates and platelet degranulation. , …”

Glycosaminoglycans as Tools to Decipher the Platelet Tumor Cell Interaction: A Focus on P-Selectin

“…In the present study, we make use of different glycosaminoglycan derivatives (RO-heparin, 2-O-desulfated heparin, hexasaccharide and decasaccharide heparin fragments, and UFH) as tools to delineate that the platelet adhesion molecule P-selectin is responsible for the interaction between platelets and tumor cells [10]. P-selectin mediates platelet aggregation and secretion of platelets αand dense granules, subsequent to tumor cell contact.…”

“…Recently, we revealed that unfractionated heparin (UFH) blocks the tumor cell induced thrombin formation and concomitantly inhibits a platelet activation mediated by direct adhesion. In contrast, the pentasaccharide fondaparinux inhibited thrombin generation but failed to reduce platelet activation induced by direct binding [10]. However, the platelet receptors responsible for the observed heparin inhibition remained elusive.…”

“…This is regarded as one of the main stimuli for platelet activation. Thrombin, in turn, induces human platelet activation via cleavage of the protease-activated receptor-1 (PAR-1) [8][9][10]. Second, cancer cell secretion of soluble mediators like ADP [11], or thromboxane A2 (TXA2) also has an impact on the status of platelet activation [12].…”

Introduction to the Molecules Special Edition Entitled ‘Heparan Sulfate and Heparin: Challenges and Controversies’: Some Outstanding Questions in Heparan Sulfate and Heparin Research

“…Both unfractionated and low molecular weight heparin reduced this platelet-induced transition and highlights the potential of heparin in oncological applications [45]. In a further report concerning the activity of platelets in cancer, Gockel et al, showed that low molecular weight heparin has the ability to moderate the platelet activation by two routes; through both coagulation dependent and independent mechanisms [46]. Continuing the cancer theme, Hellec et al, described the role of one of the sulfotransferase enzymes, HS3ST3B, responsible for the addition of 3-O-sulfate groups to glucosamine residues in HS, in enhancing tumour growth, which the authors showed is dependent on the expression of neuropilin-1 [47].…”