Abstract
Tumor cell–platelet interactions are regarded as an initial crucial step in hematogenous metastasis. Platelets protect tumor cells from immune surveillance in the blood, mediate vascular arrest, facilitate tumor extravasation, growth, and finally angiogenesis in the metastatic foci. Tumor cells aggregate platelets in the bloodstream by activation of the plasmatic coagulation cascade and by direct contact formation. Antimetastatic activities of unfractionated or low molecular weight heparin (UFH/LMWH) can undoubtedly be related to attenuated platelet activation, but molecular mechanisms and contribution of contact formation vs. coagulation remain to be elucidated. Using a set of non-anticoagulant heparin derivatives varying in size or degree of sulfation as compared with UFH, we provide insight into the relevance of contact formation for platelet activation. Light transmission aggregometry and ATP release assays confirmed that only those heparin derivatives with P-selectin blocking capacities were able to attenuate breast cancer cell-induced platelet activation, while pentasaccharide fondaparinux was without effects. Furthermore, a role of P-selectin in platelet activation and signaling could be confirmed by proteome profiler arrays detecting platelet kinases. In this study, we demonstrate that heparin blocks tumor cell-induced coagulation. Moreover, we identify platelet P-selectin, which obviously acts as molecular switch and controls aggregation and secretion of procoagulant platelets.
Highlights
Interaction of tumor cells with platelets is likely one of the most decisive steps in hematogenous cancer cell dissemination
The slightly lower capacity for platelet activation of the low metastatic MCF-7 breast cancer cell line became evident by the longer time frame until platelet aggregation, and the fact that the lowest cell density (1 × 103 MCF-7 cells/mL)
We focused on tumor cell-induced platelet dense granules secretion, 1 × 104 MDA-MB-231 or 1 × 104 MCF-7 cells/mL were added to platelets in buffer, and ATP release was quantified with a luciferin-based
Summary
Interaction of tumor cells with platelets is likely one of the most decisive steps in hematogenous cancer cell dissemination. Upon arrival in the blood, tumor cells activate platelets and, resulting thereof, are immediately encased by platelets [1]. Platelets confer a multitude of survival advantages to tumor cells and crucially contribute to successful metastatic nodule formation. Platelets protect tumor cells from shear stress and detrimental Natural killer cell assaults by downregulation of NK cell activating receptor NKG2D [2]. Platelets are able to induce an invasive epithelial to mesenchymal-like phenotype to breast cancer cells accompanied by an increased number of metastases in the lungs of mice [3]. The close interaction between platelets and tumor cells is mediated by platelet adhesion
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