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

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.

Fibrinogen/Albumin Ratio Index Is an Independent Prognosis Predictor of Recurrence-Free Survival in Patients After Surgical Resection of Gastrointestinal Stromal Tumors

“…Moreover, fibrinogen binds to fibrinogen receptors, which are expressed in malignant tumor cells and platelets to promote cell-to-cell adhesion. Tumor cells form platelet aggregation in the bloodstream by activating plasma coagulation cascades and direct contact, which increases with the progression and metastasis of the tumor (39). Furthermore, fibrinogen stimulates macrophages to produce high levels of TNF-α (40).…”

A Combined Activity of Thrombin and P-Selectin Is Essential for Platelet Activation by Pancreatic Cancer Cells

“…P-selectin was traditionally regarded as a simple adhesion receptor on platelets that contributed to aggregate formation and stability without any signaling function [ 25 , 26 , 27 ]. Nevertheless, accumulating evidence suggests that P-selectin indeed has a signaling function that regulates the status of platelet activity [ 23 , 24 ]. AsPC-1 and Capan-2 cells revealed an increased binding to immobilized P-selectin compared to MIA PaCa-2 cells, which refers to an enhanced expression of P-selectin ligands on membranes of both cell lines ( Figure 4 E).…”

“…Podoplanin expressed by stromal fibroblasts in the pancreatic tumor tissue is supposed to induce platelet activation via the C-type lectin-like receptor-2 (CLEC-2) [ 22 ]. Platelet P-selectin, traditionally regarded as a simple adhesion receptor is also capable of expediting platelet aggregation and secretion [ 23 , 24 ]. For pancreatic cancer cells, selective platelet activation mechanisms have been investigated individually, but data of combinatorial approaches, blocking different pathways concomitantly to confine platelet activation are hardly available.…”

Antineoplastic drug‐loaded polymer‐modified magnetite nanoparticles: Comparative analysis of EPR‐mediated drug delivery

“…Preclinical data confirm that HP can interfere with metastatic spread as a multi‐target drug, e.g. affecting tumor cell adhesion or migration ( Schwarz et al, 2020). A HP‐binding domain, essential for interactions with HP, is also the binding site for the fibroblast growth factors (FGFs).…”