The mechanisms how heparin affects the tumor cell induced VEGF and chemokine release from platelets to attenuate the early metastatic niche formation

Abstract

Metastasis is responsible for the majority of cancer associated fatalities. Tumor cells leaving the primary tumor and entering the blood flow immediately interact with platelets. Activated platelets contribute in different ways to cancer cell survival and proliferation, e.g. in formation of the early metastatic niche by release of different growth factors and chemokines. Here we show that a direct interaction between platelets and MV3 melanoma or MCF7 breast cancer cells induces platelet activation and a VEGF release in citrated plasma that cannot be further elevated by the coagulation cascade and generated thrombin. In contrast, the release of platelet-derived chemokines CXCL5 and CXCL7 depends on both, a thrombin-mediated platelet activation and a direct interaction between tumor cells and platelets. Preincubation of platelets with therapeutic concentrations of unfractionated heparin reduces the tumor cell initiated VEGF release from platelets. In contrast, tumor cell induced CXCL5 and CXCL7 release from platelets was not impacted by heparin pretreatment in citrated plasma. In defibrinated, recalcified plasma, on the contrary, heparin is able to reduce CXCL5 and CXCL7 release from platelets by thrombin inhibition. Our data indicate that different chemokines and growth factors in diverse platelet granules are released in tightly regulated processes by various trigger mechanisms. We show for the first time that heparin is able to reduce the mediator release induced by different tumor cells both in a contact and coagulation dependent manner.

Role of platelets and platelet receptors in cancer metastasis

“…Both CXCL5 and CXCL7 are released due to platelet activation and attract granulocytes by activation of the granulocyte receptor CXCR2. CXCL5 and CXCL7 release is either initiated by direct contact between platelets and tumor cells or by activation of the coagulation cascade [ 106 ]. The prometastatic interplay between platelets, tumor and myeloid cells is corroborated by earlier publications [ 107 ].…”

microRNAs Orchestrate Pathophysiology of Breast Cancer Brain Metastasis: Advances in Therapy

“…PMP encapsulated miR-183 can suppress NK cell activation, possibly via the silencing of DAP12 a key accessory protein critical for surface NK receptor stabilization and downstream signal transduction [32]. Platelets also contribute to attenuate the early formulation of a metastatic niche [97]. Thus, platelet-derived miRNA also helps in the survival of CTCs after intravasation.…”

Chemokines and Chemokine Receptors: Orchestrating Tumor Metastasization

“…Colorectal cancer [19,34] Neutrophils [49,53,56] Lung cancer [19] MDSCs [54,55] Pancreatic cancer [19] Platelets [52,[57][58][59]] Prostate cancer [19] Renal cancer [19] Melanoma [32,33,60] Breast cancer [61] CXCR3 CXCL9 CXCL10 CXCL11 CXCL4L1…”

“…However, platelets have also been demonstrated to promote the survival of circulating tumor cells (CTCs) in the bloodstream by conferring their resistance to shear stress and attack from NK cells [178]. Within the tumor microenvironment platelets secrete CXCL5 and CXCL7, as a consequence of direct contact with tumor cells [57] or following activation of the coagulation cascade [59], thus supporting the recruitment of CXCR2-positive myeloid cells [58]. Platelet granules contain several other chemokines, including CXCL1, CXCL8/IL-8, CXCL12, CCL2, CCL3, CCL5, and CCL17 [52].…”