The impact of platelets on the metastatic potential of tumour cells

Abstract

In cancer, activation of platelets by tumor cells is critical to disease progression. Development of precise antiplatelet targeting may improve outcomes from anticancer therapy. Alongside a distinct shift in functionality such as pro-metastatic and pro-coagulant properties, platelet production is often accelerated significantly early in carcinogenesis and the cancer-associated thrombocytosis increases the risk of metastasis formation and thromboembolic events. Tumor-activated platelets facilitate the proliferation of migrating tumor cells and shield them from immune surveillance and physical stress during circulation. Additionally, platelet-tumor cell interactions promote tumor cell intravasation, intravascular arrest, and extravasation through a repertoire of adhesion molecules, growth factors and angiogenic factors. Particularly, the presence of circulating tumor cell (CTC) clusters in association with platelets is a negative prognostic indicator. The contribution of platelets to the metastatic process is an area of intense investigation and this review provides an overview of the advances in understanding platelet-tumor cell interactions and their contribution to disease progression. Also, we review the potential of targeting platelets to interfere with the metastatic process.

Fig. 1

Platelets are key mediators in both the early and late stages of cancer. Top-down from left: In forming the PMN, TAPs produce chemokines such as CXCL5 and CXCL7 to recruit protumorigenic immune cells including neutrophils and MDSCs to the PMN. In addition, TAPs secrete growth factors such as VEGF, PDGF and TGF-β to facilitate the formation and progression of PMN. In the bone marrow, thrombopoietin and G-CSF can boost platelet production more than 20 times, leading to thrombocytosis. Cancer-associated thrombocytosis and increased levels of inflammatory cytokines, proteases, PAI-1, TF, and vWF lead to hypercoagulation and thromboembolism. In the bloodstream, activated platelets may form clusters with cancer cells and shield them from immune-mediated elimination and physical stress. Due to the wall-directed deviation, CTCs clusters approach the vessel wall, creating a vortex of plasma and shear force that activate platelets and endothelial adhesion molecules, easing the arrest and intravasation process (Fig. 2). In the TME, TAPs release α-granules containing chemokines, growth factors and clotting factors, promoting angiogenesis. Platelet-derived chemokines attract MDSCs to promote immune suppression. bFGF: basic fibroblast growth factor. CTCs: Circulating tumor cell. CXCL5: Chemokine (C-X-C motif) ligand 5. CXCL7: Chemokine (C-X-C motif) ligand 7. G-CSF: Granulocyte colony-stimulating factor. MDSC: Myeloid-derived suppressor cell. PAI-1: plasminogen activator inhibitor-1. PDGF: Platelet-derived growth factor. PMN: premetastatic niche. TAPs: Tumor-activated platelet. TF: tissue factor. TGF-β: Transforming growth factor-beta. TME: Tumor microenvironment. VEGF: Vascular endothelial growth factor. vWF: von Willebrand Factor. Figure made on biorender.com.

Fig. 2

Major receptors and ligands on platelets and tumor cells involved in hyper-coagulation and the formation of CTCs clusters and tumor cell/platelet/leukocyte aggregates. VIIa: coagulation factor VIIa. ADP: adenosine diphosphate. CLEC-2; C-type lectin-like receptor 2. CTCs: circulating tumor cells. P2Y12: purinergic receptor P2Y, G-protein coupled, 12 protein. PAR-1: Protease-activated receptor-1. PSGL-1: P-selectin glycoprotein ligand-1. TF: tissue factor. TGFβ: Transforming growth factor β. TSP-1: Thrombospondin 1. vWF: von Willebrand Factor. Figure made on biorender.com.

Fig. 3

In the TME, TAPs secrete cytokines and growth mediators stimulating hemostasis, angiogenesis and cell adhesion. These signals promote EMT and the intravasation of cancer cells. Once in the bloodstream, CTCs can adhere to the vessel wall and extravasate to a secondary site with the assistance of platelets. Rolling along the vessel wall, platelets attached to CTCs further activate and increase the expression of PECAM-1. PECAM-1 and integrins help slow down the CTCs while expanding the endothelial gaps and easing the migration and invasion of CTCs. CEP: Cancer-educated platelets, CTCs: circulating tumor cell, EMT: epithelial-mesenchymal transition. PECAM-1: platelet endothelial cell adhesion molecule 1. TAPs: tumor-activated platelet. TME: tumor microenvironment. Figure made on biorender.com.