Contribution of platelets to tumour metastasis

Abstract

Extensive experimental evidence shows that platelets support tumour metastasis. The activation of platelets and the coagulation system have a crucial role in the progression of cancer. Within the circulatory system, platelets guard tumour cells from immune elimination and promote their arrest at the endothelium, supporting the establishment of secondary lesions. These contributions of platelets to tumour cell survival and spread suggest platelets as a new avenue for therapy.

Figure 1.. Platelet biology

During thrombus formation, thrombin activates G protein-linked protease-activated receptors (PARs) at the platelet surface, thereby triggering a flux in intracellular calcium and a decrease in cyclic adenosine monophosphate (cAMP). This allows for rapid reorganization of the platelet cytoskeleton and shape change, maximizing platelet adhesion during thrombus formation. Other platelet agonists include collagen of the subendothelial matrix exposed during vascular injury, adenosine diphosphate (ADP), and thromboxane A₂ (TXA₂). The latter bind G protein-coupled receptors P2Y and TXA₂R respectively, to stimulate platelet degranulation and release of their contents as part of an amplification loop of platelet activation and aggregation. For instance, thrombosis is perpetuated by prothrombin, fibrinogen, von Willebrand factor (VWF), platelet factor 4 (PF4), P-selectin, TXA₂, and adenosine diphosphate (ADP) ^, . Platelets are now also recognized as modulators of endothelial integrity and immune cell trafficking between the blood stream and sites of inflammation through their released factors ^, . Platelets sustain vascular stability through maintenance of endothelial cell junctions via the release of brain-derived neutrophic factor (BDNF), epidermal growth factor (EGF), sphingosine 1 -phosphate (S1P), angiopoietin −1 (ANGPT1), and platelet-activating factor acetylhydrolase (PAF) . Activated platelets dispense interleukin-8 (IL-8), IL-1β, C-C motif chemokine 5 (CCL5, also known as RANTES), CD40 ligand (CD40L) and histamine that stimulate endothelial cells to upregulate adhesion receptors and chemokine release to promote leukocyte recruitment and tissue infiltration during the inflammatory response ^, . The potential role of platelets in cancer progression and target organ colonization by circulating tumor cells is summarized in this review.

Figure 2.. Molecular coordination between platelets and tumor cells supports metastasis from the blood stream.

As platelets become activated, they undergo a shape change, increase their adhesiveness, release granules and microparticles, and perpetuate cohesion of heteroaggregates containing tumor cells, platelets and leukocytes. Platelet granules contain growth factors, chemokines, and proteases. Cohesion: Circulating tumor cells can interact with activated platelets and leukocytes, and form heteroaggregates that support attachment to the endothelium and thereby contribute to metastasis. Coagulation: Platelet-initiated coagulation steps can activate receptors on tumor cells (e.g. PAR1/2) and promote release of tissue factor that further enhances procoagulant activity. Adhesion: Initial, transient adhesion involving selectins, mucins, CD44, and other sialyl Lewis X/A containing glycoconjugates is followed by firm attachment mediated by integrins and intercellular cell adhesion molecules. Immune evasion: Multivalent plasma proteins form intercellular bridges, and activated platelets and fibrin(ogen) protect tumor cells from natural killer cell lysis during hematogenous metastasis. Coincidently, tissue factor and FVIIa activate thrombin to cleave protease-activated receptors on platelets and tumor cells to promote invasion and metastasis. GP (Glycoprotein), PAR (Protease-activated receptor), ICAM (Intercellular adhesion molecule, ICAM-1), VCAM (Vascular cell adhesion molecule, VCAM-1), PSGL1 (P-selectin-glycoprotein ligand 1), sLex/a (Sialyl Lewis X/A antigens), VWF (Von Willebrand factor).