Microparticle Phosphatidylserine Mediates Coagulation: Involvement in Tumor Progression and Metastasis

Abstract

Tumor progression and cancer metastasis has been linked to the release of microparticles (MPs), which are shed upon cell activation or apoptosis and display parental cell antigens, phospholipids such as phosphatidylserine (PS), and nucleic acids on their external surfaces. In this review, we highlight the biogenesis of MPs as well as the pathophysiological processes of PS externalization and its involvement in coagulation activation. We review the available evidence, suggesting that coagulation factors (mainly tissue factor, thrombin, and fibrin) assist in multiple steps of tumor dissemination, including epithelial-mesenchymal transition, extracellular matrix remodeling, immune escape, and tumor angiogenesis to support the formation of the pre-metastatic niche. Platelets are not just bystander cells in circulation but are functional players in primary tumor growth and metastasis. Tumor-induced platelet aggregation protects circulating tumor cells (CTCs) from the blood flow shear forces and immune cell attack while also promoting the binding of CTCs to endothelial cells and extravasation, which activates tumor invasion and sustains metastasis. Finally, in terms of therapy, lactadherin can inhibit coagulation by competing effectively with coagulation factors for PS binding sites and may similarly delay tumor progression. Furthermore, we also investigate the therapeutic potential of coagulation factor inhibitors within the context of cancer treatment. The development of multiple therapies targeting platelet activation and platelet-tumor cell interactions may not only reduce the lethal consequences of thrombosis but also impede tumor growth and spread.

Keywords: coagulation cascade; microparticles; phosphatidylserine; treatment strategies; tumor progression.

Figure 1

Mechanisms of MP formation and PS externalization. (A) Signs of damage (activation and apoptosis) cause increased cytosolic Ca²⁺ concentration, induce membrane asymmetry disruption and actin cytoskeletal rearrangement and promote MP release. (B) In cells undergoing apoptosis, caspase-dependent Xkr8 activation and P4-ATPase inactivation together result in persistent PS exposure. (C) In the process of TF activation controlled by caspase-11- and gasdermin D-dependent pathways, PS exposure is mediated by TMEM16F. EGFR; Epithelial growth factor receptor; MPs: microparticles; PS: phosphatidylserine; Xkr8: Xk-related protein 8; TF: Tissue factor, TMEM16F: Transmembrane protein 16F.

Figure 2

PS-mediated coagulation cascade involved in tumor progression. (A) Following platelet activation, platelets tightly bind to tumor cells by various adhesion receptors and promote CTC survival and immune escape. PS on MPs derived from tumor cells and blood cells mediate the coagulation cascade. PS-mediated coagulation cascade protects CTCs from the shear forces of blood flow and immune cell attack. Coagulation activation further promotes the extravasation of CTCs. Coagulation factors enter the tumor microenvironment by leaking tumor vessels and are involved in EMT, ECM degradation, and angiogenesis. (B) Platelets promote immune escape of CTCs via multiple mechanisms. Thrombin can directly cleave C5 to generate C5a, which induces an immunosuppressive microenvironment by the recruitment of MDSCs. (C) In addition to through integrin α4β1, αVβ1 or αVβ3, tumor cells can adhere to endothelium with the help of leukocytes. Activated platelets release ATP from dense granules, activate endothelial P2Y2 receptors and allow trans-endothelial migration of tumor cells by increasing the permeability of blood vessels. Thrombin activates PKC pathways or mediates PAK activity to increase the permeability of the endothelial barrier. EMT: epithelial-mesenchymal transition; ECM: extracellular matrix; MMPs: matrix metalloproteinases; T-MPs: tumor-derived MPs; TCIPA: tumor cell-induced platelet aggregation; CLEC-2: C-type lectin-like receptor 2, CTCs: circulating tumor cells; PS: Phosphatidylserine; CAFs: cancer-associated fibroblasts; MDSCs: myeloid-derived suppressor cells; mø: Macrophages; Neu: Neutrophils; NETs: Neutrophil extracellular traps, DC: Dendritic cells, YAP1: yes-associated protein-1, GITRL: the glucocorticoid-induced tumor necrosis factor receptor ligand; NK: natural killer, PKC: protein kinase C; PAK; p21-activated kinase, VEC: VE-cadherin, ICAM-1: intercellular adhesion molecule 1, VCAM1: vascular cell adhesion molecule-1,L1CAM: L1cell adhesion molecular; ECs: Endothelial cells; VEGF: Vascular endothelial growth factor.

Figure 3

PS-mediated coagulation cascade involved in tumor angiogenesis. (A) Angiogenesis in the tumor microenvironment. (B) The mechanisms of angiogenesis induced by coagulation factors. TF promotes tumor-directed angiogenesis through upregulating vascular VEGF expression and downregulating the angiogenesis inhibitor (thrombospondin) expression. TF/FVIIa complexes cause Ca²⁺ oscillations and activate MAPK pathway, resulting in VEGF expression. The TF/FVIIa/FXa complexes activate one or more PARs to support angiogenesis. Thrombin/PAR-1 activation can produce strong mitogen activity on ECs and vascular progenitor cells to induce EC tubular formation in the matrix membrane. Additionally, Thrombin/PAR-1 activated platelets lead to their aggregation and degranulation (VEGF). The fibrin matrix can upregulate the expression of αVβ3 integrin receptor to promote angiogenic responses. The fibrin matrix sequesters and protects numerous growth factors (VEGF) from being degraded by proteinase in ECM. Fibrin fragments (E fragments) are shown to stimulate angiogenesis. VEGF: vascular endothelial growth factor; ECs: endothelial cells; MDSCs: myeloid-derived suppressor cells; CAFs: cancer-associated fibroblasts; t-PA: tissue-type plasminogen activator; u-PA: urokinase-type plasminogen activator; TF: tissue factor; PARs: Protease-activated receptors; MAPK: the mitogen-activated protein kinase; FVIIa: activated factor VII; FXa: activated factor X.