Platelets as crucial players in the dynamic interplay of inflammation, immunity, and cancer: unveiling new strategies for cancer prevention

Abstract

Inflammation plays a critical role in the pathogenesis of various diseases by promoting the acquisition of new functional traits by different cell types. Shared risk factors between cardiovascular disease and cancer, including smoking, obesity, diabetes, high-fat diet, low physical activity, and alcohol consumption, contribute to inflammation linked to platelet activation. Platelets contribute to an inflammatory state by activating various normal cells, such as fibroblasts, immune cells, and vascular cells. This activation is achieved by releasing diverse molecules from platelets, including lipids (eicosanoids), growth and angiogenic factors, and extracellular vesicles (EVs) rich in various RNA species. Antiplatelet agents like low-dose aspirin can prevent cardiovascular disease and cancer by inhibiting platelet functions beyond the antithrombotic action. Throughout the initial phases of tumorigenesis, the activation of platelets induces the overexpression of cyclooxygenase (COX)-2 in stromal cells, leading to increased biosynthesis of prostaglandin (PG)E₂. This prostanoid can contribute to tumor development by inhibiting apoptosis, promoting cancer cell proliferation and migration, and immune evasion. Notably, platelets induce the epithelial-mesenchymal transition (EMT) in tumor cells, enhancing their metastatic potential. Two platelet eicosanoids, PGE₂ (generated as a minor product of COX-1) and 12S-hydroxyeicosatetraenoic acid (HETE) [derived from the platelet-type 12-lipoxygenase (LOX)], contribute to EMT. In addition to the pharmacological inhibition of eicosanoid biosynthesis, a potential strategy for mitigating platelet-induced metastasis might encompass the inhibition of direct interactions between platelets and cancer cells. For example, there is promise in utilizing revacept to inhibit the interaction between platelet collagen receptors (particularly GPVI) and galectin-3 in cancer cells. Identifying these novel platelet functions suggests the potential application of antiplatelet agents, such as low-dose aspirin, in mitigating cancer risk, particularly in the case of colorectal cancer. It is necessary to investigate the effectiveness of other antiplatelet drugs, such as ADP P2Y₁₂ receptor antagonists, in cancer prevention. Other new antiplatelet drugs, such as revacept and selective 12-LOX inhibitors, currently under clinical development, are of interest due to their low risk of bleeding. Platelets and EVs carry important clinical information because they contain specific proteins and RNAs associated with disease conditions. Their analysis can improve the accuracy of liquid biopsies for early cancer detection, monitoring progression, and assessing drug response.

Keywords: 12-lipoxygenase; antiplatelet agents; aspirin; cancer; extracellular vesicles; inflammation; platelets; revacept.

FIGURE 1

Platelet activation triggers the early phases of tumorigenesis. (1) Activated platelets release many mediators [including eicosanoids (such as TXA₂), ADP, cytokines (such as IL-1β), growth and angiogenic factors, and extracellular vesicles (EVs) containing genetic material (such as mRNAs and microRNAs)] that contribute to (2) COX-2 overexpression in stromal cells (including macrophages and fibroblasts). (3) The crosstalk with epithelial cells leads to COX-2 induction. (4) Additionally, COX-2 is overexpressed in endothelial cells, leading to angiogenesis. (5) These events lead to the release of PGE₂, which translates to inhibition of apoptosis, an increase in proliferation and migration, and induction of epithelial-mesenchymal transition (EMT). The inhibition of platelet COX-1 by low-dose aspirin prevents the downstream signaling pathways involved in the early events of tumorigenesis and indirectly inhibits COX-2 induction. In contrast, NSAIDs and coxibs have an antitumorigenic effect by directly inhibiting COX-2 activity and prostanoid generation in stromal cells, epithelial cells, and endothelial cells.

FIGURE 2

Different stages of platelet activation from resting to aggregation, by high resolution scanning electron microscopy. Platelets possess multifaceted functions beyond thrombosis contributing to inflammation, atherosclerosis and cancer metastasis.

FIGURE 3

The role of platelet COX-1 in intestinal tumorigenesis of Apc ^Min/+ mice. (A) The platelet COX-1-dependent TXA₂ (also from extravasated platelets) can contribute to intestinal neoplasia by triggering the expression of COX-2 in stromal cells, which is involved in the biosynthesis of PGE₂; the selective inhibition of COX-1 in platelets by aspirin can prevent the biosynthesis of TXA₂ and indirectly the upregulation of COX-2. (B) In Apc ^Min/+ mice, the specific deletion of platelet COX-1 caused a profound reduction in platelet TXA₂ biosynthesis in vivo, which was associated with decreased COX-2 expression and PGE₂ biosynthesis, and a reduced number and size of intestinal adenomas.

FIGURE 4

Potential roles of 12-lipoxygenase (LOX) in platelet activation by heparin-platelet factor 4 (PF4) immune complexes. PF4 is a chemokine released from platelet a-granules upon activation. It can form immune complexes with negatively charged substances, such as heparin. The formation of PF4-heparin complexes leads to the synthesis of antibodies, which activate platelets via FcγRIIa receptors. 12-LOX can amplify platelet activation through FcγRIIa via three different pathways: i) the arachidonic acid (AA)-derived compound 12S-HETE generated by 12-LOX, ii) the 12S-HETE receptor GPR31, and iii) the interaction with PLCγ2 or upstream signaling and adaptor molecules, such as Syk (spleen tyrosine kinase), PI3K (phosphoinositide 3-kinase), and LAT (T-cell activation linker). Modified from Alison H. Goodal et al. Blood 2014; 124 (14): 2166–2168 (comment on Yeung et al., Blood 2014; 124:2271-2279).

FIGURE 5

Platelets and tumor cells’ immune evasion via activation of PD-1 on T-cells by its ligands PD-L1. Platelets, like cancer cells, can activate the immune checkpoint protein PD-1, which controls the immune response of cytotoxic CD⁸⁺ T cells that carry out their killing function by releasing two types of preformed cytotoxic proteins: the granzymes, which seem able to induce apoptosis in any target cell, and the pore-forming protein perforin, which punches holes in the target cell membrane through which the granzymes can enter.