The Platelet Lifeline to Cancer: Challenges and Opportunities

Abstract

Besides their function in limiting blood loss and promoting wound healing, experimental evidence has highlighted platelets as active players in all steps of tumorigenesis including tumor growth, tumor cell extravasation, and metastasis. Additionally, thrombocytosis in cancer patients is associated with adverse patient survival. Due to the secretion of large amounts of microparticles and exosomes, platelets are well positioned to coordinate both local and distant tumor-host crosstalk. Here, we present a review of recent discoveries in the field of platelet biology and the role of platelets in cancer progression as well as challenges in targeting platelets for cancer treatment.

Keywords: anti-platelet therapy; aspirin; biomarker; cancer; cancer therapy; metastasis; microparticles; platelets; thrombocytosis; tumor angiogenesis.

Figure 1. Mechanisms of Trousseau’s Syndrome

Paracrine secretion of interleukin-6 (IL-6) from tumor cells stimulates the production of thrombopoietin (TP) by the liver. In turn, this fuels megakaryopoiesis and platelet genesis. The combination of these events contributes to thrombocytosis and hypercoagulability in cancer patients known as Trousseau’s Syndrome.

Figure 2. Platelet involvement in cancer growth and metastasis

Platelet activation releases growth factors and small molecules that facilitate growth and invasion. Once tumor cells enter the blood stream, platelet-tumor cell aggregates form and platelets protect CTCs from NK-cell and TNFα-induced cell death. Additionally, platelets stimulate and aid cancer cell adhesion and extravasation thereby supporting cancer cell transmigration and metastasis formation. On the other hand, tumor cells mediate platelet activation leading to platelet aggregation and granule release. Activated platelets are also able to extravasate into the tumor microenvironment via focal adhesion kinase (FAK) to fuel tumor growth.

Figure 3. The interactions between platelets and cancer cells during transmigration and circulation

(A) Tumor cells release complement (enzymatically processed to anaphylatoxin, C3a and C5a), prostaglandin E2 (PGE2), IL-1alpha (IL-1α), and matrix metalloproteases that assist transmigration of cancer cells across the endothelium (both into and out of blood vessels). Concurrently, ATP secreted from dense granules of platelets activates P2Y₂ on endothelial cells, increasing permeability of the endothelium and promoting transmigration of cancer cells. Furthermore, activated platelets release the content of their alpha granules that contain numerous growth factors such as platelet-derived growth factor (PDGF) and vascular endothelial growth factor (VEGF) that promote tumor growth and angiogenesis. (B) Tumor cell-induced platelet aggregation leads to formation of heterotypic platelet-cancer cell aggregates, activation and degranulation of platelets. Platelet dense granules release G-protein coupled receptor agonists such as adenosine diphosphate (ADP) and serotonin (5-HT). Alpha granules release growth factors including VEGF and PDGF. Through a multistep synthetic process, arachidonic acid in activated platelets is converted to thromboxane A2 (TXA₂) that in turn activates TXA₂ receptors on other platelets and endothelial cells. Tissue factor (TF) expressed on cancer cells and platelet microparticles (PMP) further magnifies the procoagulant milieu generated by the interaction between platelets and cancer cells and result in thrombin generation and venous thrombosis.

Figure 4. Platelet involvement in inflammation and immunity

Bone marrow derived cell (BMDC) induction and differentiation is stimulated by platelet secretion of CXCL5 and CXCL7 which promotes granulocyte recruitment to tumor cells. Transforming growth factor-beta (TGF-β) released from platelets and microenvironmental PGE2 accumulation also stimulate marrow derived stem cells (MDSC) and T-cell differentiation or inhibition, which encompasses CD8⁺ cytotoxic T-cells, T-helper1 (TH1), T-helper17 (TH17) and T-regulatory cells (Treg). Secreted TGF-β induces epithelial-mesenchymal-transition (EMT) genes and also facilitates myeloid polarization of macrophages and neutrophils towards immunosuppressive phenotypes. This can generate microenvironmental niches at platelet facilitated arrest sites for cancer cells during the establishment of metastasis. Thus, these platelet-tumor cell microenvironmental niches may direct tumor-associated immune cells to convert from a pro-inflammatory to an immunosuppressive phenotype.

Figure 5. Platelet receptors, intracellular signaling, and targeted therapeutics

This figure is accompanied by table 3, which lists the targeted receptors or enzymes, ligands or substrates/products, and signal pathways in platelets and the relevant drugs. Adhesion receptors, Platelet A: Adhesion molecules on platelets bind platelets to the vessel wall at sites of damaged endothelium, these interactions result in intracellular signaling, actin polymerization, and shape change in platelets. The key interactions are between Von Willebrand factor (VWF) in the subendothelium and Glycoprotein (GP) Ib-IX-V complex and integrin α_IIbβ₃ on platelets, and between collagen in the in the subendothelium and GPVI and integrin α₂β₁. Focal adhesion kinase (FAK) facilitates GPVI binding to collagen. Tumor cell mucins interact with P-selectin on platelets, E-selectin on endothelial cells and L-selectin on leukocytes. Eicosanoid Pathway, Resting Platelet: Prostacylin (PGI2) activates G_αs-protein coupled receptor (IP) on platelets that stimulates cyclic adenosine monophosphate (cAMP) production by adenylate cyclase (AC) and prevents aggregation. Eicosanoid Pathway, Platelet B: One key platelet prostaglandin is the potent pro-aggregatory (TX)A₂ synthesized by TXA₂ synthase (TXAS) from PGG₂ and then PGH₂ that in turn are generated by cyclooxygenase-1 (COX-1) from arachidonic acid. TXA2 stimulates G-protein coupled TP receptors. Cyclooxygenase 2 (COX- 2) in cancer cells generates prostaglandin E2 (PGE2) that activates EP₁ and EP₃ receptors on platelets stimulating calcium release. Another abundant eicosanoid produced from arachidonic acid is 12(S)-HETE [12-(S)-hydroxyeicosatetraenoic acid] via the activity of platelet-type lipoxygenase (p12-LOX). Tumor cell podoplanin interacts with platelet C-type lectin domain family 2 (CLEC-2). GPCR, Platelet C: Platelet activation occurs through protease-activated receptors (PAR1 and 4) via Tissue factor (TF)-Factor VII-Factor X-mediated thrombin production. ADP (adenosine diphosphate) released from cancer cells and from dense granules of platelets stimulates P2Y₁ or P2Y₁₂ receptors. Serotonin (5-hydroxytryptamine) is also released from dense granules that act through 5-hydroxytryptamine receptors (5HT_2AR).