Platelet Metabolism and Other Targeted Drugs; Potential Impact on Immunotherapy

Abstract

The role of platelets in cancer progression has been well recognized in the field of cancer biology. Emerging studies are elaborating further the additional roles and added extent that platelets play in promoting tumorigenesis. Platelets release factors that support tumor growth and also form heterotypic aggregates with tumor cells, which can provide an immune-evasive advantage. Their most critical role may be the inhibition of immune cell function that can negatively impact the body's ability in preventing tumor establishment and growth. This review summarizes the importance of platelets in tumor progression, therapeutic response, survival, and finally the notion of immunotherapy modulation being likely to benefit from the inclusion of platelet inhibitors.

Keywords: aspirin; cyclooxygenase; immunotherapy; non-steroidal anti-inflammatory drugs; platelet inhibitors; platelets.

Figure 1

Platelet targeted therapeutics. The platelet plasma membrane displays multiple receptors that can interact with agonists, antagonists, matrix proteins, collagen, other platelets, endothelial cells, immune cells, and tumor cells. (A) Platelets adhere to the damaged vascular endothelium via GPIb-IX-V complex to von Willebrand factor (vWF) and via GPVI and GPIa/IIa (α_2β1) to collagen. (B) Focal adhesion kinase (FAK) helps mediate GPVI binding to collagen among other integrin-mediated interactions. FAK inhibitors could also potentially inhibit GPIIb/IIIa (α_IIbβ3) interactions that stimulate calcium and integrin-binding protein 1 (CIB-1) or paxillin that is linked to Rho guanine nucleotide exchange factor (Rho-GEF) signaling. Alternatively, FAK inhibition may also alter actin-related protein 2/3 complex interactions during actin polymerization and shape change. Direct inhibition of GPIIb/IIIa interactions with fibrinogen or fibronectin during platelet aggregation can be disrupted by receptor antagonists. Similarly, direct inhibition of a_vb₃ interactions with vitronectin can also be inhibited. (C) Thrombin G_q-protein-coupled receptors involved in platelet activation are protease-activated receptors (PAR) 1 and 4. PARs are stimulated by tumor cell tissue factor-factor VII-factor X complex. Thrombin stimulation of PAR 1 acts through the Rho-GEF pathway while PAR4 G_q activation occurs through beta arrestin-2. Signal transduction targets include Rho-associated kinase (ROCK) or the cytoskeletal protein myosin II. Tumor cell podoplanin interacts with platelet C-type lectin domain family 2 (CLEC-2) that transduce signals through spleen tyrosine kinase (Syk) and phospholipase C gamma2 (PLCγ₂). Tumor cell mucins and other carbohydrate moieties interact with P-selectin are also targets. These P-selectin targets include interactions with lymphocyte L-selectins or endothelial cell E-selectins. (D) The release of alpha granules leads to localized increases in growth factors such as platelet-derived growth factors (PDGFs) and vascular endothelial cell growth factor (VEGF) and tyrosine kinase receptor stimulating molecules such as fc receptor stimulating molecules FcgammaRIIa. (E) The activation of platelets by ADP (adenosine diphosphate) released from dense granules mainly involves P2Y₁ or P2Y₁₂ receptors. P2Y₁ signals through G_ag-protein-coupled receptors that stimulate PLCγ followed by phosphatidylinositol 4,5-bisphosphate (PIP₂) and inositol trisphosphate 3 (IP₃) that stimulates its receptor embedded in the endoplasmic reticulum (ER), which causes calcium ion release (Ca²⁺). Alternately, diacylglycerol (DAG) interacts with protein kinase C (PKC). These interactions impinge upon DAG-regulated guanine nucleotide exchange factor I (CalDAG-GEFI)-Ras-related protein 1 (Rap1) releasing Rap1-GTP-interacting adaptor molecule (RIAM) leading to actin changes. (F) Serotonin (5-hydroxytryptamine) is also released from dense granules that act through 5-hydroxytryptamine receptors (5HT_2AR) that activate the G_aq pathway and Ca²⁺ release. (G) An important antiplatelet agent is aspirin that is well known to prevent cancer progression. Aspirin irreversibly acetylates cyclooxygenase 1 (COX-1) eliminating all prostaglandin (PG) synthesis. COX-1 enzymatically adds two oxygens to arachidonic acid to produce PGG₂ and then PGH₂, which is converted to various PGs by synthase enzymes. Key platelet PGs are the potent pro-aggregatory agent thromboxane (TX)A₂ synthesized by TXA₂ synthase. (H) Also, PGE₂ synthesized by PGE₂ synthase. TXA₂ and PGE₂ cause different platelet responses by stimulating various isoforms of G-protein-coupled TP or EP receptors. TP signals through G_12/13 and Rho-GEF followed by Rho-associated kinase (ROCK), LIM domain kinase (LIMK), and cofilin and subsequent interactions with actin. Additional interactions include those with myosin light chain kinase followed by myosin. Similarly, EP₃ receptors stimulate the same signal transduction pathways as G_aq-calcium release linked receptors. (I) An important G_as-protein-coupled receptor is the IP for prostacyclin (PGI₂) that prevents aggregation by stimulating cyclic adenosine monophosphate (cAMP) production by adenylate cyclase (AC) and is influenced by phosphodiesterase 3 or 5 activity. Another abundant eicosanoid produced from arachidonic acid by platelets is 12(S)-HETE [12(S)-hydroxyeicosatetraenoic acid] via the activity of the platelet-type lipoxygenase (p12-LOX). Recently, 12-(S)HETE is proposed to activate orphan receptor GPR31.