Aspirin and antiplatelet treatments in cancer

Abstract

Platelets have been hypothesized to promote certain neoplastic malignancies; however, antiplatelet drugs are still not part of routine pharmacological cancer prevention and treatment protocols. Paracrine interactions between platelets and cancer cells have been implicated in potentiating the dissemination, survival within the circulation, and extravasation of cancer cells at distant sites of metastasis. Signals from platelets have also been suggested to confer epigenetic alterations, including upregulating oncoproteins in circulating tumor cells, and secretion of potent growth factors may play roles in promoting mitogenesis, angiogenesis, and metastatic outgrowth. Thrombocytosis remains a marker of poor prognosis in patients with solid tumors. Experimental data suggest that lowering of platelet count may reduce tumor growth and metastasis. On the basis of the mechanisms by which platelets could contribute to cancer growth and metastasis, it is conceivable that drugs reducing platelet count or platelet activation might attenuate cancer progression and improve outcomes. We will review select pharmacological approaches that inhibit platelets and may affect cancer development and propagation. We begin by presenting an overview of clinical cancer prevention and outcome studies with low-dose aspirin. We then review current nonclinical development of drugs targeted to platelet binding, activation, and count as potential mitigating agents in cancer.

Keywords: P-selectin; PLATELETS/adhesion and adhesion receptors; PLATELETS/disorders of platelets; PLATELETS/physiology of normal platelets; PLATELETS/platelet interactions with other cells; PLATELETS/platelets: signal transduction; aspirin; cancer; cancer metastasis; platelet count.

Graphical abstract

Figure 1.

Overview of platelet and tumor cell interaction. Platelet activation can occur by many routes, initiated here by tumor-derived adenosine diphosphate (ADP) interaction with platelet P2Y₁₂, which can be blocked by thienopyridines. Endothelial damage exposes subendothelial matrix proteins, allowing von Willebrand factor (vWF) to bind and tether to platelet GPIb. Cyclooxygenase (COX) inhibitors prevent platelet-expressed COX-1 production of TXA₂. Aspirin also inhibits COX-2–mediated endothelial prostacyclin (PGI₂) production and platelet adhesion. Upregulation of GPIIb/IIIa allows platelet-platelet and platelet–tumor cell aggregation. Upregulation of P-selectin from platelet α granules interacts with many ligands on tumor cells (eg, PSGL-1, sialyl-Lewis^x–modified CD24 [sLe^x-modified CD24], CD44 variant [CD44_v], PCLP1). Platelet release of platelet-derived growth factors (eg, platelet-derived growth factor [PDGF], vascular endothelial growth factor [VEGF], epithelial growth factor [EGF], transforming growth factor β [TGFβ], and cytokines) promotes tumor cell immune evasion, migration, epithelial-mesenchymal transition (EMT), invasion, and proliferation. AA, arachidonic acid; cAMP, cyclic adenosine monophosphate; CLEC-2, C-type lectin-like receptor 2; PCLP1, podocalyxin-like protein 1; PDGFR, PDGF receptor; PGI₂, prostacyclin; PSGL-1, P-selectin glycoprotein ligand-1; TPα, thromboxane receptor α; TXA₂, thromboxane A2.