Aspirin blocks formation of metastatic intravascular niches by inhibiting platelet-derived COX-1/thromboxane A2
Serena Lucotti, … , Anne J. Ridley, Ruth J. Muschel
Serena Lucotti, … , Anne J. Ridley, Ruth J. Muschel
Published May 1, 2019; First published March 25, 2019
Citation Information: J Clin Invest. 2019;129(5):1845-1862. https://doi.org/10.1172/JCI121985.
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Research Article Oncology Therapeutics

Aspirin blocks formation of metastatic intravascular niches by inhibiting platelet-derived COX-1/thromboxane A2

Abstract

Because metastasis is associated with the majority of cancer-related deaths, its prevention is a clinical aspiration. Prostanoids are a large family of bioactive lipids derived from the activity of cyclooxygenase-1 (COX-1) and COX-2. Aspirin impairs the biosynthesis of all prostanoids through the irreversible inhibition of both COX isoforms. Long-term administration of aspirin leads to reduced distant metastases in murine models and clinical trials, but the COX isoform, downstream prostanoid, and cell compartment responsible for this effect are yet to be determined. Here, we have shown that aspirin dramatically reduced lung metastasis through inhibition of COX-1 while the cancer cells remained intravascular and that inhibition of platelet COX-1 alone was sufficient to impair metastasis. Thromboxane A2 (TXA2) was the prostanoid product of COX-1 responsible for this antimetastatic effect. Inhibition of the COX-1/TXA2 pathway in platelets decreased aggregation of platelets on tumor cells, endothelial activation, tumor cell adhesion to the endothelium, and recruitment of metastasis-promoting monocytes/macrophages, and diminished the formation of a premetastatic niche. Thus, platelet-derived TXA2 orchestrates the generation of a favorable intravascular metastatic niche that promotes tumor cell seeding and identifies COX-1/TXA2 signaling as a target for the prevention of metastasis.

Authors

Serena Lucotti, Camilla Cerutti, Magali Soyer, Ana M. Gil-Bernabé, Ana L. Gomes, Philip D. Allen, Sean Smart, Bostjan Markelc, Karla Watson, Paul C. Armstrong, Jane A. Mitchell, Timothy D. Warner, Anne J. Ridley, Ruth J. Muschel

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Figure 1

Medium-dose aspirin reduces COX-1–dependent platelet aggregation.

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Medium-dose aspirin reduces COX-1–dependent platelet aggregation. (A) Di...
(A) Diagram of COX-1 and COX-2 products. Serum TXB2 represents COX-1 activity in platelets. Plasma PGE2 represents COX-2 activity in monocytes. (B) TXB2 in serum from C57BL/6 mice treated with vehicle or aspirin (ASA; low, medium, or high) for 2 days before blood sampling (n = 3). (C and D) Agonist-induced aggregation of CD61-stained platelets from mice treated with vehicle or aspirin for 2 days. Arachidonic acid, U46619, and ADP were the agonists (n = 7 for vehicle group, 4 for all other groups). (E and F) Experimental design (E) and ex vivo PGE2 levels (F) in plasma from mice in B (n = 4). Data are represented as mean + SD (B and F), mean ± range (C). One-way ANOVA with Tukey’s multiple-comparisons test. *0.01 < P ≤ 0.05; **0.001 < P ≤ 0.01; ***P ≤ 0.001.