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 March 25, 2019
Citation Information: J Clin Invest. 2019;129(5):1845-1862. https://doi.org/10.1172/JCI121985.
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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 10

TXA2 from platelets mediates the generation of the prometastatic intravascular niche.

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TXA2 from platelets mediates the generation of the prometastatic intrava...
(A–C) MIP (median filter) of 3D confocal stacks of tumor cells (B16F10-CMAC, white) and platelets (Plts-PKH26, red) in lungs of platelet-depleted Cx3cr1gfp/+ mice (A) and quantification of the number (B) and volume (C) of clots per tumor cell (n = 3), at 8 hours after injection of tumor cells and COX-1+/+ or COX-1–/– platelets. Scale bar: 10 μm. (D–F) MIP (median filter) of 3D confocal stacks of lung sections labeled for E-selectin (green) and VCAM-1 (magenta) (D), number of tumor cells associated with E-selectin– or VCAM-1–expressing vessels (E), and fluorescence intensity of E-selectin or VCAM-1 (F) (n = 3) in lung sections from platelet-depleted Cx3cr1gfp/+ mice injected with tumor cells and COX-1+/+ or COX-1–/– platelets. Scale bar: 50 μm. (G and H) MIP of 3D confocal stacks (×20, top row) and surface reconstruction (bottom row) of tumor cells (B16F10-CMAC, white), platelets (Plts-PKH26, magenta), and Cx3CR1+ monocytes/macrophages (GFP, green) (G) and quantification of the volume of monocyte/macrophage clusters (H) (n = 3) in whole lungs of platelet-depleted Cx3cr1gfp/+ mice injected with tumor cells and COX-1+/+ or COX-1–/– platelets. Scale bars: 50 μm. Data are represented as mean + SD. Unpaired t test, 2-tailed. *0.01 < P ≤ 0.05; ***P ≤ 0.001.