Abstract 4196: Aspirin inhibits metastasis in the intravascular phase through the blockade of COX-1-TXA2 pathway in platelets

Evidence from experimental studies and clinical trials has shown that aspirin reduces the incidence of distant metastases. Aspirin inhibits cyclooxygenase (COX)-1 and COX-2, triggering anti-thrombotic and anti-inflammatory effects, respectively. However, the mechanisms underlying the anti-metastatic effect of aspirin are still largely unknown. By employing mouse models of experimental and spontaneous metastasis, we have shown that aspirin and a selective COX-1 inhibitor dramatically reduced metastatic lung nodules, an effect that was not replicated by selective inhibition of COX-2. Metastasis was impaired in COX-1 deficient mice as well, suggesting a pivotal role of microenvironmental COX-1 in the metastatic process. In particular, COX-1 activity was essential during the intravascular phase of pulmonary metastasis. Using a model of platelet depletion and re-infusion we identified platelet-derived thromboxane A2 (TXA2) as the main product of COX-1 responsible for its permissive effect on metastasis. The inhibition of the COX-1-TXA2 pathway in platelets decreased the aggregation of platelets on tumor cells and was associated with a reduction in endothelial activation, in tumor cell adhesion to the endothelium, in recruitment of metastasis-promoting monocytes/macrophages and in transendothelial migration. Thus, platelet-derived TXA2 orchestrates the generation of a favorable intravascular metastatic niche that promotes tumor cell seeding and metastasis. Taken together, our data suggest that COX-1 inhibition in platelets by aspirin is sufficient to exert an anti-metastatic effect and shed a new light on COX-1-TXA2 signalling in the context of tumor cell dissemination. From this perspective, TXA2 might present a more selective therapeutic target for the prevention of metastasis. Citation Format: 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. Aspirin inhibits metastasis in the intravascular phase through the blockade of COX-1-TXA2 pathway in platelets [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr 4196.