Editors' ChoiceCancer

An aspirin a day keeps metastasis at bay

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Science Translational Medicine  17 Apr 2019:
Vol. 11, Issue 488, eaax1728
DOI: 10.1126/scitranslmed.aax1728

Abstract

Aspirin’s inhibition of COX-1/thromboxane A2 prevents metastasis by blocking adhesion between platelets, circulating tumor cells, and the endothelium.

Given recent advances in primary cancer detection and treatment, metastasis has become the main cause of cancer-related death. Attempts to understand and prevent metastasis are ongoing, with several studies describing a role for platelets and platelet activation in the metastatic cascade. Anecdotal and prospective clinical trials have demonstrated that patients taking aspirin are less likely to experience metastasis. However, questions remain regarding how aspirin prevents metastasis.

Lucotti et al. used both intravenous injection and spontaneous models of metastasis to demonstrate that medium to high doses of aspirin inhibited the metastasis to lung of melanoma and breast cancer cell lines. Aspirin’s ability to prevent platelet activation reduced lung metastasis in animals, while prevention of platelet aggregation by aspirin did not affect metastatic spread. To determine the optimal timing of aspirin treatment, mice were injected two days before melanoma cell injection into the tail vein which strongly reduced metastatic seeding, whereas aspirin induction after tumor cell injection had less of an effect. Further, in spontaneous breast cancer metastasis models, reduced metastatic seeding occurred when aspirin was administered during the period in which spontaneous metastases develop. The authors then utilized specific inhibitors of the pathways downstream of aspirin to determine that platelet cyclooxygenase (COX-1) enzyme activation and subsequent thromboxane A2 release was the primary driver of metastasis, playing a major role during premetastatic niche formation and platelet-mediated binding of tumor cells to endothelial cells during extravasation.

Further studies will be needed to determine whether selective inhibition of platelets, COX-1, or thromboxane A2 can prevent metastasis. In this study, aspirin and inhibitors needed to be administered before tumor cells entered the bloodstream, making any intervention in patients more difficult. Also, higher concentrations of aspirin were required to reduce metastasis in the murine models but due to differences in species and bioavailability, these concentrations may not directly equate to the doses prescribed for patients. Low dose aspirin regimens carry bleeding risks and other potential side effects. A current phase III clinical trial, ADD-ASPIRIN, is underway to test whether an aspirin regimen after cancer diagnosis will prevent metastasis in patients with breast, colorectal, stomach, esophageal, or prostate cancers.

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