Journal
PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA
Volume 116, Issue 13, Pages 6292-6297Publisher
NATL ACAD SCIENCES
DOI: 10.1073/pnas.1804000116
Keywords
metabolomics; eicosanoids; resolvins; inflammation; metastasis
Categories
Funding
- National Institutes of Health [R01 01CA170549, R0CA148633, 5P01 GM095467]
- Credit Unions Kids at Heart Team
- Stop and Shop Pediatric Brain Tumor Fund
- C.J. Buckley Pediatric Brain Tumor Fund
- Alex's Lemonade Stand
- Molly's Magic Wand for Pediatric Brain Tumors
- Markoff Foundation Art-In-Giving Foundation
- Kamen Foundation
- Joe Andruzzi Foundation
- Jared Branfman Sunflowers for Life
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Inflammation in the tumor microenvironment is a strong promoter of tumor growth. Substantial epidemiologic evidence suggests that aspirin, which suppresses inflammation, reduces the risk of cancer. The mechanism by which aspirin inhibits cancer has remained unclear, and toxicity has limited its clinical use. Aspirin not only blocks the biosynthesis of prostaglandins, but also stimulates the endogenous production of anti-inflammatory and proresolving mediators termed aspirin-triggered specialized proresolving mediators (AT-SPMs), such as aspirin-triggered resolvins (AT-RvDs) and lipoxins (AT-LXs). Using genetic and pharmacologic manipulation of a proresolving receptor, we demonstrate that AT-RvDs mediate the antitumor activity of aspirin. Moreover, treatment of mice with AT-RvDs (e.g., AT-RvD1 and AT-RvD3) or AT-LXA4 inhibited primary tumor growth by enhancing macrophage phagocytosis of tumor cell debris and counter-regulating macrophage-secreted proinflammatory cytokines, including migration inhibitory factor, plasminogen activator inhibitor-1, and C-C motif chemokine ligand 2/monocyte chemoattractant protein 1. Thus, the pro-resolution activity of AT-resolvins and AT-lipoxins may explain some of aspirin's broad anticancer activity. These AT-SPMs are active at considerably lower concentrations than aspirin, and thus may provide a nontoxic approach to harnessing aspirin's anticancer activity.
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