Journal
PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA
Volume 116, Issue 5, Pages 1698-1703Publisher
NATL ACAD SCIENCES
DOI: 10.1073/pnas.1803999116
Keywords
debris; cyclooxygenase; soluble epoxide hydrolase; inflammation; oxylipins
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Funding
- National Cancer Institute [R01 01CA170549-02, ROCA148633-01A4]
- National Institute on Environmental Health Sciences Superfund Research Program [P42 ES004699, R01 ES002710]
- Stop and Shop Pediatric Brain Tumor Fund
- CJ Buckley Pediatric Brain Tumor Fund
- Alex Lemonade Stand
- Molly's Magic Wand for Pediatric Brain Tumors
- Markoff Foundation Art-In-Giving Foundation
- Kamen Foundation
- Joe Andruzzi Foundation
- Credit Unions Kids at Heart
- Jared Branfman Sunflowers For Life
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Although chemotherapy is a conventional cancer treatment, it may induce a protumorigenic microenvironment by triggering the release of proinflammatory mediators. In this study, we demonstrate that ovarian tumor cell debris generated by first-line platinum-and taxane-based chemotherapy accelerates tumor progression by stimulating a macrophage-derived surge of proinflammatory cytokines and bioactive lipids. Thus, targeting a single inflammatory mediator or pathway is unlikely to prevent therapy-induced tumor progression. Here, we show that combined pharmacological abrogation of the cyclooxygenase-2 (COX-2) and soluble epoxide hydrolase (sEH) pathways prevented the debris-induced surge of both cytokines and lipid mediators by macrophages. In animal models, the dual COX-2/sEH inhibitor PTUPB delayed the onset of debris-stimulated ovarian tumor growth and ascites leading to sustained survival over 120 days postinjection. Therefore, dual inhibition of COX-2/sEH may be an approach to suppress debris-stimulated ovarian tumor growth by preventing the therapy-induced surge of cytokines and lipid mediators.
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