Journal
JOURNAL OF EXPERIMENTAL MEDICINE
Volume 215, Issue 1, Pages 115-140Publisher
ROCKEFELLER UNIV PRESS
DOI: 10.1084/jem.20170681
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Funding
- National Institutes of Health [R01 AI079320, CA169354]
- National Cancer Institute [R01 01CA170549-02, R0CA148633-01A4, GM095467]
- 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
- Jared Branfman Sunflowers for Life
- Wellcome Trust [086867/Z/08]
- NATIONAL CANCER INSTITUTE [R01CA170549, R01CA169354] Funding Source: NIH RePORTER
- NATIONAL INSTITUTE OF ALLERGY AND INFECTIOUS DISEASES [R01AI079320] Funding Source: NIH RePORTER
- NATIONAL INSTITUTE OF GENERAL MEDICAL SCIENCES [P01GM095467] Funding Source: NIH RePORTER
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Cancer therapy reduces tumor burden by killing tumor cells, yet it simultaneously creates tumor cell debris that may stimulate inflammation and tumor growth. Thus, conventional cancer therapy is inherently a double-edged sword. In this study, we show that tumor cells killed by chemotherapy or targeted therapy (tumor cell debris) stimulate primary tumor growth when coinjected with a subthreshold (nontumorigenic) inoculum of tumor cells by triggering macrophage proinflammatory cytokine release after phosphatidylserine exposure. Debris-stimulated tumors were inhibited by antiinflammatory and proresolving lipid autacoids, namely resolvin D1 (RvD1), RvD2, or RvE1. These mediators specifically inhibit debris-stimulated cancer progression by enhancing clearance of debris via macrophage phagocytosis in multiple tumor types. Resolvins counterregulate the release of cytokines/chemokines, including TNF alpha, IL-6, IL-8, CCL4, and CCL5, by human macrophages stimulated with cell debris. These results demonstrate that enhancing endogenous clearance of tumor cell debris is a new therapeutic target that may complement cytotoxic cancer therapies.
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