Resolvins suppress tumor growth and enhance cancer therapy

Journal of Experimental Medicine - Tập 215 Số 1 - Trang 115-140 - 2018
Megan L. Sulciner1,2,3, Charles N. Serhan4, Molly M. Gilligan1,2,3, Dayna K. Mudge1,2,3, Jaimie Chang1,2,3, Allison Gartung1,2,3, Kristen Lehner1,2,3, Diane R. Bielenberg5, Birgitta Schmidt6, Jesmond Dalli4, Emily R. Greene1,2,3, Yael Gus‐Brautbar1,2,3, Julia Piwowarski1,2,3, Tadanori Mammoto5, David Zurakowski7,8, Mauro Perretti9, Vikas P. Sukhatme1,10, Arja Kaipainen11, Mark W. Kieran12,13, Sui Huang14, Avi Schroeder1,2,3
1Cancer Center, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA 3
2Center for Vascular Biology Research, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA 1
3Department of Pathology, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA 2
4Center for Experimental Therapeutics and Reperfusion Injury, Department of Anesthesiology, Perioperative and Pain Medicine, Brigham and Women’s Hospital, Harvard Medical School, Boston, MA 4
5Vascular Biology Program, Boston Children's Hospital, Harvard Medical School, Boston, MA 5
6Department of Pathology, Boston Children’s Hospital, Harvard Medical School, Boston, MA 6
7Department of Anesthesia, Boston Children’s Hospital, Harvard Medical School, Boston, MA 7
8Department of Surgery, Boston Children's Hospital, Harvard Medical School, Boston, MA 8
9The William Harvey Research Institute, Barts and The London School of Medicine, Queen Mary University of London, London, England, UK 12
10Department of Medicine, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA 9
11Human Biology Division, Fred Hutchinson Cancer Research Center, Seattle, WA 13
12Department of Pediatric Hematology/Oncology, Boston Children’s Hospital, Harvard Medical School, Boston, MA 11
13Division of Pediatric Oncology, Dana-Farber Cancer Institute, Harvard Medical School, Boston, MA 10
14Institute of Systems Biology, Seattle, WA 14

Tóm tắt

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 TNFα, 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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