Resolvins suppress tumor growth and enhance cancer therapy

  • J Exp Med. 2018 Jan 2;215(1):115-140. doi: 10.1084/jem.20170681.
Megan L Sulciner  1  2  3 ,  Charles N Serhan  4 ,  Molly M Gilligan  1  2  3 ,  Dayna K Mudge  1  2  3 ,  Jaimie Chang  1  2  3 ,  Allison Gartung  1  2  3 ,  Kristen A Lehner  1  2  3 ,  Diane R Bielenberg  5 ,  Birgitta Schmidt  6 ,  Jesmond Dalli  7 ,  Emily R Greene  1  2  3 ,  Yael Gus-Brautbar  1  2  3 ,  Julia Piwowarski  1  2  3 ,  Tadanori Mammoto  5 ,  David Zurakowski  8  9 ,  Mauro Perretti  10 ,  Vikas P Sukhatme  3  11 ,  Arja Kaipainen  12 ,  Mark W Kieran  13  14 ,  Sui Huang  15 ,  Dipak Panigrahy  16  2  3
Affiliations
  • 1. Center for Vascular Biology Research, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA.
  • 2. Department of Pathology, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA.
  • 3. Cancer Center, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA.
  • 4. Center for Experimental Therapeutics and Reperfusion Injury, Department of Anesthesiology, Perioperative and Pain Medicine, Brigham and Women's Hospital, Harvard Medical School, Boston, MA [email protected].
  • 5. Vascular Biology Program, Boston Children's Hospital, Harvard Medical School, Boston, MA.
  • 6. Department of Pathology, Boston Children's Hospital, Harvard Medical School, Boston, MA.
  • 7. Center for Experimental Therapeutics and Reperfusion Injury, Department of Anesthesiology, Perioperative and Pain Medicine, Brigham and Women's Hospital, Harvard Medical School, Boston, MA.
  • 8. Department of Anesthesia, Boston Children's Hospital, Harvard Medical School, Boston, MA.
  • 9. Department of Surgery, Boston Children's Hospital, Harvard Medical School, Boston, MA.
  • 10. The William Harvey Research Institute, Barts and The London School of Medicine, Queen Mary University of London, London, England, UK.
  • 11. Department of Medicine, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA.
  • 12. Human Biology Division, Fred Hutchinson Cancer Research Center, Seattle, WA.
  • 13. Division of Pediatric Oncology, Dana-Farber Cancer Institute, Harvard Medical School, Boston, MA [email protected].
  • 14. Department of Pediatric Hematology/Oncology, Boston Children's Hospital, Harvard Medical School, Boston, MA.
  • 15. Institute of Systems Biology, Seattle, WA [email protected].
  • 16. Center for Vascular Biology Research, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA [email protected].
PMID: 29191914 DOI: 10.1084/jem.20170681
Abstract

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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