Resolvins suppress tumor growth and enhance cancer therapy.
J Exp Med
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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 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.
AuthorsSulciner, ML; Serhan, CN; Gilligan, MM; Mudge, DK; Chang, J; Gartung, A; Lehner, KA; Bielenberg, DR; Schmidt, B; Dalli, J; Greene, ER; Gus-Brautbar, Y; Piwowarski, J; Mammoto, T; Zurakowski, D; Perretti, M; Sukhatme, VP; Kaipainen, A; Kieran, MW; Huang, S; Panigrahy, D
- Inflammation