Abstract 1664: Cancer progression: The failure to resolve
Authors: Sulciner Megan L. , Mudge Dayna K. , Bielenberg Diane R. , Benny Ofra , Dalli Jesmond , Huang Sui , Serhan Charles N. , Kieran Mark W. , Panigrahy Dipak 
Published: May 2015

Background: Failure to resolve inflammation contributes to disease pathogenesis. Inflammation in the tumor microenvironment is now recognized as one of the hallmarks of cancer. Anti-inflammatory therapies have focused on suppressing pro-inflammatory mediators, cytokines and eicosanoids. However, a new direction has emerged with the discovery of a novel genus of endogenous anti-inflammatory and pro-resolving lipid-autacoid mediators derived from omega-3 polyunsaturated fatty acids, specifically resolvins (Rvs). Resolvins have potent novel inflammation clearing (pro-resolution) activity without being immunosuppressive and are also anti-inflammatory, anti-angiogenic, anti-infective and anti-fibrotic. We hypothesize the failure of the resolution of inflammation can lead to cancer progression and resolvins inhibit tumor progression and metastasis. Results: Resolvins potently inhibited primary tumor growth in subcutaneous, orthotopic and genetically engineered models of cancer. After primary tumor resection, resolvins suppressed spontaneous lung metastasis. Resolvins prevent apoptosis-stimulated tumor growth (Révész effect) without toxicity by stimulating the resolution of inflammation at nanogram levels (at doses over 10,000 fold less than aspirin or omega-3 fatty acids). Resolvins (RvD1, RvD2, and RvE1) activated human macrophage phagocytosis of apoptotic human tumor cells (including prostate and ovarian), which was reversed with a lipoxygenase inhibitor (baicalein). Similarly, RvD1 stimulated murine macrophage phagocytosis of chemotherapy-induced apoptotic murine tumor cells (including ovarian), which was reversed by the ALX/FPR-2 selective antagonist BOC-1. Resolvins also counter-regulated chemotherapy-induced pro-inflammatory cytokines/chemokines including TNFα, IL-6, IL-8, CCL4 and CCL5. Furthermore, resolvins reduced leukocyte infiltration and VEGF-dependent tumor angiogenesis. Resolvins induce a new phenotype of tumor-associated macrophages that are M2-like (increased CD206+/F4/80+), but possess phagocytic activity (CD11bhigh/F4/80+). Electron microscopy confirmed phagocytosis of tumor cells in macrophages in RvD2-treated tumors. Depletion of macrophages promoted tumor growth in resolvin-treated mice. Resolvins display synergistic anti-tumor activity with the chemotherapeutic agent cisplatin to regress established primary tumors. The expression of the RvD1 receptor, ALX/FPR-2, decreased with spontaneous tumor (TRAMP) progression. Thus, cancer progression may be associated with the loss of an endogenous anti-inflammatory lipid mediator. Conclusions: Resolvins suppress primary tumor growth and metastasis via the stimulation of the uptake of apoptotic tumor cells by macrophages. The resolvin pathway, or the enhancement of endogenous resolution processes, therefore offers an entirely novel approach for controlling chronic inflammation as a modality of cancer treatment.

Citation Format: Megan L. Sulciner, Dayna K. Mudge, Diane R. Bielenberg, Ofra Benny, Jesmond Dalli, Sui Huang, Charles N. Serhan, Mark W. Kieran, Dipak Panigrahy. Cancer progression: The failure to resolve. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr 1664. doi:10.1158/1538-7445.AM2014-1664