Most people with advanced cancer exhibit cachexia, a syndrome of progressive weight loss that leads to the death of 20% of patients. The mechanisms underlying cachexia remain poorly understood and, as a result, no treatment has proven effective to date. Cachexia is characterized by systemic hyperinflammation, massive apoptotic cell death (“debris”), and skeletal muscle wasting. Here, we hypothesize that disrupted resolution of inflammation contributes to cancer cachexia, and pro-resolving lipid mediators, specifically novel specialized pro-resolving mediators (SPMs), could control cachexia. SPMs enhance resolution of inflammation by stimulating debris clearance, promoting tissue regeneration, and regulating major immune cell types. In testing our hypothesis, we profiled lipid mediators in a variety of metastatic cachexia models via metabololipidomics and investigated the changes of leukocytes, e.g., T lymphocyte, natural killer (NK), and macrophage cells, in various skeletal muscles (e.g., tibialis anterior and gastrocnemius). Dysregulation of SPMs was identified in different tissues in 5 cachexia models. The SPMs resolvin (RvD)2 and maresin (MaR)1 were reduced in the liver and spleen of colon cancer (CT26)-induced cachectic mice on day 35 post-tumor cell injection and RvD1, RvD2, lipoxin (LXA)4, and MaR1 were dysregulated in Lewis lung carcinoma (LLC)-induced cachectic mice on day 20. Chemotherapy was also found to dysregulate SPMs and induce cachexia in lymphoma (EL4) and ovarian cancer (ID8) mouse models. Ten days post-LLC tumor resection, the RvD1 receptor (ALX/FPR2) KO and RvE1 receptor (ChemR23/ERV) KO mice exhibited a 20-23% loss in body weight compared to WT mice. This shows that neutralizing the pro-resolving activity of RvD1 and RvE1 induces cancer cachexia. Moreover, RvD2 and PCTR (protectin conjugates in tissue regeneration)-2 prevented LLC- and B16F10 melanoma-induced cachexia at 15 ng/day. RvD4, RvD5, MCTR1, or MCTR2 inhibited inflammation-stimulated cytokine storm by counter-regulating the production of CCL3, CCL4, CXCL2, TNF-α, CCL2, G-CSF, and PAI-1. These results indicate that disrupted resolution of inflammation leads to the progression of cancer cachexia, and dysregulated SPMs are potential early markers for cachexia. This study provides a basis for the clinical translation of SPM-directed treatments as a new direction to potentially control cancer cachexia in humans. Citation Format: Ahmed Attaya, Victoria Haak, Abigail Kelly, Haixia Yang, Eva Rothenberger, Steven D. Freedman, Charles N. Serhan, Dipak Panigrahy. Potential of inflammation pro-resolving lipid mediators in controlling cancer cachexia [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 370.
Cytotoxic cancer therapies reduce tumor burden by killing tumor cells. However, the resulting apoptotic and necrotic cell bodies (tumor cell “debris”) may stimulate tumor initiation and progression by disrupting the resolution of inflammation. Thus, chemotherapy and anti-estrogen breast cancer therapy, including tamoxifen, may be a double-edged sword. A paradigm shift is emerging in understanding the resolution of inflammation as an active biochemical process with the discovery of novel specialized pro-resolving lipid autocoid mediators (SPMs), such as maresins and endogenous resolution programs. Despite approaches to block systemic inflammation, there are no current “pro-resolving” therapies in cancer. To determine whether debris stimulates breast cancer growth, we utilized tumor dormancy models with a subthreshold (nontumorigenic) inoculum of tumor cells. We demonstrated that breast tumor “debris” generated by cytotoxic anti-estrogen therapy (tamoxifen or fulvestrant) or chemotherapy (eribulin) stimulates dormancy escape by triggering a macrophage-derived pro-inflammatory and pro-angiogenic “cytokine storm”. Thus, tumor cell debris is a critical pro-tumorigenic factor in breast cancer initiation and progression. To assess whether stimulating the clearance of debris would suppress breast cancer progression, we utilized the SPMs maresin 1 (MaR1) and maresin conjugates in tissue regeneration (MCTR1, MCTR2). Each maresin (MaR1, MCTR1 and MCTR2) sharply reduced tumor growth in both debris-stimulated and spontaneous (e.g. MMTV-PyMT) breast cancer models at nanogram concentrations (15 ng/day) without toxicity. Notably, maresins enhanced immunotherapy (anti-CTLA4) to induce tumor regression in estrogen receptor (ER) positive (EO771) and inhibit ER negative tumor growth (4T1). Maresins stimulated macrophage phagocytosis of therapy (fulvestrant and tamoxifen)-generated breast cancer debris at only nanomolar concentrations (0.1 - 10 nM). Remarkably, maresins alone or in combination with chemotherapy (paclitaxel) reduced levels of pro-angiogenic factors (e.g. CXCL12/SDF-1) in the tumor microenvironment and decreased microvessel density/size, thereby inhibiting tumor angiogenesis. Maresins dampened the therapy-induced cytokine storm, by reducing levels of TNF-α, MIP-2/CXCL2, CCL2/MCP-1, IL-1ra/IL-1F3, CCL5, CXCL13, Serpin E1/PAI-1, IL-1β and G-CSF both in vitro in debris-stimulated macrophages and in vivo in plasma and tumor tissue. Stimulating the resolution of inflammation via pro-resolution lipid mediators to enhance immunotherapy is a novel host-centric therapeutic approach to prevent breast cancer initiation, dormancy escape and tumor progression via debris clearance and counter-regulation of the cytokine storm. Altogether, the maresin pathway mediators may represent a new therapeutic approach to stimulate the resolution of inflammation in breast cancer. Citation Format: Franciele Cristina Kipper, Jianjun Deng, Eva Rothenberger, Abigail Kelly, Madeline Duncan, Sui Huang, Charles N. Serhan, Dipak Panigrahy. Maresins prevent breast cancer dormancy escape via resolution of inflammation [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 1329.
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