ABSTRACT
Cancer therapy reduces tumor burden via tumor cell death ("debris"), which can accelerate tumor progression via the failure of inflammation resolution. Thus, there is an urgent need to develop treatment modalities that stimulate the clearance or resolution of inflammation-associated debris. Here, we demonstrate that chemotherapy-generated debris stimulates metastasis by up-regulating soluble epoxide hydrolase (sEH) and the prostaglandin E2 receptor 4 (EP4). Therapy-induced tumor cell debris triggers a storm of proinflammatory and proangiogenic eicosanoid-driven cytokines. Thus, targeting a single eicosanoid or cytokine is unlikely to prevent chemotherapy-induced metastasis. Pharmacological abrogation of both sEH and EP4 eicosanoid pathways prevents hepato-pancreatic tumor growth and liver metastasis by promoting macrophage phagocytosis of debris and counterregulating a protumorigenic eicosanoid and cytokine storm. Therefore, stimulating the clearance of tumor cell debris via combined sEH and EP4 inhibition is an approach to prevent debris-stimulated metastasis and tumor growth.
Subject(s)
Eicosanoids/metabolism , Epoxide Hydrolases/biosynthesis , Macrophages/immunology , Neoplasm Metastasis/pathology , Receptors, Prostaglandin E, EP4 Subtype/biosynthesis , Animals , Antineoplastic Agents/adverse effects , Antineoplastic Agents/therapeutic use , Carcinoma, Hepatocellular/pathology , Cell Death/drug effects , Cell Line, Tumor , Cytokine Release Syndrome/immunology , Cytokine Release Syndrome/prevention & control , Cytokines/metabolism , Hep G2 Cells , Humans , Liver Neoplasms/drug therapy , Liver Neoplasms/pathology , Male , Mice , Mice, Inbred C57BL , Neoplasm Metastasis/prevention & control , Pancreatic Neoplasms/drug therapy , Pancreatic Neoplasms/pathology , Phagocytosis/immunology , RAW 264.7 CellsABSTRACT
Coronavirus disease 2019 (COVID-19) due to infection with severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) has been an ongoing pandemic causing significant morbidity and mortality worldwide. The "cytokine storm" is a critical driving force in severe COVID-19 cases, leading to hyperinflammation, multi-system organ failure, and death. A paradigm shift is emerging in our understanding of the resolution of inflammation from a passive course to an active biochemical process driven by endogenous specialized pro-resolving mediators (SPMs), such as resolvins, protectins, lipoxins, and maresins. SPMs stimulate macrophage-mediated debris clearance and counter pro-inflammatory cytokine production, a process collectively termed as the "resolution of inflammation." Hyperinflammation is not unique to COVID-19 and also occurs in neoplastic conditions, putting individuals with underlying health conditions such as cancer at elevated risk of severe SARS-CoV-2 infection. Despite approaches to block systemic inflammation, there are no current therapies designed to stimulate the resolution of inflammation in patients with COVID-19 or cancer. A non-immunosuppressive therapeutic approach that reduces the cytokine storm in patients with COVID-19 and cancer is urgently needed. SPMs are potent immunoresolvent and organ-protective lipid autacoids that stimulate the resolution of inflammation, facilitate clearance of infections, reduce thrombus burden, and promote a return to tissue homeostasis. Targeting endogenous lipid mediators, such as SPMs, offers an entirely novel approach to control SARS-CoV-2 infection and cancer by increasing the body's natural reserve of pro-resolving mediators without overt toxicity or immunosuppression.