Stimulation of Resolution of Inflammation via Pro‐Resolving Lipid Mediators Prevents Ethanol‐Induced Tumor Growth

Abstract

Alcohol consumption is a common cause of various cancers such as hepatocellular carcinoma (HCC) by inducing inflammation. Alcohol is oxidized in the body to aldehydes, mostly acetyldehyde which is a group 1 carcinogen. However, effective therapies to stimulate the resolution of inflammation to prevent alcohol‐induced cancers have not been elucidated. Ethanol and acetyldehyde generate apoptotic cell (“debris”) which may stimulate inflammation and tumor growth via an inflammatory response. Thus, controlling ethanol‐stimulated inflammation will be critical to prevent HCC and other tumor‐types caused by ethanol. This could be addressed with specialized pro‐resolving lipid mediators (SPMs), such as maresins and protectins, which are derived from essential fatty acids and stimulate the resolution of tumor‐promoting inflammation by activating macrophage clearance of cellular debris. In contrast to traditional anti‐inflammatories (e.g. NSAIDs and steroids), SPMs are not immunosuppressive and are active at nanomolar concentrations. SPMs are currently being evaluated in clinical trials for various inflammatory diseases. Here, we demonstrate that ethanol‐generated cell debris stimulates primary tumor growth in vivo by stimulating the release of pro‐inflammatory cytokines and bioactive lipid mediators. Aldehyde‐generated debris also stimulated tumor growth via oxidative stress and reactive oxygen species. Systemic administration of SPMs prevent ethanol‐induced cancers in mice via resolution of inflammation. Cytokine array analysis demonstrated that ethanol‐generated tumor and non‐tumor cell debris of multiple tumor types each triggered human or murine macrophages to release a storm of pro‐inflammatory and pro‐angiogenic cytokines. Maresins, maresin conjugates, and protectin conjugates stimulated macrophage phagocytosis of ethanol‐generated and aldehyde‐generated cell debris and suppressed the release of pro‐inflammatory, tumor‐promoting cytokines by debris‐activated macrophages. Thus, ethanol‐generated cell debris triggers a cytokine storm providing a potential mechanism whereby ethanol harbors the potential to stimulate or induce tumor initiation, growth, and/or metastasis. Uncovering the mechanism of ethanol‐induced cell death and debris‐induced tumor progression is paramount to preventing cancer induced by ethanol‐generated inflammation. Dead cells generated by cytotoxic ethanol or aldehyde exposure may inadvertently stimulate proliferation of dormant tumor cells in patients. While generation of cell debris may explain risk of alcohol causing cancer, enhancing endogenous clearance of cell debris via SPMs, such as maresin conjugates and protectin conjugates, represents a novel approach to prevent ethanol‐induced cancer.