Pharmacology & Therapeutics 218 (2021) 107670 Contents lists available at ScienceDirect Pharmacology & Therapeutics journal homepage: www.elsevier.com/locate/pharmthera Carcinogenesis: Failure of resolution of inflammation? Anna Fishbein a,b,⁎, Bruce D. Hammock c, Charles N. Serhan d,1, Dipak Panigrahy a,b,1 a Center for Vascular Biology Research, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA 02215, USA b Department of Pathology, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA 02215, USA c Department of Entomology and Nematology, and UCD Comprehensive Cancer Center, University of California, Davis, CA 95616, USA d Center for Experimental Therapeutics and Reperfusion Injury, Department of Anesthesiology, Perioperative and Pain Medicine, Brigham and Women's Hospital, Harvard Medical School, Boston, MA 02115, USA article info abstract Available online 3 September 2020 Inflammation in the tumor microenvironment is a hallmark of cancer and is recognized as a key characteristic of carcinogens. However, the failure of resolution of inflammation in cancer is only recently being understood. Prod- ucts of arachidonic acid and related fatty acid metabolism called eicosanoids, including prostaglandins, leukotri- Keywords: enes, lipoxins, and epoxyeicosanoids, critically regulate inflammation, as well as its resolution. The resolution of Eicosanoid inflammation is now appreciated to be an active biochemical process regulated by endogenous specialized pro- Carcinogen resolving lipid autacoid mediators which combat infections and stimulate tissue repair/regeneration. Environ- Inflammation mental and chemical human carcinogens, including aflatoxins, asbestos, nitrosamines, alcohol, and tobacco, in- Resolution duce tumor-promoting inflammation and can disrupt the resolution of inflammation contributing to a Resolvin devastating global cancer burden. While mechanisms of carcinogenesis have focused on genotoxic activity to in- Soluble epoxide hydrolase duce mutations, nongenotoxic mechanisms such as inflammation and oxidative stress promote genotoxicity, proliferation, and mutations. Moreover, carcinogens initiate oxidative stress to synergize with inflammation and DNA damage to fuel a vicious feedback loop of cell death, tissue damage, and carcinogenesis. In contrast, stimulation of resolution of inflammation may prevent carcinogenesis by clearance of cellular debris via macro- phage phagocytosis and inhibition of an eicosanoid/cytokine storm of pro-inflammatory mediators. Controlling the host inflammatory response and its resolution in carcinogen-induced cancers will be critical to reducing carcinogen-induced morbidity and mortality. Here we review the recent evidence that stimulation of resolution of inflammation, including pro-resolution lipid mediators and soluble epoxide hydrolase inhibitors, may be a new chemopreventive approach to prevent carcinogen-induced cancer that should be evaluated in humans. © 2020 Elsevier Inc. All rights reserved. Contents 1. Introduction............................................... 2 2. InflammationandCancer......................................... 3 3. Carcinogens and inflammation....................................... 3 4. Humancarcinogens............................................ 6 5. Carcinogenesisisamulti-stage,multi-mechanismprocess.......................... 7 6. Detectionofcarcinogens.......................................... 7 7. Mechanismsofpro-tumorigenicactivitybycarcinogens........................... 8 8. Therapeuticapproaches.......................................... 14 Abbreviations: 12-O-tetradecanoylphorbol-13-acetate, TPA; 4-nitroquinaline 1-oxide, 4-NQO; 7,12-dimethylbenz[a]anthracene, DMBA; Aflatoxin B1,AFB1; Azoxymethane, AOM; benzo[a]pyrene, BaP; Dextran sodium sulfate, DSS; Diethylstilbestrol, DES; Hepatocellular carcinoma, HCC; Inducible nitric oxide synthase, iNOS; Lipopolysaccharide, LPS; Liquid chromatography-tandem mass spectrometry, LC-MS/MS; N-butyl-N-(4-hydroxybutyl)-nitrosamine, BBN; N-nitrosobis(2-oxopropyl)amine, BoP; N-nitrosodiethylamine, NDEA / Diethylnitrosamine DEN; N-nitrosodimethylamine, NDMA / Dimethylnitrosamine DMN; N-nitrosomethylbenzylamine, NMBA; Nitrosamine 4-(methylnitrosamino)-1-(3-pyridyl)-1- butanone, NNK; Nuclear factor erythroid-2 related factor 2, Nrf2; Perfluorinated carboxylic acids, PCFAs; Perfluorooctanoic acid, PFOA/C8; Phorbol 12-myrisate 13-acetate, PMA; Polycyclic aromatic hydrocarbons, PAHs; Soluble epoxide hydrolase, sEH; Specialized pro-resolving mediators, SPMs. ⁎ Corresponding author at: 99 Brookline Ave. Rm 220, Boston, MA 02215, USA. E-mail address: [email protected] (A. Fishbein). 1Contributed equally. https://doi.org/10.1016/j.pharmthera.2020.107670 0163-7258/© 2020 Elsevier Inc. All rights reserved. A. Fishbein, B.D. Hammock, C.N. Serhan et al. Pharmacology & Therapeutics 218 (2021) 107670 9. Outlook................................................. 23 Acknowledgments............................................... 23 DeclarationofCompetingInterest........................................ 23 References................................................... 23 1. Introduction microenvironment (Serhan, 2017; Sulciner et al., 2018). In healthy indi- viduals, the acute inflammatory response(s) is self-limited and can be Carcinogens induce inflammation, an established hallmark of cancer classically divided into initiation and resolution phases (Serhan, 2014). (Greten & Grivennikov, 2019; Hanahan & Weinberg, 2011; Mantovani, Neutrophils (polymorphonuclear leukocytes) are one of the first im- Allavena, Sica, & Balkwill, 2008). With potential exposure to greater mune cell types to enter the wounded area and remove microbes as than 15 million environmental chemicals worldwide, controlling in- well as cellular debris (Serhan & Levy, 2018). Cancer is viewed as a flammation and its resolution will be a critical component of the suc- wound that does not heal, thus attracting similar cell types and mecha- cessful prevention and treatment of cancer (Gilligan et al., 2019; nisms as wound healing and tissue regeneration (Dvorak, 1986). A par- Panigrahy et al., 2019; Sulciner et al., 2018). Uncontrolled local and sys- adigm shift is emerging in our understanding of the pathogenesis of temic hyperinflammation is an underlying driving force of diseases in- pathological inflammation which not only results from the persistent cluding cardiovascular disease (e.g. atherosclerosis and myocardial activation of inflammatory signals, but also the failure of engaging infarction), abdominal aortic aneurysm, heart arrhythmias, arthritis, pro-resolving mechanisms including clearance of cell death “debris” central nervous system disorders, periodontal disease, inflammatory and counter-regulation of pro-inflammatory cytokines (Serhan, 2014; bowel disease, gallstones, sepsis, infection, stroke/epilepsy, infection, Serhan & Levy, 2018). Experimental and human studies suggest that acute respiratory distress syndrome (ARDS), fibrosis (e.g. liver, kidney cancer progression results from the “failure to clear debris” after chemo- and lung), portal hypertension, fatty liver, neurodegenerative diseases therapy, radiation, or surgery (Chaurio et al., 2013; da Silva-Jr, (e.g. Alzheimer's disease), traumatic brain injury, asthma, obesity, dia- Chammas, Lepique, & Jancar, 2017; Ford et al., 2015; Gartung et al., betes, pain, severe coronavirus disease (e.g. COVID-19), and autoim- 2019; Gilligan et al., 2019; Gunjal et al., 2015; Huang et al., 2011; mune diseases (Chelko et al., 2019; Chiang et al., 2012; Espinoza et al., Panigrahy et al., 2019; Revesz, 1956; Sulciner et al., 2018; Ye et al., 2016; Imig & Hammock, 2009; Libby, 2002; Mehta et al., 2020; 2018). Thus, failure to engage resolution of inflammation mechanisms Serhan, 2014; Spite et al., 2009). Over the past century, the study of including clearance of debris may lead to carcinogenesis. Differentiating anti-inflammatory mechanisms has focused on the suppression of between suppression and resolution of inflammation is critical to mech- pro-inflammatory mediators, such as cytokines, eicosanoids, and en- anistic studies in inflammation-driven diseases including cancer zymes (Wang & Dubois, 2010). In recent years, a new direction has (Fishbein et al., 2020; Gilligan et al., 2019; Kuang, Hua, Zhou, & Yang, emerged to “turn off” inflammation with the discovery of a new super- 2016; Panigrahy et al., 2019; Serhan, 2014; Shan et al., 2020; Sulciner family of endogenous specialized pro-resolving lipid-autacoid media- et al., 2018); Ye et al., 2018). tors (SPMs), such as resolvins, which have potent novel inflammation A key concept in resolution of inflammation is that the immune sys- clearing (‘pro-resolution’) activity without being immunosuppressive tem can be beneficial in fighting cancer, in accordance with the increas- (Serhan, 2014; Serhan et al., 2002; Serhan et al., 2009). Unlike the ma- ing interest in immune-mediated approaches in targeting cancer jority of anti-inflammatory agents including the nonsteroidal anti- (Serhan, 2011; Sharma & Allison, 2015). In 1790 the Scottish surgeon inflammatory drugs (NSAIDs) such as celecoxib and ibuprofen that John Hunter remarked “Inflammation in itself is not to be considered work by directly suppressing cyclooxygenase (COX-2) enzyme activity, as a disease” (Turk, 1994). In 1893 William Coley successfully treated SPMs are endogenous inhibitors of inflammation, which function as sarcomas with bacterial mixtures, leading to tumor regression (Coley, “brake signals” to turn