Carcinogenesis: Failure of resolution of inflammation?

Abstract

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. Products of arachidonic acid and related fatty acid metabolism called eicosanoids, including prostaglandins, leukotrienes, lipoxins, and epoxyeicosanoids, critically regulate inflammation, as well as its resolution. The resolution of inflammation is now appreciated to be an active biochemical process regulated by endogenous specialized pro-resolving lipid autacoid mediators which combat infections and stimulate tissue repair/regeneration. Environmental and chemical human carcinogens, including aflatoxins, asbestos, nitrosamines, alcohol, and tobacco, induce tumor-promoting inflammation and can disrupt the resolution of inflammation contributing to a devastating global cancer burden. While mechanisms of carcinogenesis have focused on genotoxic activity to induce 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 macrophage 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.

Keywords: Carcinogen; Eicosanoid; Inflammation; Resolution; Resolvin; Soluble epoxide hydrolase.

Fig. 1

Key characteristics of carcinogens. Represents the 10 key characteristics of carcinogens adapted from Table 1 in (M. T. Smith et al., 2016). 1. Metabolic activation 2. Is genotoxic 3. Alters DNA repair 4. Leads to epigenetic alterations 5. Generates oxidative stress, 6. Chronic inflammation, and 7. Immunosuppression 8. Activates receptor mediated signaling 9. Causes cell immortalization and 10. Increases cell proliferation. Adapted from Smith et al. Environmental Health Perspectives 124:62016.

Fig. 2

Experimental models of carcinogen-induced cancers. A) Intraperitoneal injection of male Sprague-Dawley rats with 30 mg/kg Diethylnitrosamine (DEN) twice a week for 11 weeks led to hepatocellular carcinoma B) Male C57BL/6 J mice or BALB/c mice injected intraperitoneally week one with 10 mg/kg azoxymethane (AOM) and one week later given 1.5% or 2% dextran sodium sulfate (DSS) in the drinking water for one week leading to colon carcinomas. C) Male F344 rats given 20 p.p.m. 4-nitroquinoline 1-oxide (4-NQO) in drinking water for 10 weeks led to tongue squamous cell carcinoma or papilloma. D) NMRI mice exposed to single epicutaneous application of 0.1 μmol 7,12-dimethylbenz[a]anthracene (DMBA) in acetone and two weeks later exposed twice a week to 5 nmol phorbol 12-myrisate 13-acetate (PMA) for 28 weeks leading to skin papilloma and carcinoma. E) Male A/J mice were injected intraperitoneally with 50 mg/kg 4-(methylnitrosamino)-1 (3-pyridyl)-1-butanone (nicotine-derived nitrosamine ketone (NNK)) for 4 weeks led to lung adenocarcinoma. F) Male F344 rats injected subcutaneously with 1 mg/kg N-nitrosomethylbenzylamine (NMBA) 5 times a week for 5 weeks and then once a week for 5 more weeks led to esophageal papilloma and carcinomas.

Fig. 3

Nongenotoxic mechanisms of carcinogenesis. Following carcinogen exposure inflammation is induced leading to inflammatory infiltrates at the location of exposure. With the upregulation of NF-κB, COX-2, and 5-LOX inflammatory cells are triggered to release a storm of pro-inflammatory and tissue regenerative eicosanoids, cytokines, and reactive oxygen species. The factors generate DNA mutations, cell damage, and epigenetic alterations leading to cellular transformation. In addition, the inflammation and oxidative stress leads to upregulated anti-apoptotic mechanisms, angiogenesis, and DNA damage but downregulated DNA repair, immune surveillance, and resolution. Together, these processes driven by carcinogen induced inflammation alter the microenvironment allowing for extracellular matrix remodeling, cytotoxicity and damage-associated molecular pattern (DAMP) signaling, and regenerative proliferation resulting in tumor growth.

Fig. 4

Inflammation resolution in carcinogen-induced cancer. Carcinogen (NDEA) induced inflammation causes tissue damage and cell death of normal cells (hepatocytes) generating cellular debris. These dead cells activate local macrophages (Kupffer cells) to a pro-inflammatory phenotype generating a cytokine storm. This chronic inflammation reduces pro-resolving mediators including SPMs and EETs and signals for angiogenesis, fibrosis, and inflammatory cell infiltration. Infiltrating white blood cells add to the tissue injury by producing reactive oxygen and nitrogen species triggering the upregulation of NF-κB, COX-2, 5-LOX, and MMPs in surrounding hepatocytes generating a vicious cycle leading to tumor growth. However, resolution of inflammation via SPMs or sEH inhibition may break this pro-tumorigenic cycle. Resolution promotes macrophage phagocytosis of cellular debris, inhibits the cytokine storm, suppresses inflammatory infiltration, and is not immunosuppressive leading to the downregulation of NF-κB, COX-2, 5-LOX, and MMPs and inhibition of carcinogenesis.