Carcinogenesis: Failure of resolution of inflammation?

https://doi.org/10.1016/j.pharmthera.2020.107670Get rights and content

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

Eicosanoid
Carcinogen
Inflammation
Resolution
Resolvin
Soluble epoxide hydrolase

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

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Contributed equally.

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