Chronic inflammation deregulates cellular homeostasis and can drive carcinogenesis.
Free radicals and aldehydes — produced during chronic inflammation — can induce a number of alterations, including gene mutations and post-translational modifications of key cancer-related proteins. These alterations can lead to the disruption of cellular processes such as DNA repair, cell-cycle checkpoints and apoptosis.
The ultimate effect of free radicals is complex and depends on their local concentration, the microenvironment and the genetic background of the individual.
Nitric oxide and its derivatives damage DNA and modify protein structure and function but can also protect from cytotoxicity. These 'two faces' of nitric oxide highlight the need for further study before considering nitric oxide as a target for chemoprevention in high cancer risk, chronic inflammatory diseases.
People with cancer-prone inflammatory diseases, such as ulcerative colitis, haemochromatosis and viral hepatitis, have alterations in cancer-related genes and proteins,which are associated with free-radical stress.
Transgenic and knockout animal models support the role of free radicals in carcinogenesis.
Prospective chemoprevention studies are needed to evaluate the use of antioxidants and inhibitors of pro-oxidant enzymes for the prevention of cancer in people with oxyradical overload diseases.
Free radicals are ubiquitous in our body and are generated by normal physiological processes, including aerobic metabolism and inflammatory responses, to eliminate invading pathogenic microorganisms. Because free radicals can also inflict cellular damage, several defences have evolved both to protect our cells from radicals — such as antioxidant scavengers and enzymes — and to repair DNA damage. Understanding the association between chronic inflammation and cancer provides insights into the molecular mechanisms involved. In particular, we highlight the interaction between nitric oxide and p53 as a crucial pathway in inflammatory-mediated carcinogenesis.
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We thank M. Khan for graphical assistance, D. Dudek for editorial assistance and K. McPherson for assistance in manuscript preparation. We also thank G. Wogan for his useful discussions.
A soluble protein that is produced and released by individual cells that transmit distinct messages of activation, inhibition, chemoattraction or apoptosis to other cells. This interaction triggers effector mechanisms within the responding cell. Key pro-inflammatory cytokines include IL-1β, TNF-α and IFN-γ.
- FREE RADICAL
An atom or a group of atoms that has an unpaired electron. These are highly reactive to biological molecules and will damage them.
Addition of an equivalent of NO2˙ in a free-radical mechanism, often resulting in the formation of 3-nitrotyrosine. This modification can affect the function of certain proteins and is involved in disease pathology, including cancer.
Addition of an equivalent of NO+ (nitrosonium ion or nitrosyl cation) to an amine, thiol or hydroxyaromatic group.
- LIPID PEROXIDATION
Auto-oxidation of lipids that are exposed to oxygen.
A naturally occurring, bioactive by-product of lipid peroxidation and prostaglandin synthesis that has the potential to damage DNA. It reacts with DNA to form adducts to deoxyguanosine and deoxyadenosine.
- FAS LIGAND
A 40-kDa transmembrane protein that belongs to the tumour necrosis factor (TNF) family. It is a potent pro-apoptotic factor.
- APC GENE
The adenomatous polyposis coli gene is a tumour suppressor. Mutations in the gene are responsible for familial adenomatous polyposis and most sporadic colorectal cancers. The best understood function of APC is the destabilization of β-catenin, a key effector of the WNT signalling pathway.
- NON-STEROIDAL ANTI-INFLAMMATORY DRUGS
(NSAIDs). This heterogeneous group of drugs primarily target the cyclooxygenase enzymes to treat pain, fever and inflammation.
A specific biochemical that provides a measure of a biological response to an endogenous or exogenous agent. The biological responses might be at the molecular, cellular or whole-organism level.
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Hussain, S., Hofseth, L. & Harris, C. Radical causes of cancer. Nat Rev Cancer 3, 276–285 (2003). https://doi.org/10.1038/nrc1046
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