The review by Drs. Shacter and Weitzman is an excellent and timely contribution to the field of carcinogenesis. The issue of chronic inflammation as a progenitor of cancer development has been a controversial one. To prove the importance of chronic inflammation (and the factors released in the process) to carcinogenesis, the authors provide a thorough and logical presentation of the experimental results described in the literature, including their own work. This compilation of the existing data should dispel any doubts about the association of chronic inflammation to cancer. I will review the main points discussed by the authors.

Strong Association

There is a strong association between chronic inflammatory conditions in a particular organ (tissue) and cancer specific to that organ (tissue). This association involves a time factor—the longer the inflammation persists, the higher the risk of associated carcinogenesis. The most thoroughly studied examples are the relationships between chronic inflammatory bowel disease and the increased risk of colorectal cancer, chronic gastritis resulting from Helicobacter pylori infection and gastric adenocarcinoma, and chronic hepatitis and liver cancer. Table 1 of the article lists the chronic inflammatory conditions, the associated cancers, and, when known, the etiologic agents.

The various factors known to cause cancer also induce chronic inflammatory responses. These include bacterial, viral, and parasitic infections (eg, H pylori, Epstein-Barr virus, human immunodeficiency virus, flukes, schistosomes), chemical irritants (ie, tumor promoters, such as phorbol ester 12-O-tetradecanoyl-13-phorbol acetate, also known as phorbol myristate acetate), nondigestible particles (eg, asbestos, silica), and other factors yet to be discovered. The authors could also have added that chemical carcinogens, such as polycyclic aromatic hydrocarbons, which require oxidative metabolism for their activities, induce chronic inflammation with the attendant oxidative stress, macromolecular damage, and cytokine formation.[1-3]

Oxidative Stress

All these factors promote oxidative stress characterized by the generation of reactive oxygen and nitrogen species and the cellular damage they cause, the release of inflammatory cytokines and growth factors, as well as increased formation of chemotactic factors and prostaglandins. These mediators cause oxidative DNA base modification, lipid peroxidation, and oxidation of proteins. They can also promote oxidative deamination of the DNA bases guanine, adenine, and cytosine—a mutagenic event.

Aldehydes released from lipid hydroperoxides modify cellular DNA, forming cyclic etheno derivatives.[4,5] Some oxidized DNA nucleosides (ie, 8-hydroxy-2´-deoxyguanosine [8-OHdG], also known as 8-oxo-dG, 5-hydroxymethyl-2´-deoxyuridine [HMdU], and 5-hydroxy-2´-deoxycytidine [5-OHdC]) as well as etheno derivatives were shown to be mutagenic.[6-9] Hence, they can act by inducing preneoplastic mutations.