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.
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]
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.
Peroxynitrite, formed by an avid reaction of superoxide anion radicals with nitric oxide, causes nitration of tyrosines in proteins and guanine moiety in DNA, as well as oxidation and degradation of guanine residues. Thus, in addition to DNA damage, modification of tyrosine residues is likely to interfere with signal transduction processes that require tyrosine kinases—all of which could lead to the dysregulation of the cellular machinery.
Initially, oxidative stress triggers the adaptation by up-regulating antioxidant defenses. However, a prolonged exposure to reactive oxygen and nitrogen species, cytokines, and other inflammatory factors overwhelms those protective defenses, while pathways that favor growth of mutated cells are activated. These include increased formation of prostaglandins, which enhances cell proliferation by up-regulating cytokine interleukin (IL)-6 that serves as a growth factor, and down-regulating pathways that lead to apoptosis by activating transcription factor NF-kappaB and bcl-2 oncogene.
At the same time, the activities of the tumor-suppressor genes (ie, p53 and Rb), necessary for proper regulation of the cell cycle, are inhibited. This allows cells containing modified bases in their DNA to continue replication, leading to the fixing of mutations. Some cytokines and chemotactic factors, such as IL-1-alpha and IL-8, prostaglandins, and factors derived from phagocytic or tumor cells, are also involved in angiogenesis,[10-12] thus facilitating the formation of blood vessels in tumors, their nourishment, and metastatic dissemination.
Reactive oxygen and nitrogen species generated by activated phagocytic cells (which is characteristic of chronic inflammation) cause modification of DNA bases in cells coincubated with such phagocytes, and contribute to neoplastic transformation of the coincubated cells. All these processes can be counteracted by antioxidants and antitumor promoters. Oxidized DNA bases, such as 8-oxo-dG, HMdU, and 5-OHdC, can be mutagenic and can interfere with the transcription factor binding to the recognition elements on DNA, thus modulating gene expression.
Anti-inflammatory agents, such as aspirin, nonsteroidal anti-inflammatory drugs (NSAIDs), and cyclooxygenase (COX)-2 inhibitors, suppress the neoplastic process and, at the same time, decrease oxidative stress, oxidative DNA base damage, and prostaglandin and cytokine formation. They also decrease angiogenesis and up-regulate pathways leading to apoptosis. This has been shown to occur in both animal models and in humans.
Overall, Drs. Shacter and Weitzman present a compelling rationale well grounded in experimental facts that strongly support their main thesis that chronic inflammation unleashes a plethora of agents, such as cytokines, prostaglandins, chemotactic factors, reactive oxygen and nitrogen species (which cause the mutations in neighboring cells), as well as changes in gene expression favoring the activation of oncogenes and down-regulation of tumor suppression genes.
These factors also change the responses of cells to apoptosis signals and up-regulate angiogenesis factors as well as factors favoring the growth of tumor cells. Moreover, some of the same factors cause impairments in immune surveillance, which facilitates the escape of tumor cells from that surveillance and their clonal expansion. The association of activated phagocytic cells with a tumor mass contributes to changes in vascular permeability and systemic dissemination of metastatic cells.
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