Oxidative stress in ulcerative colitis-associated carcinogenesis

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Abstract

Oxidative stress is defined as an imbalance between generation of reactive oxygen species (ROS) and decreased antioxidant defense systems. Oxidative stress develops particularly in inflammatory reactions because the inflammatory cells, neutrophils, and macrophages produce large amounts of ROS. It has been known for a long time that oxidative stress in inflamed tissue can pave the way for malignant tumors, and that it is a major pathogenetic factor for the well-established correlation between inflammatory diseases and cancer. Oxidative stress has long been associated with the pathogenesis of chronic inflammatory bowel disease (IBD)-related colorectal cancer. This article provides an overview of the pathology of ROS and presents recent advances concerning the role of ROS in IBD-related colorectal carcinogenesis (Fig. 1).

Section snippets

Basic principles of oxidative life

When life developed, the atmosphere of the planet was considerably different from the present atmosphere, as there was no oxygen in it. Therefore, the early organisms in evolution were anaerobic. In the course of evolution, cyanobacteria developed which are capable of photosynthesis. With the energy adopted by photosynthesis, they split water and reduce CO2 to carbohydrates. As a by-product of this reaction, they synthesize O2, which has accumulated in the atmosphere to the current atmospheric

Impact of ROS on DNA

Oxidation of DNA by ROS can result in damage to all four bases and to the deoxy-ribose-molecule. The DNA base products of interaction with ROS are manifold and comprise a great variety of modified DNA molecules, which need not be discussed at the chemical level in detail here in this context [5], [24]. One of the most abundant molecules which is a product of this oxidation is 8-oxo-7,8-dihydro-2,-deoxyguanosine (8-OH-dG). This molecule is of practical importance because it can easily be

Antioxidant defense mechanisms

Among the antioxidant defenses in the human body enzymes play a major role [52]. Superoxide dismutases (SOD) are the particularly important ones, i.e., the mitochondrial MnSOD and the largely cytosolic CuZnSOD. The SODs form a mutually supportive group of enzymes with peroxydases and catalases to provide a defense against different ROS [45], [57], [83], [85]. SODs can convert O2-radicals into O2 and H2O2. H2O2 is then further metabolized by the peroxidases and catalases. Of these, glutathione

Role of ROS in cell signaling

It has been known for a long time that bacteria respond to changes in the concentration of ROS in their environment with a precise signaling pathway and a corresponding pattern of gene expression [7]. The last few years have shown that ROS do not have only toxic effects in mammalian cells but also have an important role as signaling molecules, which regulate many genes. Among the ligands of ROS are inflammatory cytokines, growth factors coupled to receptor tyrosine kinases, and ligands

Sources of ROS in preneoplasias and tumors

It has been estimated that nearly 20% of the global human cancers are attributable to infective and inflammatory diseases [109]. The most important cancers with infection etiology are gastric cancer and Helicobacter pylori gastritis, hepatocellular carcinoma and chronic HBV or HCV infection of the liver or parasitic infection of the liver such as liver flukes, as well as parasitic infection by schistosoma haematobium and bladder cancer [65].

Inflammatory diseases with non-infective etiology have

Occurrence and etiology of inflammatory bowel disease

Ulcerative colitis (UC) and Crohn's disease (CD) are the two major types of IBD. They are characterized by a recurrent chronic inflammation in the bowel wall. Both UC and CD can pave the way for colorectal cancer. In the United States, about 30,000 new cases of IBD are reported each year [55]. The risk of developing colorectal cancer in UC is estimated as 2.5% after 20 years, 7.6% after 30 years, and 10.8% after 40 years [119]. In CD, the estimation of cancer risk has been controversial over

Conclusions

In the last few years, the molecular mechanisms of IBD-related carcinogenesis could well be established. Their hallmarks are as follows: inflammatory infiltration leading to increased production of ROS, impairment of antioxidant defenses resulting in oxidative stress following lipid peroxidation, DNA damage, and genetic and epigenetic alterations in the transforming epithelial cells, eventually resulting in colorectal cancer. The description of these molecular mechanisms has profoundly improved

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