Review series of the upper gastrointestinal tractInflammation and Barrett's carcinogenesis
Introduction
The assumption of a connection between cancer and inflammation is not new. Cancer was first linked to carcinogenesis by Virchow in 1863 [10], [181]. Epidemiological studies conducted over the last several years have shown that diseases characterized by inflammatory reactions in different organs predispose to cancer development. Up to 25% of human cancer diseases are considered to be inflammation-related [81]. Particularly, in the gastroenterological organs, a notably strong association between inflammation and carcinogenesis has been observed. Patients with chronic inflammatory bowel disease (IBD) have a high risk of developing colon cancer [86]. Chronic Helicobacter pylori gastritis is the most frequent and important causative factor for gastric cancer [21], [45]. Hepatitis B and C infections in the liver predispose to liver cancer [177]. Reflux esophagitis and Barrett's metaplasia are the prestages of esophageal adenocarcinoma (EA) [189].
Inflammation is the host response to tissue injury with a complex network of cellular reactions and chemical signals. Normally, it is self-limiting, but under certain conditions, it can take a prolonged course, and this may be a factor for paving the way to carcinogenesis [34]. The cellular and molecular pathways linking inflammation and cancer have increasingly been unraveled in the last several years. An accumulating number of molecular factors have emerged from these investigations as attractive targets for cancer therapy [65], while acetylation events can be of major importance [68]. In the first instance, inflammation can act as a classical tumor promoter, increasing cancer risk and promoting tumor progression [120]. In addition to promoting effects, increasing evidence suggests that chronic inflammation can also generate tumor-initiating DNA alterations [77], [123]. However, whether inflammation is causally linked to tumor initiation still needs to be clarified [65]. It is of particular importance that inflammation can trigger the production of reactive oxygen species (ROS) released preferentially by neutrophils and macrophages [107]. ROS are toxic to the DNA molecule, resulting in oxidized DNA-bases, the most important of which is 8-OHdG. Furthermore, in inflammation, mutagenic enzymes, such as activation-induced-cytidine-deaminase (AID), can be induced [122], [172]. Additionally, it has also been reported that inflammation can induce epigenetic alterations. Hahn et al. [69] showed that methylation of polycomb target genes is mediated by inflammation in intestinal cancer. Inflammation and hypoxia can result in epigenetic repression of DNA mismatch repair genes in IBD-associated colorectal cancer [42]. Inflammatory mediators can also down-regulate important factors in the DNA damage repair system [32]. For example, decreased levels of the hMLH1 protein were detected by immunohistochemistry in gastric epithelial cells in patients with H. pylori-induced gastritis [125]. In conclusion, the well-known fact that inflammatory diseases in different organs can promote cancer development has a molecular basis which is increasingly unraveled. The most important factors are ROS, cytokines, and chemokines. In view of the numerous molecular links between cancer and inflammation, it has been suggested that inflammation should be considered as the seventh hallmark of cancer [32], in addition to the well-known six hallmarks of cancer described by Hanahan and Weinberg [73].
Gastroesophageal reflux disease (GERD) and BE are the major risk factors for the development of EA. Both are associated with inflammation of the esophageal squamous epithelium, a condition called reflux esophagitis. Therefore, EA and Barrett's metaplasia are common in the context of inflammation as a result of acid and bile reflux (Fig. 1). Chronic inflammation leads to DNA damage and altered expression of genes involved in cellular proliferation and inhibition of apoptosis. Inflammatory key players in Barrett's carcinogenesis also include ROS, activation of kinase pathways and transcription factors (CDX2, NFκB), and production of cytokines and inflammatory enzymes (Fig. 1). The current review highlights the link between reflux-induced inflammation culminating in genetic and epigenetic alterations and Barrett's carcinogenesis. Genetic and epigenetic events affect the cell cycle and, therefore, the DNA damage checkpoints, and this leads to growth-sufficiency and ignoration of anti-growth signals, which are important hallmarks of cancers. In Barrett's carcinogenesis, the principle genetic and epigenetic alterations are comparable to those known from other epithelial malignancies: loss of p16 gene expression by deletion or hypermethylation (epigenetic silencing), loss of p53 expression by mutation and deletion, increase in Cyclin expression, and losses of Rb, APC, as well as various chromosomal loci.
Section snippets
Inflammation and genetic alterations in Barrett's carcinogenesis
It is not yet completely clear whether chronic inflammation alone suffices to initiate carcinogenesis [87]. Data collected over the last few years have shown that cancer-related inflammation can induce genetic alterations and genetic instability by inflammatory mediators with development of genetic alterations in cancer cells [32]. As has already been mentioned, ROS-mediated DNA damage is a critical factor for carcinogenesis [97]. The damage to the DNA molecule by ROS can result in altered
Inflammation and epigenetic alterations in Barrett's carcinogenesis
The fundamental role of epigenetics in cancer has long been established [16]. In addition to the initiation of DNA damage and genetic alterations, chronic inflammation is also considered an important factor for triggering epigenetic alterations [107]. Epigenetic alterations are early events in tumorigenesis and do not occur only in malignant tumors, but also in premalignant lesions. The most important epigenetic alterations in carcinogenesis are aberrant DNA methylation and histone
Pathogenetic factors triggering reflux esophagitis
Gastroesophageal reflux is a central pathogenetic factor for reflux esophagitis and Barrett's metaplasia. Esophagitis comprises a response of the organism induced by the reflux of bile acids leading to the release of inflammatory cytokines. Gillison et al. [61], [62] were the first to demonstrate that bile acid can cause reflux esophagitis. Furthermore, it could be shown that mixed reflux of gastric and duodenal juices are more harmful to the esophagus than gastric juice alone [96]. Reflux of
Reflux esophagitis and development of Barrett's metaplasia
From textbooks of general pathology, it is well known that metaplasia typically occurs in association with chronic inflammation [106]. Chronic inflammation can stimulate a high rate of cell turnover, which is also typical of Barrett's metaplasia. The high cell turnover can bring forward alterations in the pattern of gene expression by epithelial cells. In response to inflammatory mediators, the transcription factor CDX2 is induced via NFκB, thus playing a key role in the development of
Inflammatory cells and cytokines in Barrett's carcinogenesis
The stromal cells, including the recruitment of inflammatory cells as a consequence of reflux injury, are of major importance. Stromal–epithelial–luminal interactions may influence the behavior of the cells, acting in the development of Barrett's metaplasia and carcinogenesis [110]. The inflammatory cells in reflux esophagitis and BE were thoroughly analyzed by Fitzgerald et al. [53], [54]. According to their results, inflammation was maximal at the squamous–columnar junction with increase of
Role of inflammation-associated reactive oxygen and nitrogen species
Oxidative stress, particularly developed during inflammatory reactions, is defined as an imbalance between generation of ROS and decreased antioxidant defense systems. A central pathogenetic mechanism is seen in the ability of inflammatory cells, such as neutrophils and macrophages, to generate enzymes e.g. NADPH-oxidase, myeloperoxidase, and inducible nitric oxide synthase, resulting in increased amounts of ROS at the site of inflammatory damage [7], [8], [34], [81], [82], [186]. In
Role of DNA damage checkpoints
It is well known that cells – as a biological barrier – are provided with DNA damage checkpoints such as the G2/M DNA damage checkpoint to control cell cycle progression (Fig. 2). Firstly, the damage is recognized by sensors like ATM/ATR, and secondly, the signals are transmitted to mediators and transducers [146]. Once activated, Chk1 and Chk2 phosphorylate down-stream targets culminating in cell cycle arrest at the G1-S and G2-M transition [145]. Thus, overcoming cell cycle control via
MAPKs
It is known that ROS are stress signals for the cell, culminating in the activation of mitogen-activated protein kinases (MAPKs). Importantly, besides their activation of transcription factors triggering proliferation, MAPKs also play a role in cell cycle checkpoint control [146]. Souza et al. [168] described a second mechanism by which acid may stimulate the proliferative response in BE through activation of the MAPK pathway. Although the phosphorylated (activated) MAPKs ERK and JNK were found
Conclusions
Reflux esophagitis leading to Barrett's carcinogenesis is one of the most frequent, clinically important, and pathogenetically well-documented examples of a chronic inflammatory disease, contributing to tumor promotion, and with overwhelming evidence, also to tumor initiation. As the histological steps of Barrett's carcinogenesis have been defined very precisely, this disease can almost be considered as a model for describing the molecular pathogenetic steps of inflammation-associated cancer.
Acknowledgments
We thank Bernd Wuesthoff and Thomas Weber for their crucial suggestions regarding manuscript preparation. We apologize to colleagues whose work could only be cited indirectly.
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The antioxidant response in Barrett's tumorigenesis: A double-edged sword
2021, Redox BiologyCitation Excerpt :Subsequently, oxidative DNA damage levels (detected by 8-OHdG) and double strand DNA breaks (detected by γH2AX) were significantly increased after ABS exposure [22,25]. EAC is considered a model of oxidative stress and inflammation-driven cancer [29,30]. Chronic GERD induces chronic inflammation (esophagitis) that persists through the BE and EAC progression cascade.
Achalasia and associated esophageal cancer risk: What lessons can we learn from the molecular analysis of Barrett's–associated adenocarcinoma?
2019, Biochimica et Biophysica Acta - Reviews on CancerCitation Excerpt :Metaplasia can be accompanied by acute and chronic inflammation of the lower esophagus resulting in increased release of proinflammatory mediators [28]. Key mediators connecting inflammation and BE carcinogenesis include ROS, NFκB pathway activation, inflammatory cytokines, prostaglandins, and immune modulatory microRNAs [28]. For instance, IL-1β, a pleiotropic pro-inflammatory cytokine upstream of inflammatory IL-6 and TNF-α signaling cascades, is overexpressed in BE.