Chronic Helicobacter pylori Infection and DNA-Damaged Stem Cells: A Recipe for Disaster
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EDITORIAL
Chronic Helicobacter pylori Infection and DNA-Damaged Stem Cells: A Recipe for Disaster Richard M. Peek Jr.
Published online: 31 October 2012 Ó Springer Science+Business Media New York 2012
Helicobacter pylori is the most common bacterial infection worldwide. Biological costs incurred by chronic colonization include increased risk for gastric adenocarcinoma [1]. Approximately 660,000 new cases of gastric cancer per year are attributable to H. pylori; eradication of this pathogen significantly decreases the risk of developing cancer in infected individuals. Nevertheless, only a small percentage of colonized persons develop neoplasia; enhanced risk is related to H. pylori strain differences, host responses governed by genetic diversity, and/or specific interactions between host and microbial determinants [2]. Universal test and treat strategies for H. pylori are not feasible due to the high prevalence of infection combined with the expense and side effects of antibiotic therapy [1]. These observations, in conjunction with evidence that carriage of certain strains is inversely related to esophageal adenocarcinoma and atopic diseases [1, 3], underscore the importance of identifying mechanisms that regulate interactions of H. pylori with its human host which promote carcinogenesis. One H. pylori strain-specific virulence locus that augments gastric cancer risk is the cag pathogenicity island, which encodes a type IV secretion system (TFSS) [4–6]. The product of the cagA gene (CagA) is translocated by the R. M. Peek Jr. Department of Medicine, Vanderbilt University, Nashville, TN, USA R. M. Peek Jr. Department of Cancer Biology, Vanderbilt University, Nashville, TN, USA R. M. Peek Jr. (&) Division of Gastroenterology, Vanderbilt University, 1030C MRB IV, 2215B Garland Avenue, Nashville, TN 37232-2279, USA e-mail: [email protected]
TFSS into epithelial cells, undergoing targeted tyrosine phosphorylation by Src and Abl kinases at motifs (termed A, B, or C/D) containing the amino acid sequence EPIYA [7–10]. Phosphorylated CagA activates a cellular phosphatase (SHP-2) and ERK mitogen-activating protein kinases (MAPK) leading to morphological aberrations that mirror changes induced by growth factor stimulation [11, 12]. Moreover, non-phosphorylated intracellular CagA can exert effects with carcinogenic potential including activation of ß-catenin [13, 14]. DNA damage resulting from inflammation-associated reactive oxygen and nitrogen species (RONS) also is contributory towards the development of pre-malignant lesions within H. pylori-infected gastric mucosa. Loss of a key enzyme, alkyladenine DNA glycosylase (AAG) that repairs DNA damage induced by RONS, augments the severity of atrophy and foveolar hyperplasia in the stomachs of mice challenged with H. pylori [15]. H. pylori can also directly induce DNA damage in gastric epithelial cells via activation of a pathway mediated by spermine oxidase (SMO). SMO catabolizes the formation of the polyamine spermine, which produces H2O2, leading to DNA damage [16].
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