pylorigenome have been identified including the so-called plasticity zone and cytotoxin associated gene (cag) pathogenicity island. exceedingly prevalent in most of the developing world, and is the second leading cause of cancer-related death worldwide [1]. Most gastric cancers are still detected at an advanced stage. Consequently, the prognosis of this disease remains very poor, even after extensive surgery and adjuvant therapy [2]. Gastric MALT lymphoma is considerably less common than gastric carcinoma, accounting for 3% of all gastric tumors [3]. Both gastric carcinomas and MALT lymphomas have long been recognized to occur on a background of chronic gastric inflammation. For the past two decades it has been evident that the usual cause of this gastritis is persistent infection by the gram-negative micro-aerophilic bacteriumHelicobacter pylori(H. pylori). Approximately 70% of MCL-1/BCL-2-IN-4 all gastric cancer cases worldwide are directly attributable to priorH. pyloriinfection [4], as are the majority of gastric MALT lymphomas [3]. Currently, about half of the worlds population is infected byH. pylori,with rates in the developed world in the order of 70% [5]. Gastric colonization byH. pyloriis usually asymptomatic and although about 20% of the infected population progress to some extent down the Correa pathway of pre-neoplastic changes over several decades, gastric neoplasms develop in fewer than 2% [6]. Gastric lymphoma is an even rarer consequence ofH. pyloriinfection, occurring in fewer than 1% of those who are infected. However, based upon the available epidemiological evidence, the World Health Organizations International Agency for Research on Cancer classifiedH. Rabbit polyclonal to CD59 pylorias a group I or definite carcinogen (the only bacterium to be thus classified) in 1994 [7]. Since that time evidence linkingH. pylorito gastric cancer has continued to accumulate and strengthen. Numerous epidemiological, animal and experimental studies support a positive association between chronicH. pyloriinfection and the development of distal gastric cancer and gastric MALT lymphoma. However, the molecular cellular events responsible for the promotion of these gastric malignancies byH. pyloriremain poorly defined. Current evidence suggests that the bacterium itself has carcinogenic effects and that the inflammatory response toH. pylori, which is highly variable, can contribute to lowering the threshold for gastric cancer development. Among the molecular mechanisms that are thought to be important inH. pylori-induced gastric carcinogenesis are the induction of oxidative and nitrosative stress with consequent cellular and DNA damage followed by cycles of repair. Ultimately, as antioxidant defenses and damage- repair responses are overwhelmed and depleted, genetic errors that arise under the pressure of accelerated gastric epithelial turnover may accumulate to the point at which neoplastic transformation is inevitable. Many of these events occurring in the chronically inflamed gastric mucosa are common to other inflammation-associated MCL-1/BCL-2-IN-4 malignancies, while some are unique MCL-1/BCL-2-IN-4 toH. pyloriinfection [8]. In this review we shall discussHelicobacter pylorias an agent in gastric carcinogenesis and consider the mechanisms responsible for its pathogenesis. == 2. Helicobacter pylori == == 2.1 Biology, heterogeneity and niche == Helicobacter pylori(H. pylori) is a gram-negative spiral-shaped bacterium. Usually acquired in infancy, this bacterium induces chronic gastric inflammation persisting for the life of its host [5]. Spontaneous loss ofH. pylorifrom the stomach is rare unless the gastric MCL-1/BCL-2-IN-4 mucosa has become hostile to continued colonization, as may happen during extensive intestinal metaplasia of the gastric epithelium. BecauseH. pyloridoes not adhere well to intestinal mucosal cells, the evidence linkingH. pyloriinfection with intestinal-type gastric cancer may not be apparent when intestinal metaplasia dominates gastric topography. For the same reasons, serum antibody levels againstH. pyloriantigens decline during progression to gastric cancer. Thus, the role ofH. pyloriin gastric carcinogenesis was initially underappreciated since early studies of gastric cancer relied on the detection ofH. pyloriexposure by histological analysis of resection specimens or simultaneous serology. H. pyloriadheres to surface epithelial cells of the stomach; however, it may also colonize the proximal duodenum (or rarely the esophagus) when there is gastric metaplasia in those sites. Rare colonization of the gastric metaplasia of a Meckels diverticulum or in the rectum has also been described [9]. ThoughH. pyloriis predominantly extracellular,H. pylorihas been occasionally described in an intracellular location within gastric epithelial cells, particularly in cancers [10]. It has been postulated that the intracellular location ofH. pylorimay facilitate persistence and the MCL-1/BCL-2-IN-4 acquisition of resistance to antibiotics [11]. H. pyloripossesses several mechanisms to survive and persist in the gastric lumen. For example, it utilizes its highly active urease enzyme to buffer a gastric environment of pH1-2 [12] and survival is facilitated by its helical morphology and unipolar flagella enabling movement within the gastric mucous layer overlaying gastric epithelial cells [13]. Coccoidal forms ofH. pylorimorphology have also been observedin vivoafter antibiotic treatment andin vitroas bacterial cultures age, but it is not clear whether these coccoidal forms are viable and therefore retain.