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Chronic gastritis induced by Helicobacter pylori (H. pylori) is the strongest known risk factor for adenocarcinoma of the distal stomach, yet the effects of bacterial eradication on carcinogenesis remain unclear. H. pylori isolates possess substantial genotypic diversity, which engenders differential host inflammatory responses that influence clinical outcome. H. pylori strains that possess the cag pathogenicity island and secrete a functional cytotoxin induce more severe gastric injury and further augment the risk for developing distal gastric cancer. Carcinogenesis is also influenced by host genetic diversity, particularly involving immune response genes such as interleukin-1ß and tumor necrosis factor-α. Human trials and anima studies have indicated that eradication of H. pylori prior to the development of atrophic gastritis offers the best chance for prevention of gastric cancer. However, although the timing of intervention influences the magnitude of suppression of premalignant and neoplastic lesions, bacterial eradication, even in longstanding infections, is of clear benefit to the host. It is important to gain insight into the pathogenesis of H. pylori-induced gastritis and adenocarcinoma not only to develop more effective treatments for gastric cancer, but also because it might serve as a paradigm for the role of chronic inflammation in the genesis of other malignancies that arise within the gastrointestinal tract.
The gastrointestinal tract is a dynamic interactive barrier that normally segregates microbial populations from their cognate human hosts. An aberrant consequence of contact between microbes and gut epithelial cells is the development of mucosal inflammation, which, if allowed to become persistent, can initiate carcinogenic pathways. Microbial species participate in the genesis of a substantial number of malignancies worldwide, and conservative estimates indicate that at least 15% of all cancer cases are attributable to infectious agents, translating to a neoplastic burden of 41 million cases/year [Coussens and Werb, 2002].
Gastric adenocarcinoma is the second leading cause of cancer-related death in the world [Beswick et al. 2006; Ernst et al. 2006; Moss and Blaser, 2005; Blanchard et al. 2004; Correa, 2004; Peek, Jr and Blaser, 2002]. Approximately 750,000 persons die annually from this malignancy with an estimated 900,000 new diagnoses each year, and 5-year survival rates in the United States are 515% [Lochhead and El-Omar, 2007; Correa, 2004]. Two histologically distinct variants of gastric adenocarcinoma have been described. Diffuse-type gastric cancer consists of individually infiltrating neoplastic cells that do not form glandular structures. Intestinal-type gastric adenocarcinoma was first identified nearly a century ago and progresses through a well-defined series of histologic steps initiated by the transition from normal mucosa to chronic superficial gastritis, which then leads to atrophic gastritis and intestinal metaplasia, and finally to dysplasia and adenocarcinoma (Fig. 1) [Correa and Houghton, 2007; Peek, Jr and Blaser, 2002; Sipponen and Marshall, 2000; Correa, 1996]. The rate of progression across this cascade exceeds the rate of spontaneous regression [Correa and Houghton, 2007], and in one study, the rate of progression from nonatrophic gastritis to gastric atrophy was 7.5 per 100 person-years, while the rate of progression from atrophy to intestinal metaplasia was 6.7 per 100 person-years [Correa et al. 1990]. A recent study extended these results by quantifying gastric cancer risk among a large population of patients residing in the Netherlands who had premalignant lesions. In this population, the annual incidence of gastric cancer was 0.1% for patients with atrophy, 0.25% for patients with intestinal metaplasia, 0.6% for persons with mild to moderate dysplasia, and 6% for persons with severe dysplasia within five years after diagnosis [de Vries et al. 2008]. Thus, the natural history of premalignant lesions in this cascade is one of steady progression, the tempo of which varies among different individuals.
Helicobacter pylori (H. pylori) are Gram-negative bacteria that selectively colonize gastricepithelium and represent the most common bacterial infection worldwide [Peek, Jr and Crabtree, 2006; Moss and Sood, 2003]. Compelling evidence indicates that H. pylori has colonized human stomachs for >58,000 years, at least since the Paleolithic era [Linz et al. 2007]. Virtually all persons infected by this organism develop co-existing gastritis, asignature feature of which is the capacity to persist for decades. However, there are biological costs to these long-term relationships.
Epidemiological studies in humans and experimental infections in rodents have clearly demonstrated that sustained interactions between H. pylori and its host significantly increase the risk for atrophic gastritis, intestinal metaplasia, and distal gastric adenocarcinoma, and colonization by H. pylori is the strongest identified risk factor for malignancies that arise within the stomach [Peek, Jr and Crabtree, 2006; Peek, Jr and Blaser, 2002; Uemura et al. 2001, Barreto-Zuniga et al. 1997; Miehlke et al. 1997; Siman et al. 1997; Watanabe et al. 1997, 2001; Correa 1996, Kokkola et al. 1996; Kikuchi et al. 1995; Hu et al. 1994; Hansson et al. 1993; Sipponen et al., 1992; Peterson 1991; Parsonnet et al. 1991; Nomura et al. 1991; Karnes, Jr et al. 1991; Forman et al. 1991]. Based on these data, the World Health Organization has classified H. pylori as a class I carcinogen for gastric cancer, and since virtually all infected persons have superficial gastritis, it is likely that the organism plays a causative role early in this progression (Figure 1). However, only a fraction of colonized persons ever develop neoplasia, and disease risk involves specific and well-choreographed interactions between pathogen and host, which, in turn, are dependent upon strain-specific bacterial factors and/or host characteristics. These observations, in conjunction with evidence that carriage of certain H. pylori strains is inversely related to the prevalence of Barrett's esophagus, esophageal adenocarcinoma, and asthma [Chen and Blaser, 2007; Blaser and Kirschner, 2007; Vaezi et al. 2000; Loffeld et al. 2000; Vicari et al. 1998; Chow et al. 1998], underscore the importance of defining mechanisms that regulate the interactions of these organisms with their hosts that promote carcinogenesis. These studies will ultimately enable physicians to appropriately focus diagnostic testing and eradication therapy on targeted high-risk populations to potentially prevent the development of gastric cancer [Czinn, 2005]. However, the effect of eliminating H. pylori on gastric cancer risk remains unclear.
H. pylori strains isolated from different individuals are extremely diverse and genetically unique derivatives of a single strain are present simultaneously within an individual human host [Israel et al. 2001a,b]. One microbial determinant that augments disease risk is the cag pathogenicity island, which is present in ^60% of strains harvested from the United States. Although all H. pylori strains induce gastritis, cag+ strains significantly increase the risk for severe gastritis, peptic ulceration, and distal gastric cancer compared to strains that lack the cag island [Vorobjova et al. 1998; Torres et al. 1998; Shimoyama et al. 1998; Queiroz et al. 1998; Rudi et al. 1997; Parsonnet et al. 1997; Peek Jr et al. 1995a,b; Kuipers et al. 1995; Blaser et al. 1995; Crabtree et al. 1991, 1993; Cover et al. 1990].
Elements encoded by the H. pylori cag island alter signaling pathways in gastric epithelial cells. Several cag genes encode products that bear homology to components of a type IV bacterial secretion system which functions as a molecular syringe to export proteins, and the product of the terminal gene in the island (CagA) is translocated into host epithelial cells after bacterial attachment (Figure 2). Following its injection into epithelial cells by the cag secretion system, CagA undergoes tyrosine phosphorylation by Src and Abl kinases [Tammer et al. 2007; Selbach et al. 2002; Stein et al. 2000; Odenbreit et al. 2000; Backert et al. 2000; Asahi et al. 2000; Segal et al. 1999]. Phospho-CagA subsequently activates a eukaryotic phosphatase (SHP-2) as well as ERK, a member of the mitogenactivated protein kinase (MAPK) family, leading to morphological changes (e.g., cell scattering) that are reminiscent of unrestrained stimulation by growth factors [Higashi et al. 2002a,b; Selbach et al. 2002; Asahi et al. 2000; Backert et al. 2000; Odenbreit et al. 2000; Stein et al. 2000, 2002; Segal et al. 1999].
Nonphosphorylated CagA also exerts effects within host cells that contribute to pathogenesis. Translocation, but not phosphorylation, of CagA leads to aberrant activation of b-catenin, disruption of apical-junctional complexes, and a loss of polarity [Saadat et al. 2007; Murata-Kamiya et al. 2007; Suzuki et al. 2005; Franco et al. 2005; Bagnoli et al. 2005; Amieva et al. 2003], cellular alterations that play a role in carcinogenesis [Utech et al. 2006]. Two recent studies have more firmly implicated CagA as a bacterial oncoprotein by demonstrating that CagA can inhibit apoptosis, thereby promoting cell survival within an inflammatory milieu, and that transgenic expression of CagA per se in mice leads to the development of aberrant gastric epithelial proliferation and gastric adenocarcinoma [Ohnishi et al. 2008; Mimuro et al. 2007]. Inactivation of cagA and/or other genes within the cag locus also attenuates the development of inflammation and cancer in rodent models of H. pylori-induced injury [Franco et al. 2008; Fox et al. 2003a,b; Israel et al. 2001a,b; Ogura et al. 2000]. Collectively, these data indicate that cag+ strains are disproportionately represented among hosts who develop serious sequelae of H. pylori infection and that contact between cag+ strains and gastric epithelial cells in vitro activates multiple signaling pathways that regulate cellular responses, which may heighten the risk for transformation.
Another H. pylori locus linked with disease is vacA, which encodes a secreted bacterial toxin (VacA). Unlike the cag island, vacA is present in virtually all H. pylori strains; however, strains vary in cytotoxin activity due to variations in vacA gene structure. The regions of greatest diversity are localized near the 5’ end of vacA (allele types s1a, s1b, s1c, or s2), the mid-region of vacA (allele types m1 or m2), or the intermediate region (allele types i1 or i2) [Rhead et al. 2007; Atherton et al. 1995]. H. pylori strains that possess s1/m1/i1 vacA alleles are associated with an increased risk of gastric cancer compared to vacA s2/m2/i2 strains [Rhead et al. 2007]. Similar to the molecules encoded by the cag island, VacA exerts effects on epithelial cells that may lower the threshold for carcinogenesis. Inoculation of mice with purified VacA leads to epithelial injury, and when added to polarized epithelial cell monolayers, VacA increases paracellular permeability to organic molecules, iron, and nickel. VacA has also been shown to actively suppress T-cell proliferation and activation in vitro [Sundrud et al. 2004; Gebert et al. 2003], which may contribute to the longevity of H. pylori colonization.
in vivo, ~20% of H. pylori bind to gastric epithelial cells. Several different host receptors for H. pylori have been identified that regulate the intensity of gastritis, including decay accelerating factor (DAF) [O'Brien et al. 2006]. Sequence analysis of the genomes from the completely sequenced H. pylori strains 26695, J99, and HPAG1 has revealed that an unusually high proportion of identified open reading frames are predicted to encode outer membrane proteins (OMPs). OMPs function as adhesins and permit H. pylori to engage in a range of interactions with host cells, some of which play a role in pathogenesis. The H. pylori adhesin SabA binds sialyl-Lewisx, an established host tumor antigen and marker of gastric dysplasia [Mahdavi et al. 2002]. H. pylori-induced inflammation induces the expression of sialyl-Lewisx on epithelial cells, which amplifies interactions between this molecule and SabA. BabA, encoded by babA2, binds the Lewis (Le) antigen on gastric epithelial cells [Ilver et al. 1998] and carriage of H. pylori strains that possess babA2 increases the risk for gastric cancer. The presence of babA2 is associated with cagA and vacA s1 alleles and strains that possess all three of these genes incur the highest risk for gastric cancer [Gerhard et al. 1999].
Although H. pylori components clearly influence disease risk, they are not absolute determinants of carcinogenesis, which has highlighted the need to identify host factors that also contribute to the development of gastric cancer (Table 1). Polymorphisms within the human IL-1 ß gene promoter that are associated with increased expression of IL-1ß (a pro-inflammatory cytokine with potent acid-suppressive properties), heighten the risk for gastric adenocarcinoma [El-Omar et al. 2000]. These relationships are only present among H. pylori-colonized persons, emphasizing the importance of host-environment interactions and inflammation in the progression to gastric cancer. High-expression tumor necrosis factor (TNF)-a polymorphisms as well as polymorphisms that reduce the production of anti-inflammatory cytokines, such as IL-10, also increase the risk for gastric cancer [El-Omar et al. 2003]. The combinatorial effect of these polymorphisms on cancer risk is synergistic, such that three polymorphisms increase the risk of cancer 27-fold over baseline [El-Omar et al. 2003]. Studies have identified the —251 site within the promoter region encoding the pro-inflammatory cytokine IL-8 as being significantly associated with gastric cancer [Fox and Wang, 2007; Taguchi et al. 2005]. Polymorphisms in pattern recognition receptors such as Toll-like receptor (TLR)-4 have also been linked with an enhanced susceptibility to H. pylori-induced gastric cancer [Hold et al. 2007]. Among persons harboring high-risk genetic polymorphisms, such as high-expression IL-1ß alleles, who are also colonized by cag+ or toxigenic strains, the relative risks for gastric cancer are further augmented to 25- and 87-fold over baseline, respectively [Figueiredo et al. 2002], indicating that interactions between specific host and microbial determinants are biologically significant for the development of gastric cancer. In total, these observations indicate that individuals with a pro-inflammatory genotype respond to the presence of H. pylori by developing more severe inflammation and hypochlorhydria [Lochhead and El-Omar, 2007].
The risk of gastric carcinoma is also influenced by environmental factors exogenous of H. pylori infection. One environmental factor uniformly associated with an increased risk of gastric cancer is high dietary salt intake [Correa, 1992]. This association has been detected in prospective studies, case-control studies, and in a study that compared urinary salt excretion with gastric morbidity rates [Kim et al. 2004; Lee et al. 2003; Joossens et al. 1996]. A prospective study of a Japanese population [Shikata et al. 2006] and a case–control study in Korea [Lee et al. 2003] each reported that H. pylori-infected subjects consuming a high-salt diet had an increased risk of gastric cancer when compared to H. pylori-infected subjects who consumed lower levels of salt. Another study reported a positive correlation between the prevalence of H. pylori infection and the levels of dietary salt intake [Beevers et al. 2004]. Exciting new data have now indicated that salt may augment the ability of H. pylori to induce epithelial cell responses with carcinogenic potential. Loh et al.  demonstrated an important role for salt in the regulation of CagA expression and in the regulation of the effects of CagA on gastric epithelial cells. In rodent models of H. pylori infection, high-salt diets similarly enhance the ability of H. pylori to induce gastric carcinogenesis, indicating that H. pylori infection and salt act synergistically to augment the risk for gastric cancer [Tatematsu et al. 2007].
Animal models are useful in that they represent tractable systems that permit insights into the effects of host, pathogen, and environmental factors on gastric carcinogenesis [Rogers and Fox, 2004]. H. pylori infection of Mongolian gerbils can lead to gastric adenocarcinoma, without the co-administration of carcinogens [Franco et al. 2008; Franco et al. 2005; Zheng et al. 2004; Ogura et al. 2000; Honda et al. 1998; Watanabe et al. 1998], and gastric cancer in this model occurs in the distal stomach, as in humans. Thus, Mongolian gerbils have been used to evaluate the effects of interventional therapy against H. pylori on host responses with carcinogenic potential. Cao et al.  reported that antimicrobial therapy induces apoptosis and inhibits proliferation in H. pylori-infected gerbil gastric mucosa. However, the effect of H. pylori eradication on premalignant (e.g., dysplasia) and malignant lesions was not examined. Treatment of H. pylori in gerbils has been reported to decrease tumor formation; however, this required co-administration of both H. pylori and N-methyl-N-nitrosourea to induce tumors [Nozaki et al. 2003], which does not completely reflect gastric carcinogenesis that develops in humans infected with H. pylori alone.
Recently, our laboratory infected Mongolian gerbils with a cancer-inducing strain of H. pylori to more precisely define the role of targeted anti-microbial therapy in gastric carcinogenesis [Romero-Gallo et al. 2008]. Gerbils were infected with H. pylori for four or eight weeks, treated with anti-microbial agents or control, and then euthanized eight weeks following completion of therapy. All infected gerbils developed gastritis and, as expected, inflammation was significantly attenuated in animals receiving anti-microbial therapy. Gastric dysplasia or cancer developed in 460% of gerbils that remained persistently colonized with H. pylori, but in none of the animals treated with antibiotics following four weeks of infection [Romero-Gallo et al. 2008]. Of interest, infection with H. pylori for eight weeks prior to antibiotic therapy resulted in an attenuation, but not complete prevention, of pre-malignant and malignant lesions, indicating that the effectiveness of eradication is dependent upon the timing of intervention.
An advantage of the gerbil model of carcinogenesis is that gastric carcinoma develops following infection with H. pylori per se, and occurs within a time-frame sufficient to rigorously evaluate endpoints following interventions. However, there are limitations to using this model. Mongolian gerbils are outbred, which increases the variability of responses to any stimulus. Further, the ability to utilize inbred mice with defined genotypes as well as transgenic lines allows a more detailed analysis of host susceptibility to H. pylori virulence determinants. Therefore, investigators have also utilized murine models of H. pylori infection to examine the efficacy of therapy on the development of gastric cancer.
Transgenic mice that over-express gastrin (INS-GAS mice) spontaneously develop gastric cancer, but this requires the virtual lifetime of the animal [Wang et al. 2000]. Concomitant infection with H. pylori or a related Helicobacter species, H. felis, accelerates this process, suggesting that persistently elevated gastrin levels synergize with Helicobacter to augment cancer progression [Fox et al. 2003a,b; Wang et al. 2000]. H. felis has also been used to induce gastric adenocarcinoma in wild-type C57/BL6 mice, with virtually all colonized mice developing carcinoma by 15 months of infection [Cai et al. 2005]. An advantage of this model is that carcinoma parallels the histologic sequence seen in human intestinal-type gastric cancer. Cai et al.  utilized this model to demonstrate that targeted anti-microbial therapy can reverse inflammation, metaplasia, and dysplasia in H. felis-infected C57/ Bl6 mice if delivered within six months of infection. Eradication therapy given at later timepoints when more severe grades of metaplasia and dysplasia were present resulted in partial reversion of these lesions, and the incidence of cancer-related gastric outlet obstruction and death was also decreased [Cai et al. 2005]. These results indicate that although the timing of intervention influences the magnitude of suppression of premalignant and neoplastic lesions, bacterial eradication, even in longstanding Helicobacter infection, is of clear benefit to the host [Correa and Houghton, 2007].
The decades-long process of gastric carcinogenesis lends itself to prevention trials that can evaluate the effects of removing an etiologic agent on disease progression. However, studies focused on the consequences of H. pylori eradication in human populations have yielded mixed results. Nonrandomized trials have clearly established the importance of H. pylori as an etiologic factor in the development of gastric cancer. Of interest, one of the first clinical trials to suggest a benefit of H. pylori eradication for gastric cancer was a case control study from Sweden in which rates of gastric cancer were significantly reduced in patients undergoing hip replacement who had received high-dose prophylactic antibiotics [Akre et al. 2000]. Uemura et al.  reported on a cohort of 1526 Japanese patients followed over 7.8 years. Gastric cancer did not develop in any patients who were uninfected or who were infected and subsequently treated with antibiotics. In contrast, 36 (2.9%) new cases of gastric cancer developed among 971 H. pylori-infected subjects with gastritis alone, gastric ulceration, or hyperplastic gastric polyps [Uemura et al. 2001]. Another nonrandomized study from Japan reported that among 1233 patients followed for 7.7 years, 1% of subjects in whom H. pylori was eradicated developed cancer compared to 4% of persons who remained persistently colonized [Correa and Houghton, 2007]. In an eight-year follow-up study performed in China that included 41000 subjects, the presence of H. pylori was associated with a four-fold increase in the incidence of gastric cancer (1.6% vs. 0.4% in uninfected persons) [Zhou et al. 2005]. Similarly, treatment of H. pylori following endoscopic resection of early gastric cancers resulted in a significant reduction in the incidence of metachronous lesions compared to persons who remain persistently infected post-resection [Uemura et al. 1997].
Randomized trials to evaluate the effect of H. pylori eradication on gastric cancer incidence are more limited in number. Wong et al.  investigated the effects of anti-H. pylori therapy in a randomized controlled trial focused on a population of infected subjects residing in China. Among 4800 persons who received antibiotics, seven new cases of gastric cancer developed over a mean follow-up period of 7.5 years, compared to eleven new cases that developed in placebo-treated persons and who, therefore, remained persistently infected [Wong et al. 2004]. Although these differences were not statistically significant, a secondary analysis revealed that treatment of H. pylori was effective in preventing gastric cancer in persons who lacked premalignant lesions (e.g., gastric atrophy, intestinal metaplasia and dysplasia). In that analysis, six new cases of gastric cancer developed in persons without premalignant lesions who remained persistently infected versus no new cases in H. pylori-infected persons with gastritis only who received antibiotics (Figure 3) [Wong et al. 2004]. These results reflect data from animal studies emphasizing the importance of timing of intervention. In another large, randomized controlled trial, You et al.  reported that the combined incidence of atrophy, intestinal metaplasia, dysplasia, and cancer were reduced following treatment directed against H. pylori, but when the incidence of gastric cancer was analyzed separately, there was no significant benefit for eradication therapy. Another study performed in Japan followed 1120 subjects with peptic ulcer disease who received H. pylori eradication therapy. Over a mean follow-up period of 3.4 years, eight cases of gastric cancer were diagnosed among 944 patients in whom H. pylori was successfully eradicated versus four new cancers in 176 subjects who failed eradication (p ¼ 0.04) [Take et al. 2005].
A limitation of these studies is that the mean follow-up period following intervention ranged from four to eight years. Gastric cancer usually only develops after decades of H. pylori-induced injury and it is unlikely that treatment of this infection will translate into perceptible risk reductions within a shorter time frame. Additional trials have, therefore, focused specifically on gastric cancer precursor lesions. Sung et al.  treated H. pylori-infected subjects with antibiotics or placebo and found that, at one year, the activity of intestinal metaplasia was decreased in the antrum; however, there was no significant regression of intestinal metaplasia or atrophy at this time-point [Sung et al. 2000]. Four years after intervention, however, there was a significant regression of antral intestinal metaplasia in persons who received antimicrobial agents directed against H. pylori [Zhou et al. 2003]. Correa and colleagues reported the results of an intervention trial in Colombia in which H. pylori treatment resulted in a significant increase in the regression rate of gastric atrophy (relative risk 8.7) and intestinal metaplasia (relative risk 5.4) over a period of 72 months [Correa et al. 2000]. Another randomized, double-blind, placebo-controlled trial reported the potential for improvement in the severity of intestinal metaplasia, but improvement was primarily restricted to persons with less-advanced lesions [Ley et al. 2004].
A recently completed chemoprevention trial in Colombia demonstrated that earlier interventions against H. pylori led to more effective reductions in the severity of premalignant lesions compared with later interventions [Mera et al. 2005]. During the first three years following eradication therapy, there were no significant differences noted in the severity of premalignant lesions between treated and untreated patients. At six years of follow-up, histologic scores were significantly lower among treated patients, but the differences were less than the expected 50% reduction identified at twelve years post-intervention. These findings indicate that the prevention process, similar to gastric carcinogenesis itself, follows an exponential curve in which the first years of exposure (or lack thereof) have minimal measurable effects on markers of progression, but this is followed by greater effects in subsequent years [Peek Jr et al. 2006]. Therefore, on the basis of existing data, the effects of chemoprevention for gastric cancer can only truly be evaluated following at least four years from the initial intervention.
Decision analyses have indicated that a strategy which couples H. pylori screening and treatment of infected persons would be cost effective if H. pylori eradication reduced the risk of gastric cancer by 430% [Fox and Wang, 2007; Parsonnet et al. 1996]. However, an unambiguous recommendation regarding treatment of H. pylori for prevention of gastric cancer cannot be forged from data that are currently available, and strategies will undoubtedly evolve as new knowledge emerges. Physicians should only attempt to diagnose H. pylori if they are unequivocally committed to treating the infection. Eradication before gastric atrophy develops offers the best chance of achieving a meaningful reduction in the risk of gastric cancer (Figure 1). However, of the approximately one-half of the world's population that is infected with H. pylori, only 1–3% will ever develop cancer. Side effects associated with eradication therapy, including the development of antibiotic resistant strains, also preclude a global test and treat strategy. Thus, techniques to identify subpopulations at high risk for disease appear to be most optimal at this time but must utilize other biological markers than simply detection of H. pylori per se.
It is apparent that gastric cancer risk is the summation of the polymorphic nature of the bacterial population in the host, the host genotype, and environmental exposures, each affecting the level of long-term interactions between H. pylori and humans. Analytical tools now exist, however, including genome sequences (H. pylori and human), measurable phenotypes (CagA phosphorylation), and practical animal models, to discern the fundamental biological basis of H. pylori-associated neoplasia, which should have direct clinical applications. For example, identification of persons with polymorphisms associated with high levels of IL-1b expression who are colonized by cag+ strains may be most likely to derive benefit from H. pylori eradication as such treatment could result in a substantially reduced cancer risk. It is important to gain more insight into the pathogenesis of H. pylori-induced gastric adenocarcinoma, not only to develop more effective treatments for this cancer, but also because it might serve as a paradigm for the role of chronic inflammation in the genesis of other malignancies.
Supported in part by National Institutes of Health grants DK58587, DK73902, and CA77955.