We might design effective interventions to disrupt such a progression to invasive cancer by understanding the mechanisms of initiation and progression of gastric carcinogenesis and identifying the factors which influence and drive this process. It is likely that such a strongly causation-based prevention strategy may meet the expectations for an effective substantial reduction of cancer incidence.

Here, we discuss whether the background of chemoprevention allows hopes for the realization of the goal to combat gastric cancer.

(1) Magnitude of genetic and environmental contribution to gastric carcinogenesis

The proportion of contribution of environmental and genetic risk factors in the causation of cancer has been highly debated. Epidemiological studies of migrant population and in twins are the gold standards for distinguishing genetic from environmental traits. Recent large epidemiological studies overwhelmingly implicate a substantial and significant contribution of heritable effects in the causation of prostate, colon, and breast cancer, but a limited only (non-significant) contribution of inherited genetic factors in the causation of sporadic gastric cancer.[5,6] Environmental effects are the major causes for gastric cancer. This assessment is clinically important because identifying and eliminating the environmental exposures it would be possible to inhibit the progression to cancer. By contrast for cancers in which no environmental exposure has been identified to increase the risk of cancer development, as for example prostate cancer, such a prevention intervention with elimination of the environmental factor is not feasible.

(2) The role of Helicobacter pylori as an exogenous factor in gastric carcinogenesis

Worldwide, approximately 3 billion people (half of the world's population) are actually infected by Helicobacter pylori although there is now a declining prevalence in the developed world.[7] This inflammation of the stomach tissue will ultimately lead a small minority either to gastric or duodenal ulcer or to gastric neoplasia (gastric adenocarcinoma, gastric MALT lymphoma), but the majority of infected persons (>80%) will never develop a significant clinical disease in their lifetime. The paradox is that H. pylori-induced gastritis leads to duodenal ulcer, characterized by antral-predominant gastritis, high acid secretion and duodenal ulcer on one hand and to corpus-predominant gastritis, gastric atrophy and hypochlorhydria that increase gastric cancer risk to the other.[8] The reasons for this diverged clinical outcome as well as why high prevalence of H. pylori infection in Africa is not associated with high rates of gastric cancer have remained poorly understood. Two major theories have been reported for explaining this, that of H. pylori virulence factors and bacterial gene polymorphisms[9] and that of host genetic factors.[10] It is very likely that interactions of both result in a diverged outcome.

Although the World Health Organization and the International Agency for Research on Cancer classified H. pylori as a class I carcinogen in 1994[11] subsequent meta-analyses indicated a weak only relative risk (around 2) of noncardia cancer when a conventional IgG Elisa serology was used.[12] However, this weak relationship may be caused by misclassification of exposure. Most recently, a more accurate assessment of H. pylori infection status with CagA antibodies[13] or with all three methods i.e., histology, serology and rapid urease test[14] or serology many years before tumor detection[15] indicate a much stronger relationship between H. pylori and gastric cancer. This odds ratio (OR) roses from 2.2 (95% confidence interval (CI) 1.4-3.6) using IgG ELISA only, to 21.0 (95% CI, 8.3-53.4) using CagA+ technique.[13] In the study by Uemura at al.[14] gastric cancer was not developed among uninfected subjects. Estimates based on the revised excess risk, if it is true, indicate that even in the general population of low-risk Western world (Sweden), about 70%[13] of noncardia cancers are attributable to H. pylori and thus preventable. In high-risk countries, as for example Japan,[14] this preventable H. pylori-attributable gastric cancer risk is probably even higher. Based on these current findings, some investigators[16] support that the association between H. pylori infection and gastric cancer ranks with the association between smoking and lung cancer.

(3) Gene-environment interactions

Cancer genetics has been focused for many years on mutational events that have their primary effect within the cancer cell. Recently that focus has widened, with evidence of the importance of epigenetic events that lie outside the cancer cell, suggesting new targets for interventions.[17]H. pylori-attributable gastric carcinogenesis is a superb model of gene-environment interaction. Individuals with proinflammatory high interleukin-1b production (polymorphisms in IL-1b genes) and infected by the bacterium are at significantly higher risk (OR 7.5 [95% CI, 1.8-31] of developing hypochlorhydria and gastric atrophy, and also gastric cancer but in a weaker relationship (OR 1.6 [95% CI 1.2-2.2]).[18] In addition to the IL-1b gene, El-Omar et al. have recently confirmed a positive but weaker role of polymorphisms in the TNF-a gene that correlates with high tumor necrosis factor (TNF)-a levels.[10] It is very likely that several other polymorphic genes, encoding proinflammatory and anti-inflammatory mediators, will also contribute to the host genetic constitution that determines the outcome to H. pylori infection and risk of gastric cancer. A proinflammatory host genetic makeup therefore facilitates the development of a hypochlorhydric, atrophic phenotype that increases the risk of gastric cancer.[19] However not everyone infected by H. pylori and with such a genetic makeup develops gastric cancer indicating that, as El-Omar[18] points out, many other still unidentified host genetic and environmental factors determine the progression of atrophy to invasive cancer. Indeed, as gene-environment interactions are intrinsic to the mode of action of low-penetrant genes[17, 19-21] is highly possible that, as for example the mode smoking-lung cancer, a large number of low-penetrant genes is also involved in gastric carcinogenesis. The search of such a large number of low-penetrant genes is difficult but may be facilitated by the recent completion of human genome project and the use of microarray technology. This technology has already started to be applied in the investigation of both H. pylori[22] and host[23] gene-expression profiling of gastric cancer.

(4) Identification of environmental exposures

H. pylori infection causing transformation of normal mucosa through superficial gastritis to gastric atrophy and intestinal metaplasia is undoubtedly the initial step in gastric carcinogenesis. However, the factors which drive the dynamic of regression or progression to invasive cancer and the mechanisms by which this occurs once these premalignant lesions (atrophy, intestinal metaplasia) have been established are still to be determined and elucidated. Therefore, whether or not the available chemoprevention interventions are able to inhibit progression to cancer in persons with established atrophy, intestinal metaplasia or dysplasia is highly debated. It is suggested that still unidentified host genetic factors,[10] bacterial gene polymorphisms[9] and environmental exposures, such as infection, diet and lifestyle, interact in a complex fashion that determines the dynamic of regression or progression over a decades-long period of time. Several studies have recently been focused on the identification of environmental risk factors suggesting that H. pylori infection, low levels of dietary antioxidants (vitamin C), and cigarette smoking may enhance the progression of premalignant lesions to dysplasia and gastric cancer.[2]

Taken into account the little progress that has been made over the last decades in the multimodality treatment of gastric cancer it is time to rethink and probably change the current management towards more effective strategies.[24] The data reported provide evidence that chemoprevention curing H. pylori-infection at initial stage of carcinogenesis (H. pylori superficial gastritis) may be effective by disrupting further progression to atrophic gastritis and/or intestinal metaplasia. However, much more research is needed to improve our understanding of the underlying biological mechanisms that drive the progression of these pre-malignant lesions to invasive cancer. This is the scientific way to develop target molecular drugs that will provide a highly effective reduction of gastric cancer incidence due chemoprevention.

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