Published online Apr 15, 1998. doi: 10.3748/wjg.v4.i2.93
Revised: March 20, 1998
Accepted: March 27, 1998
Published online: April 15, 1998
- Citation: Xia HHX. Association between Helicobacter pylori and gastric cancer: current knowledge and future research. World J Gastroenterol 1998; 4(2): 93-96
- URL: https://www.wjgnet.com/1007-9327/full/v4/i2/93.htm
- DOI: https://dx.doi.org/10.3748/wjg.v4.i2.93
In 1994 Helicobacter pylori infection was classified as a definite (class 1) carcinogen by the International Agency for Research on Cancer (IARC) on the basis of available epidemiological and clinical research. However, data collected over the past 3 years has failed to provide unequivocal support for the conclusion. The mechanisms by which H. pylori increases the risk of developing gastric cancer remain unclear, despite many significant experimental observations.
While gastric cancer is the second most common cause of cancer death, the incidence has decreased dramatically in some developed countries over the past decades[2,3]. There is also good evidence that the prevalence of H. pylori infection has dropped markedly in these countries, and it is unlikely that these two events have happened coincidently. Recent studies has shown that the geographic variation in the incidence of gastric cancer is related to the prevalence of H. pylori infection; an increased incidence and mortality of gastric cancer in a region is strongly associated with a high prevalence of H. pylori infection in the population within that region. However, lack of association between H. pylori and gastric cancer has been reported in some areas of the world, such as the Mediterranean and Africa where the prevalence of H. pylori is high but the incidence of gastric cancer is low.
Early case control studies provided convincing support for the association between H. pylori infection and gastric cancer[5,7]. In 1994, Forman summarized all available case control studies and concluded that the relative risk for development of gastric cancer was 3.8 fold higher in patients with H. pylori infection than those without. However, more recent epidemiological studies have shown inconsistent results[5,8-13]. Two studies carried out in Chinese populations showed no significant association between H. pylori infection and gastric cancer[8,9], and this finding has been replicated in recent Japanese and Korean studies[11-13].
One limitation of current epidemiological studies is that most studies did not adjust the potential confounding factors such as dietary or socioeconomic characteristics, thus bias may exist. For example, poor living conditions are usually related to a high prevalence of H. pylori infection and a high incidence of gastric cancer. Misclassification is another limitation in current epidemiological studies. It is widely accepted that H. pylori infection is lost with advancing preneoplasia (such as atrophy, intestinal metaplasia and dysplasia) and that serum titres drop correspondingly[14,15]. Cases are more likely to have advanced preneoplasia than the controls, so that H. pylori infection may have disappeared in a substantial proportion of cases. These cases may be classified as H. pylori negative since the infection is usually assessed at the time of diagnosis of gastric cancer. Misclassification may also result from the application of serological assays with low sensitivity and specificity for H. pylori detection, and from misdiagnosis of gastric cancer. This significantly influences the outcomes of analysis, resulting in underestimation of relative risks. When the misclassification errors are taken into account, it is rare to find studies that do not link H. pylori infection to gastric cancer. Therefore, understanding the limitations of these epidemiological studies is critical in interpreting the research findings.
Approximately 50% of H. pylori strains express the CagA protein. It has been shown that persons with CagA-expressing strains are more likely to develop atrophic gastritis, intestinal metaplasia and gastric cancer than those infected with CagA negative strains[16,17]. Thus, variation in CagA prevalence among populations may explain some of the discre-pancies observed in the case-control studies. In populations with a high prevalence of CagA positive strains, H. pylori infection is more likely to beidentified as a cancer risk factor. For example, the prevalence of CagA positive strains is substantially higher in Europeans than in African-born subjects. Similarly, CagA positive strains are more prevalent in blacks than in whites in the USA. However, this remains controversial as studies from Asian countries, such as China, Japan and South Korea, failed to show that infection with CagA positive strains is associated with these lesions[18-21].
There is no evidence, so far, that H. pylori infection is, in itself, directly genotoxic or mutagenic. Thus, it is unlikely that there is some direct interaction between the bacterium and host DNA which leads to mutations and transformed cell phenotypes. However, H. pylori produces a variety of substances that may indirectly cause DNA damage of the gastric epithelial cells. These products include ammonia or ammonium-containing chemicals, phospholipases, and cytotoxin(s). All these factors may impair the host defence and render the gastric epithelial cells prone to the activity of direct-acting carcinogens.
The host’s immune response to H. pylori may eventually result in DNA damage. In theory, stimulation of leukocyte cells by a bacterial infection should lead to the activation of both specific and non specific immune defence mechanisms that would cause limitation and resolution of the infection. However, the human immune response to H. pylori is not capable of eradicating the infection from the stomach, as the bacteria can avoid the human immune defence system. Thus, stimulation of the leukocyte cells continues as long as the infection persists. This toxic response may, over an extensive time period, lead to structural and biological damage to the gastric epithelium. For example, the excessive production of reactive oxygen metabolites by stimulated neutrophil polymorphs and monocytes may cause extensive DNA damage and molecular mutation. It has been shown that H. pylori infected gastric epithelium has a significantly higher level of these compounds than normal epithelium and that eradication of H. pylori infection returned to normal levels. Genetic damage by persistent inflammation may be mediated by other chemicals, such as oxidates of nitrogen, and lead to the formation of N-nitroso-compounds and nitric oxide which can induce DNA damage.
Cell division is vital to the development of cancer and an elevated rate of mitosis increases the likelihood of a somatic DNA mutation. Studies in varied populations have shown that H. pylori infection is associated with an approximately doubling of cell turnover and that the turnover level returns to the normal level following eradication of the infection[24,25]. It has also been shown that H. pylori increases epithelial cell proliferation in vitro. On the other hand, H. pylori infection has been reported to induce epithelial apoptosis (programmed cell death) in vivo[27-29] and eradication of the infection results in a significant reduction in apoptosis. Moreover, a recent study showed that increased cell proliferation was not associated with a corresponding increase in apoptosis in patients infected with cagA+ strains, indicating that failure to delete cells with genetic damage may result in malignant transformation.
Telomeres are specialised structures at the ends of chromosomes that are important in protection and replication of chromosomes. Normally, there is progressive shortening of telomeric repeats with each cell division, whereas germline cells compensate for the end replication problem by telomerase expression which permits the synthesis of telomeres, telomerase activity is not expressed at detectable levels in normal somatic cells. So, telomeres in somatic cells progressively shorten with each cell division. Telomere reduction could cause chromo-some instability and additional genetic changes, resulting in increased cell proliferation and reactivation of telomerase. Studies have shown that telomerase activity can be detected in most gastric cancers as well as precancerous lesions such as gastric intestinal metaplasia and adenoma, suggesting that the expression of telomerase activity is an early event of gastric carcinogenesis[31-32]. A recent study from Japan showed that the level of human telomerase RNA (hTR) and telomerase activity increased in parallel with the density of H. pylori infection, which was also associated with the grade of intestinal metaplasia. This finding suggests that H. pylori infection may be a strong trigger for hTR over-expression in intestinal metaplasia, which may lead to telomerase reactivation.
Ascorbic acid (Vitamin C) is a critical antioxidant which has important functions as a scavenger of re-active oxygen species and inhibits N nitrosation. This antioxidant property of ascorbic acid plays a central role in the chemoprevention against gastric cancer. It has been shown that H. pylori infection is associated with a significant decrease in the concentration of ascorbic acid in gastric juice, and that eradication of the infection normalizes the level of ascorbic acid[34,35]. Similarly, the gastric level of β carotene, which is also an antioxidant, is significantly decreased in patients with H. pylori infection.
Current epidemiological studies are limited by their small sample size and failure to adjust potential confounders. Well designed prospective and case control studies using large populations are still needed. These may confirm or refute the established “guilty” sentence for H. pylori infection in the development of gastric cancer.
The model of pathogenesis of gastric cancer has been proposed as a multi-step process; H. pylori infection may progress to acute gastritis, chronic gastritis, atrophic gastritis, then intestinal metaplasia, dysplasia, and eventually gastric cancer. However, the role of H. pylori infection in each step of this progression remains unclear. Moreover, the exact “point of noreturn” is unknown. Therefore, investigation of the association of H. pylori infection and precancerous lesions may provide key answers to the issues. Recently, it has been reported that H. pylori infection is associated with antralization (presence of antral type mucosa) at the gastric incisura, body and fundus, which is, in turn, related to intestinal metaplasia at these sites. Whether antralization is a step before intestinal metaplasia, and is reversible, needs to be clarified.
At present, an eradication rate of up to 95% has been achieved with the triple therapy and serological or urea breath tests with high sensitivity and specificity for detection of H. pylori infection are available. If H. pylori infection is proven to be an initiating factor in the development of gastric cancer, then, screening and eradication of H. pylori with antimicrobial therapy in large scale populations, in particular, those at high risk, should be considered. However, feasibility, safety and appropriate timing of this strategy remains to be determined. Moreover, side effects and the potential spread of drug resistant strains limits its practical application.
Encouraging results have been reported on the vaccination against H. pylori infection. Studies using animal models have shown that immunization against H. pylori not only prevents the infection but also can eradicate it£Û39£Ý. Vaccination as the optimal strategy in humans will be confirmed in the management of H. pylori infection.
Preliminary epidemiological data support the link between H. pylori infection and the development of gastric cancer. However, well-designed prospective and case-control studies using large populations are still required. Moreover, the mechanisms through which H. pylori infection leads to gastric cancer are not fully understood, and studies on this issue are urgently needed. Further research should also explore the possibility of preventing gastric cancer by eradicating H. pylori infection, with vaccines.
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