Correspondence to: Pelayo Correa, M.D., Department of Pathology, Louisiana State University Health Sciences Center, New Orleans, LA 70112-1393 (e-mail: correa{at}lsuhsc.edu).
Journal of the National Cancer Institute, Vol. 95, No. 6, © Oxford University Press 2003, all rights reserved.
HISTORICAL PERSPECTIVES
Cancer research in the 20th century thoroughly documented the role of major carcinogenic agents: ionizing radiation, chemical carcinogens, viruses, and especially tobacco smoke. Abundant epidemiologic studies have confirmed their role as causes of human cancer. Preventive strategies have been designed and applied with reasonably good results. Some exposures have proven difficult to avoid, especially tobacco smoking, where psychological mechanisms leading to addiction have proven cryptic and difficult to control.
The new century brings a new challenge: defining the impact of bacterial infections as a cause of cancer and design strategies for their prevention and control. Chronic inflammation has long been suspected of playing a role in carcinogenesis, but the mechanisms by which inflammation causes cancer remain poorly understood.
RECENT SCIENTIFIC CONTRIBUTIONS
Recently, infection with Helicobacter pylori has been classified as a human carcinogen by the International Agency for Research on Cancer (1). Two key papers published in 1991 in the Journal of the National Cancer Institute reported a positive association between gastric cancer and H. pylori infection. They contributed substantially to the recognition of H. pylori as a human carcinogen. Parsonnet and coworkers (2) reported on the prevalence of H. pylori infection in gastrectomy specimens from gastric cancer patients. The prevalence of infection was statistically significantly higher in 37 specimens from patients with the intestinal type (89.2%) than in 23 specimens from patients with the diffuse type (31.8%). These results demonstrate a direct association between H. pylori infection and the intestinal type of gastric carcinoma. Talley and coworkers (3) used stored serum samples of 69 patients with histologically diagnosed gastric adenocarcinoma and tested for H. pylori antibodies. They found a statistically significantly elevated infection rate for non-cardia cancer (odds ratio [OR] = 2.67, 95% confidence interval [CI] = 1.01 to 7.06) than for cancer-free controls.
One key element in the acceptance of H. pylori as a carcinogen was the evidence brought forth by three independent historical cohort studies. In Hawaii (4), California (5), and the United Kingdom (6) cohorts had been assembled in the 1960s and followed up for decades. At the initiation of each study, blood serum was collected and frozen. During the follow-up period, a total of 247 subjects developed gastric cancer. When their sera were tested for the presence of antibodies against H. pylori and compared with the sera of cohort subjects who remained free of gastric cancer, a statistically significant increased risk of cancer was found in subjects who were infected decades before cancer developed. The risk increased as time intervals between documented infection and the diagnosis of cancer increased (7). This study design practically ruled out any recall bias.
A very small fraction of infected subjects develop gastric cancer. It has been estimated that more than half of the world population is infected. The infection prevalence is high in several high-cancer-risk populations, such as Japan and Colombia. But several large populations with high infection prevalence display a very low rate of gastric cancer. This so-called "African enigma" (8) remains unexplained, but it does point out a very important fact: not all H. pylori infections increase the risk of gastric cancer. This points to a major scientific challenge: what mechanisms lead to cancer in certain subjects and what mechanisms prevent the development of cancer in other chronically infected subjects. This conundrum leads us to the search for answers in the events that precede cancer development, namely the precancerous process.
The precancerous process had been the subject of inquiry much before the scientific world was aware of H. pylori as a human pathogen. The histopathology of the precancerous stages has long been recognized: chronic gastritis, gland loss (atrophy), intestinal metaplasia (complete and incomplete), and epithelial dysplasia (9). The steady progression of the process in high-risk populations has been documented (10). It has been shown that progression represents a steady state characterized by episodes of progression to more advanced stages as well as episodes of "regression" to less advanced stages. The risk factors associated with the development of precancerous lesions are very similar to those associated with gastric cancer. A number of factors increase the risk, most prominently irritants of the gastric mucosa, such as excessive dietary salt. Others ("protectors") decrease the risk, especially adequate intake of fruits and fresh vegetables.
Clinical and epidemiologic studies have shown that diseases associated with H. pylori differ drastically in terms of cancer risk. Gastric peptic ulcer is considered part of the precancerous complex known as multifocal atrophic gastritis (MAG) (11). A retrospective ("historical") cohort study of 57,936 patients with peptic ulcer diagnosed in Swedish hospitals decades earlier were linked to gastric cancer records at the National Cancer Registry (12). Patients diagnosed with gastric ulcer not subjected to gastrectomy had an increased relative risk of gastric cancer in approximately two decades of follow-up (relative risk [RR] = 1.8, 95% CI = 1.1 to 2.8). Patients with a previous diagnosis of duodenal ulcer displayed a lower RR of gastric cancer (approximately 0.7). Because both locations of peptic ulcer are linked to H. pylori infection, it follows that the infection increases cancer risk in gastric ulcer but not in duodenal ulcer patients. Ulcers of both locations are associated with chronic inflammatory changes linked to H. pylori infection. A comprehensive literature review of the natural history of duodenal ulcer before effective treatment of H. pylori infection was available registered the fact that clinical manifestations of the ulcer tend to persist for decades (13).
A recent Japanese experience report by Uemura et al. (14) provides strong confirmation of the previous Swedish findings. A total of 1246 patients with H. pylori infection were followed for approximately 7 years; 36 of them (2.9%) developed cancer. A total of 280 not infected patients and 253 cured of their infection did not develop any gastric cancer during the follow-up period. Infected patients with gastric ulcer (229) or gastric atrophy (208) had a statistically significantly increased risk of cancer. A total of 275 infected patients with duodenal ulcer, however, did not develop any gastric cancer in the follow-up period.
DETERMINANTS OF CANCER RISK
The knowledge briefly summarized above leads to the exploration of the mechanisms that determine the divergent outcomes of H. pylori infection: carcinogenic versus not carcinogenic. The classical epidemiologic approach to causality postulates that such outcomes depend on the interplay of three sets of factors: those associated with the agent, with the host, and with the environment. Recent scientific inquiries have focused on these premises.
Factors associated with the agent have been explored and have led to interesting and intriguing findings. Studies of virulence factors of the bacterium have concentrated on two genes: cagA and vacA. Polymorphisms of the vacA gene have shown a peculiar association with ethnicity and human migration (15). The type vacA s1a is strongly associated with populations of northern European origin. Type vacA s1c is characteristic of Southeast Asia. Populations of Mediterranean origin have both s1a and s1b genotypes; the same combination is found in the United States. In Africa, type s1b predominates. In Latin America, including aboriginal Indian tribes, type s1b is also predominant. In most populations with historically high gastric cancer risk (present or past) type s1 (a or b) predominates. In low-risk populations the genotype distribution is not well documented. A number of preliminary reports indicate a relatively higher frequency of s2 genotypes, which tend to be less pathogenic. One common problem in international comparisons is that many studies are based on patients with duodenal ulcer or other severe clinical manifestations that are known to be associated with more virulent (mostly s1) bacterial genotypes. Selection bias, therefore, interferes with relevant findings, especially in low-cancer-risk populations. Relevant progress, therefore, has been made recently. In the near future it may be possible to classify H. pylori genotypes as "oncogenic" or "non-oncogenic," as has been done for human papillomaviruses.
Host related factors can indicate genetic susceptibility (or resistance) or acquired influences, which may stimulate defenses of the host against environmental carcinogens. Recent research has pointed to genetic trends associated with the expression of cytokines during the inflammatory process. El-Omar has reported that genetic polymorphisms of the interleukin 1 beta (1L-1) determine outcomes of gastric inflammation toward oncogenic or non-oncogenic pathways (16). Certain IL-1
subtypes increase gastric cancer risk and are also associated with inhibition of acid secretion by the gastric mucosa. Similar effects are linked to the expression of tumor necrosis factor alpha (TNF
) or 1L-10. Other genetic polymorphisms possibly associated with cancer risk have been reported for mucins (MUC-1) (17) and human lymphocyte antigens (HLA) (18). This type of research may lead to the identification of individuals within a community that may be at especially high risk.
Environmental factors linked to gastric cancer risk have been described by multiple epidemiologic studies. They are mostly associated with poverty and diet: excessive use of salt and deficient intake of fresh fruits and vegetables in the diet. Excessive salt may be an irritant to the gastric mucosa. Fresh fruits and vegetables have been linked to antioxidants such as ascorbic acid, beta-carotene, vitamin E, folates, and non-nutrients such as polyphenols (19-21).
Taken together, factors associated with gastric cancer risk may be conceived as dominated by infection of the gastric mucosa with H. pylori. The infection results in chronic active inflammation that lasts for decades. The inflammatory process can be modulated by multiple forces. These may be genetic: inherited traits determining either susceptibility or resistance to carcinogenesis. Environmental factors playing a role in carcinogenesis may also act as enhancers or inhibitors of the inflammatory process. Enhancers may be gastric irritants, whereas inhibitors appear to act mostly as antioxidants, which points to the possible role of reactive oxygen species (ROS) as a common final pathway of carcinogenesis (22).
A good example of environmental factors as determinants of "oncogenic" outcomes of the infection has been provided by epidemiologic studies (23). Early infection in JapaneseHawaiian children is associated with elevated gastric cancer risk. Later infection increases the risk of duodenal ulcer, a non-oncogenic outcome.
The interactions among different etiologic factors have been illustrated recently in the Journal of the National Cancer Institute. Figueiredo et al. (24) examined the influence of more virulent ("oncogenic?") H. pylori genotypes on more susceptible hosts. Cag A positive, Vac s1m1 bacterial genotypes infecting IL-1 B-511*T carriers have a much higher cancer risk: OR = 87, CI = 11-679 (24).
CANCER PREVENTION
Optimal proof of causality may depend on experimental epidemiologic studies that explore whether changes in the "cause" (H. pylori infection) influence the "effect" (cancer). This is being attempted by intervention trials being carried out in several countries (25). Some expect to measure the incidence of gastric cancer as an outcome. This will require tens of thousand of subjects to be followed up for decades. One such trial is being carried out in Great Britain: infected versus not infected subjects will be followed up for diagnoses of neoplastic diseases (25). Other trials are based on measurements of different stages of the precancerous process. Several trials based on intermediate endpoints are being carried out at the present time (25).
One randomized chemoprevention trial has been completed and published in the Journal of the National Cancer Institute (26). It was carried out in a Colombian rural population at very high risk of gastric cancer and with an extremely high prevalence (more than 90%) of H. pylori infection. Intervention arms were as follows: attempted eradication of the infection with triple anti-H. pylori therapy and/or dietary supplementation for 6 years with ascorbic acid and/or beta-carotene. Eradication of the infection resulted in a statistically significantly increased rate of regression (RR = 8.7, 95% CI = 2.7 to 28.2). Dietary supplementation for 6 years with either ascorbic acid or beta-carotene in subjects with atrophic (non-metaplastic) gastritis also increased the risk of regression of lesions: RR for ascorbic acid = 5 (95% CI =1.6 to 14.2); RR for beta-carotene = 5.1 (95% CI = 1.7 to 15).
EPILOGUE
The H. pylori-gastric cancer model of carcinogenesis represents the best available setting for the scientific study of bacterial carcinogenesis. Abundant human material is available for studies in high-risk populations. An excellent experimental model has been developed recently (27-28). Infection of Mongolian gerbils with H. pylori leads to a chronic active infection that replicates all the stages of carcinogenesis known in humans. The model is available, but the mechanisms of carcinogenesis are largely unknown. The available evidence points to the inflammatory process as the determinant of oncogenic versus non-oncogenic outcomes of the infection. Identifying mechanisms that determine a non-oncogenic outcome of the infection may bring new light and hope to the field of cancer prevention in humans.
REFERENCES
1 International Agency for Research on Cancer (IARC) Working Group. IARC monographs on the evaluation of carcinogenic risk to humans. Schistosomes, liver flukes and Helicobacter pylori. Vol. 61. Lyon (France): IARC; 1994.
2 Parsonnet J, Vandersteen D, Goates J, Sibley R, Pritikin J, Chang Y. Helicobacter pylori infection in intestinal and diffuse-type gastric adenocarcinomas. J Natl Cancer Inst 1991;83:6403.[Abstract]
3 Talley N, Zinsmeister A, Weaver, DiMagno EP, Carpenter HA, Perez-Perez GI, et al. Gastric adenocarcinoma and Helicobacter pylori infection. J Natl Cancer Inst 1991;83:17349.[Abstract]
4 Nomura A, Stemmerman GN, Chyou PH, Kato I, Perez-Perez G I, Blaser MJ. Helicobacter pylori infection and gastric adenocarcinoma among Japanese in Hawaii. N Engl J Med 1991;325:11326.[Abstract]
5 Parsonnet J, Friedman GD, Vandersteen DP, Chang Y, Vogelman JH, Oentreich N, et al. Helicobacter pylori infection and the risk of gastric carcinoma. N Engl J Med 1991;325:112731.[Abstract]
6 Forman D, Stacery AR, Sitas F, Fullerton F, Wald N, Yarnell JW. Association between infection with Helicobacter pylori and risk of gastric cancer: evidence from a prospective investigation. BMJ 1991;302:13025.[Medline]
7 Forman D, Webb P, Parsonnet J. H. pylori and gastric cancer. Lancet 1994;343: 2434.[CrossRef][Medline]
8 Holcombe C. Helicobacter pylori: the African enigma. Gut 1992;33:42931.[Medline]
9 Correa P, Haenszel W, Cuello C, Zavala D, Fontham E, Zarama G, et al. Gastric precancerous process in a high risk population: cross-sectional studies. Cancer Res 1990;50:47316.[Abstract]
10 Correa P, Haenszel W, Cuello C, Zavala D, Fontham ET, Zarama G, et al. Gastric precancerous process in a high risk population: cohort follow-up. Cancer Res 1990;50:473740.[Abstract]
11 Correa P. Helicobacter pylori and gastric carcinogenesis. Am J Surg Pathol 1995;(Suppl. 1):S3743.
12 Hansson LE, Nyren O, Hsing AW, Bergstrom R, Josefsson S, Chow WH, et al. The risk of stomach cancer in patients with gastric or duodenal ulcer disease. N Engl J Med 1996;335:2429.
13 Neil GA. Do ulcers burn out or burn on? Managing duodenal ulcer diathesis in the Helicobacter pylori era. Ad hoc committee on FDA-related matters. Am J Gastroenterol 1997;92:38793.[Medline]
14 Uemura N, Okamoto S, Yamamoto S, Matsumra N, Yamaguchi S, Yamakido M, et al. Helicobacter pylori infection and the development of gastric cancer. N Engl J Med 2001;345:7849.
15 Van Doorn LJ, Figuieredo C, Megraud F, Pena S, Midolo P, Queiroz DM, et al. Geographic distribution of vacA allelic types of Helicobacter pylori. Gastroenterology 1999;116:82330.[Medline]
16 El-Omar E, Carrington M, Chow W, McColl KE, Bream JH, Young HA, et al. Interleukin-1 polymorphism associated with increase risk of gastric cancer. Nature 2000;404:398402.[CrossRef][Medline]
17 Reis C, David L, Correa P, Carneiro F, Bolos C, Garcia E, et al. Intestinal metaplasia of human stomach displays distinct patterns of mucin (MUC1, MUC2, MUC5AC, and MUC6) expression. Cancer Res 1999;59:10037.
18 Magnusson PKE, Eurath H, Erikson I. Gastric cancer and human leukocytes antigen. Cancer Res 1996;56:323843.[Abstract]
19 Buiatti E, Palli D, Decarli A, Amadori D, Avellini C, Bianchi S, et al. A case-control study of gastric cancer and diet in Italy. Int J Cancer 1989;44:6116.[Medline]
20 Buiatti, E., D. Palli, Decarli A, Amadori D, Avellini C. Bianchi S, et al. A case-control study of gastric cancer and diet in Italy: II. Association with nutrients. Int J Cancer 1990;45:896901.[Medline]
21 Fontham ET. Vitamin C, vitamin C-enriched foods and cancer. In: B Frei, editor. Natural antioxidants in human health and disease. San Diego (CA): Academic Press. 1994;15797.
22 Miller MJ, Correa P. Nitrogen oxides and the gastric precancerous process. In: RH Hunt and GN Tytgat, editors. Helicobacter pylori: basic mechanisms to clinical cure. Boston (MA): Kluger Academic Publishers; 1998. p. 308314.
23 Blaser MJ, Chyou PH, Nomura A. Age at establishment of Helicobacter pylori infection and gastric carcinoma, gastric ulcer, and duodenal ulcer risk. Cancer Res 1995;55:5625.[Abstract]
24 Figueiredo C, Machado JC, Pharoah P, Seruca R, Sousa S, Carvalho F, et al. Helicobacter pylori and interleukin genotyping: an opportunity to identify High-risk individuals for gastric carcinoma. J Natl Cancer Inst 2002;94:16807
25 Forman D. Lessons from ongoing intervention studies. In: Hunt RH, Tygat GN, editors. Helicobacter pylori: basic mechanisms to clinical cure 1998. Dordrecht (The Netherlands): Kluwer Academic Publishers; 1998. p. 35461.
26 Correa P, Fontham ET, Bravo JC, Bravo LE, Ruiz B, Zarama G, et al. Chemoprevention of gastric dysplasia: randomized trial of antioxidant supplements and anti-Helicobacter pylori therapy. J Nat Cancer Inst 2000;92:18818.
27 Watanabe, Tada M, Nagai H, Sasaki S, Nakao M. Helicobacter pylori infection induces gastric cancer in Mongolian gerbils. Gastroenterology 1998;115:6428.[Medline]
28 Honda S, Tokieda M, Satoh R, Nishizono A, Nasu M. Development of Helicobacter pylori-induced gastric carcinoma in Mongolian gerbils. Cancer Res 1998;58:42559.[Abstract]
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