human gastric carcinogenesis: a multistep and ... · precancerous process, namely superficial...

[CANCER RESEARCH 52, 6735-6740, December 15, 1992]

Special Lecture

Human Gastric Carcinogenesis: A Multistep and Multifactorial Process First American Cancer Society Award Lecture on Cancer Epidemiology and Prevention 1

Pelayo Correa

Department of Pathology, Louisiana State University Medical Center, New Orleans, Louisiana 70112-1393

Abstract

Evidence from pathology and epidemiology studies has been provided for a human model of gastric carcinogenesis with the following sequential stages: chronic gastritis; atrophy; intestinal metaplasia; and dysplasia. The initial stages of gastritis and atrophy have been linked to excessive salt intake and infection with Helicobacter pylori. The intermediate stages have been associated with the ingestion of ascorbic acid and nitrate, determinants of intragastric nitrosation. The final stages have been linked with the supply of B-carotene and with excessive salt intake. Nitrosating agents are candidate carcinogens and could originate in the gastric cavity or in the inflammatory infiltrate.

Introduction

Although gastric cancer rates have been declining in recent decades, it remains one of the most serious health burdens throughout the world. Understanding its causation is important for the primary and secondary prevention of the disease. The highest death rates for many decades were registered in Japan, followed by northern Europe and the Andean populations of Latin America. The recent decline has been more marked in Japan and northern Europe. Fig. 1 shows the latest published death rates which are highest in Costa Rica and relatively high in eastern Europe (1). Data for China are not available in this series but gastric cancer accounts for the highest cancer mortality in that country. As of 1980, gastric cancer was the most frequent neoplasm registered in the world (2). In the United States, American Indians, Hispanics, Blacks, and immigrants from northern Europe, Asia, and Latin America display risks that are considerably higher than those of native White Amer- icans. Some of the available incidence rates are shown in Table 1 (3). The absolute number of gastric cancer deaths has been increasing recently (4). The American Cancer Society estimated 20,000 cases in 1989 and 23,800 in 1991. The reasons for this increase are not entirely clear; it may be related to population growth and immigration of high-risk groups. A sharp increase of carcinomas localized in the gastric cardia has been recently registered in white males of the United States and western Europe, thus far unexplained on etiological grounds (5).

The recent decline has been observed mainly for the so-called intestinal type of gastric carcinoma, in contrast with the diffuse type which has declined less notoriously (6). A series of changes have been identified as precursors to the intestinal type of gastric carcinoma, representing apparently sequential steps in the precancerous process, namely superficial gastritis, chronic atro-

phic gastritis (gland loss), small intestinal metaplasia, colonic metaplasia, and dysplasia (7, 8).

An etiological hypothesis, depicted in Fig. 2, has been proposed to explain the progressive tissular and cellular changes and to identify the etiological forces acting at different points in the chain of causation (9, 10). Research on the hypothesis has continued on several fronts and produced new information which will be reviewed briefly in this article. We will address the phenotypic markers, the etiological factors, and the pathways of carcinogenesis and conclude with remarks about the implica- tions for cancer prevention.

Phenotypic Markers

Hematoxylin and eosin stain remains the basic tool to assess the gastric cancer precursors and the gold standard against which other markers are compared. Studies of mucin his- tochemistry have confirmed that as the precancerous process advances, the normal neutral mucin of the superficial (foveolar) epithelium is gradually replaced by acid sialomucins of the type which characterize the small intestine and in later phases by sulfated mucins seen normally in the large intestine (11).

A second abnormality detectable in the mucin secretions is the anomalous appearance of blood group antigens, especially the Lewis antigens (12). The abnormal expression of both markers (sulfomucins and Lewis antigens) in the mucin moiety is a powerful predictor of risk, as shown in Table 2 which explores the relative risk of the most advanced precancerous lesions, based on studies of a Colombian population at high gastric cancer risk (13). Both cross-sectional tabulations and cohort follow-up studies coincide in assigning a very high risk to the concomitant expression of both phenotypic abnormalities. It appears that at this point this combination of markers may offer an excellent opportunity to identify subjects at the highest risk of neoplastic transformation.

Other markers with potential prognostic significance have been described. The pepsinogens secreted by the gastric epithelium can be detected in biopsy material and also have the great advantage of being detectable in the blood. Low serum pepsinogen I levels and low ratio of pepsinogen I to pepsinogen II are associated with high risk of dysplasia and cancer (14). The possible utilization of these markers in screening of high risk populations is being actively investigated at the present time (15-17).

Etiological Factors Received 9/10/92; accepted 10/7/92. 1 Presented at the 83rd Annual Meeting of the American Association for Cancer The original hypothesis published in 1975 considered 3 ma-

Research, May 22, 1992, San Diego, CA. The work on which a substantial portion jor etiological factors, namely excessively salty foods and low of this American Cancer Society lecture is based was supported by Grant P01- intake of ascorbic acid and carotenoids (18). Since then, a n e w CA28842 from the National Cancer Institute, NIH, and represents a collaborative effort with other investigators in the United States and Colombia. major factor has been added, infection with Helicobacterpylori.

6735

Research. on August 24, 2019. © 1992 American Association for Cancercancerres.aacrjournals.org Downloaded from

http://cancerres.aacrjournals.org/

HUMAN GASTRIC CARCINOGENESIS

Gastric cancer death rates males, 1984-1985

1 COSTA RICA

2 JAPAN

3 CHILE

4 POLAND

5 HUNGARY

6 PORTUGAL

7 SINGAPORE

8 CZECHOSLOVAKIA

9 BULGARIA

10 AUSTRIA / /

41 U.S. White / I I I I I

0 10 20 30 40 50

rate per 100,000 population

Fig. 1. Gastric cancer annual death rates/100,000 population, 1984-1985, adjusted to Segi's world population (1).

plausibility is added when the effects of concentrated salt intake on the gastric mucosa are considered. It causes excessive cell replication, an event well known to increase cancer risk because of potentiation of the action of carcinogens and the possibility of increased rate of endogenous mutations (30, 31). The acute effects of concentrated salt solutions lead to mucosal damage and its repair is associated with inflammatory changes. An excessively salty diet induces atrophy in experimental animals (32) and is associated with atrophic changes in the human gastric mucosa (18). For these reasons it probably has a dual effect at the initial stages of the chain of causation, inducing both gastritis and atrophy, as depicted in Fig. 3. Excessive salt may also increase the mutagenicity of nitrosated foods (33). The recent decline in gastric cancer rates may be related to lower salt intake, made possible by refrigeration. In Japan, a strong and effective public health effort to reduce salt intake aimed at reducing hypertensive cerebrovascular accidents antedated by more than 10 years the marked decline in gastric cancer rates (27). Salt intake may also play a role in the late stages of carcinogenesis, as discussed below.

Table 1 Gastric cancer incidence rates, males, 1978-1982, per 100,000 population

White Black Other Atlanta 6 16 New Orleans 7 17 New Mexico 6 16 (Hispanic) 18 (Indian) Los Angeles 9 16 15 (Hispanic) 25 (Japanese) Hawaii 12 31 (Hawaian) 28 (Japanese)

The current status of these factors in gastric cancer causation is described below.

H. pylori

This bacterium is not found in normal stomachs but is very frequently found in chronic gastritis. Several facts strongly support its role as a causative agent, such as the disappearance of the inflammatory reaction after elimination of the bacteria with antibiotic treatment (19). It is therefore suspected that H. pylori infection plays a causative role at the early phases of the chain, as outlined in Fig. 3. It has been proposed that infection during childhood may be a factor which distinguishes high-risk from low-risk populations (20). In some low-risk populations, the infection is very prevalent since childhood (21). It thus appears that H. pylori infection is a contributory but not a sufficient factor in gastric carcinogenesis.

The role of this chronic gastric infection has received strong support from 4 independent cohort studies which found that infection with H. pylori, detected many years before, increases the risk of gastric cancer (20-24). Since this infection typically remains active for life if not eradicated with adequate therapy, H. pylori is probably a source of active inflammation lasting for decades. The effects of H. pylori on the microenvironment of the gastric cavity and the gastric mucosa are poorly understood but an increase in cell replication and a constant attraction of polymorphonuclear leukocytes are events with suspected carcinogenic potential (25, 26).

Excessive Salt (NaCl) Intake

The epidemiological and experimental evidence for this etiological factor is strong and consistent (9, 27-29). Biological

Table 2 Estimated relative risk (RR) of colonic metaplasia and dysplasia associated with abnormal phenotypic expression of two markers

Markers RR cross-sectional RR prospective study Colonic Colonic

Sulfomucin Lewis metaplasia Dysplasia metaplasia Dysplasia - - 1.0 1.0 1.0 1.0 + - 4.0 1.0 4.9 11.0 - + 3.2 1.7 6.9 5.8 + + 48.0 11.2 32.7 13.0

I Normal ] I I Superficial Gastritis 1 I

Atrophic I Gastr i t is ]

[ High pH ] [ Bacterial N = O Growth Mutagens

I Small Intestine Metapiasia I I Colonic

Metaplasia I

J Dysplasia ] I [ Carcinoma I

Fig. 2. General hypothesis of gastric carcinogenesis. Right column, postulated successive phenotypic changes in the gastric mucosa. Left, changes in the gastric cavity.

[Normal I H. pylori d -I

! ISuperficial i Gastritis

Na CI d -I I Atrophic Gastritis[

Fig. 3. Initial steps of the chain of events indicating 2 factors which are suspected to play a causal role.

6736




Ascorbic acid

I Higher pH~ IGas' I

I Bacterial I growth I

_1

[ma)nsl l

plasia I

Fig. 4. Intermediate stage in the chain of events indicating 2 suspected etiological factors: nitrate as a starting point in nitrosation reactions; and ascorbic acid as a blocker of such reactions.

carcinogens (42). Fig. 5 outlines the postulated enhancing role of salt and the inhibiting role of fl-carotene in the late steps of the carcinogenesis model (10).

Pathways of Gastric Carcinogenesis

Although our knowledge of the modulation of the gastric carcinogenesis process has advanced, the identification of the carcinogen(s) remains elusive. Two leading hypotheses have emerged, luminal synthesis of carcinogen(s) and intramucosal carcinogenesis, outlined in Fig. 6, which depicts the last stages of the carcinogenesis model (10). Recently a new source of carcinogens has been postulated. Two studies have shown that tobacco smoking increases the risk of transformation from metaplasia to dysplasia (43, 44).

Ascorbic Acid

The next segment in the chain of causation, namely the transition from atrophic to metaplastic mucosa, represents a mor- phological mutation that is easily detected histologically. The mutant(s) are unknown, but it has been proposed that at least some of them may be N-nitroso compounds as illustrated in Fig. 4. Chronic atrophic gastritis, because of the loss of acid- secreting parietal cells, leads to higher gastric pH and prolifer- ation of anaerobic bacteria which reduce nitrate, abundant in many foods, to nitrite. The latter molecule has a propensity to react with other nitrogen-containing compounds to form N- nitroso mutagens and carcinogens. These processes may be inhibited by naturally occurring antioxidants, as shown by mul- tiple epidemiological studies which find an inverse association between gastric cancer and the ingestion of fresh fruits and vegetables. Allium vegetables are associated with lower cancer rates and may contain natural inhibitors (34). A natural inhibitor abundant in fresh fruits and vegetables is ascorbic acid. The protective effect of this vitamin continues to receive strong support from epidemiological and laboratory research. All independent case-control studies which addressed the subject have reported significant reductions of gastric cancer risk associated with ascorbic acid intake. This has been found in populations of diverse ethnicity (35). Lower blood levels of ascorbic acid have been reported in patients with intestinal metaplasia as compared to controls (36). Ascorbic acid is actively secreted into the gastric cavity. It has been shown that ascorbic acid may be oxidized to dehydroascorbic acid in the gastric cavity, losing in that way its potential to block nitrosation reactions (37).

Ascorbic acid is markedly decreased in the gastric juice in the presence of chronic gastritis, elevated pH, and infection with H. pylori (37). More research is needed to better under- stand the physiopathology of ascorbic acid in the gastric microenvironment. The findings up to the present time point to a strong antioxidant function of ascorbic acid in the gastric microenvironment.

Carotenoids

The role of fl-carotene has been linked to late events in the gastric precancerous process, especially in dysplasia and early invasive carcinoma (38, 39). Although the mechanism of its protective action has not been elucidated, its role as free-radical scavenger and its capacity to open intercellular gap junction communications have been pointed out (40, 41). In this late stage of carcinogenesis, carotenoids may have the opposite effects of dietary salt, which potentiates the effects of gastric

Intraluminal Synthesis of Carcinogens

The original hypothesis postulated the synthesis of carcinogens in the gastric cavity via nitrosation reactions induced by the high nitrite content of gastric juice (18). A potent mutagen has been identified after nitrosation of the precursor 4-chloro- 6-methoxyindole found in fava beans, the staple food of some high-risk populations (45). It has been further reported that nitrosoindoles are genotoxic, inducing sister chromatid ex- changes, and have tumor-promoting functions significantly inducing ornithine decarboxylase and inhibiting gap junction intercellular communications (46). Nitrosoindoles have also been found in other foods, such as Chinese cabbage, frequently con- sumed by high-risk populations (47).

The urinary excretion of nitrosoproline, an indicator of endogenous nitrosation, was higher in children of a high gastric cancer risk area of Costa Rica as compared to children of a

I Sm=l I Intestinal I Mete, lasia I

Metaplasia 1 /

Na CI ~ =-~ i B-carotene

~1 ,,,

I Dysplasial ~ ~,,

[ Carcinoma. I Fig. 5. Late stages of the gastric carcinogenesis model showing the opposing

effects of sodium chloride (enhancing carcinogenesis) and fl-carotene (inhibiting the process).

IM Small I Intestinal[ etaplasia~

L . j -

lumlnaJ cardnogen

(naro~ndo~?)

I MetCr

i " ~Carc

)nic I )lasia~

noma.'l

~ tOllS

(NO'- HO-?)

Fig. 6. Late stages of the gastric carcinogenesis model showing the 2 possible sources of carcinogens: luminal from dietary sources; and tissular from inflammatory cells.

6737




0

N

A

o

B

I

Fig. 7. Photomicrographs of gastric mucosa showing the close proximity of polymorphonuclear leukocytes (sources of oxidative mutants) (open arrows) to replicating and mutating cells (solid arrows). ,4, gastric epithelial cells stained with proliferating cell nuclear antigen (PCNA), indicating DNA synthesis. B, dysplastic gastric epithelial cells stained with antibody against p53 protein.

low-risk area. The same high-risk children had high levels of nitrosamino acids in their urine (48). Colombian patients with intestinal metaplasia and dysplasia had higher excretion of nitrosoproline (adjusted for nitrate) than subjects without such lesions (49). Anaerobic bacteria, which frequently colonize stomachs with intestinal metaplasia, induce endogenous formation of nitroso compounds (50). These findings point to a role for bacterially catalyzed (as opposed to acid-catalyzed) nitrosao tion in the gastric cavity.

Intramucosal Carcinogens

Intramucosal nitrosation was reported by Stemmermann and Mower (51) in 1981. They detected nitroso compounds, derived from hydroxyzine and diazepam given by i.m. injection as pre- anesthetic agents, in homogenates of gastric antral biopsies with intestinal metaplasia. The rapidity of the reaction and the subsite specificity suggested that the nitrosation reaction took place in the mucosa itself rather than in the lumen.

While studying urinary excretion of nitrate, Tannenbaum et al. (52) confirmed old reports of in vivo nitrate synthesis and went on to demonstrate that it was the product of chemical reactions stimulated by bacterial lipopolysaccharides. Cellular components of inflammatory infiltrate, namely activated mac- rophages and polymorphonuclear leukocytes, are directly in-

volved in these reactions through a biochemical pathway in which NO is produced (53). The same investigators have shown that NO induces mutations in human cells. These could alter the p53 suppressor gene in different ways. The p53 mutations reported in colon cancer could be induced by NO-related deam- ination of thymine while those reported in liver and lung cancers could be induced by NO via depurination (53). Poly- morphonuclear leukocytes attracted by H. pylori are seen in the immediate vicinity of replicating cells, some of which stain positive for mutant p53 protein as shown in Fig. 7. The TRP-MET translocation (chromosome 741) , a mutation reported in gastric carcinomas, has been detected at earlier points in the chain of events, such as intestinal metaplasia and even superficial gastritis (54).

Prevention of Gastric Carcinoma

The accumulated knowledge on gastric carcinogenesis in hu- mans can be used to adopt prevention measures. Primary prevention should be achieved by intervention on the etiological factors already identified, namely excessive salt intake, deficient intake of fresh fruits and vegetables (containing micronutrient antioxidants), and H. pylori infection. The diet of wealthy western societies seems to have been doing just that in an unplanned way for several decades. One or more of these factors is still

6738




present in the communities which today continue to display very high rates of gastric cancer and efforts should be made to achieve primary prevention by correcting them.

For those subjects who already have the precursor lesions, a different strategy may be indicated. The first need is to identify patients with advanced precursors or with neoplasia in the "early" or "superficial" stage. If a small malignant lesion is identified, surgical resection is indicated. Excellent results in terms of survival have been reported (55). In the absence of neoplastic lesions, markers of progression of the precancerous process are needed. In terms of histological markers, our results indicate a high degree of efficiency of the combined expression of sulfomucins and Lewis antigen abnormalities, two easily ac- cessible histological techniques. Screening populations at high risk could identify the individuals who need special attention. One screening method tested in Japan is based on double-contrast X-ray techniques administered to the general population and followed by endoscopy in those subjects with X-ray abnormalities. The efficiency of this methodology has been only par- tially evaluated (56). The cost of the procedures involved pre- cludes their application to large populations of low economic potential.

Screening with pepsinogen serum levels has been attempted but still requires more thorough evaluation. Low pepsinogen I levels indicate loss of chief cells in the corpus (atrophy), an indirect marker of advanced cancer precursor lesions. Pepsino- gen II, the only type normally secreted in antral glands, is abnormally synthesized by some preneoplastic and neoplastic cells. The ratio of pepsinogen I to pepsinogen II may therefore reflect the risk with more fidelity. Research on this subject is in progress in populations with different profiles of risk factors.

The "spontaneous" decline in gastric cancer rates observed in many countries could be generalized to the populations expe- riencing high risk at the present time by applying primary and secondary prevention strategies based on the progress made in elucidating the carcinogenic mechanisms. Chemoprevention trials using micronutrient antioxidants and anti-Helicobacter therapy are under way. Human gastric carcinogenesis may be useful as a model in elucidating the carcinogenic process in other organs.

Acknowledgments

I am especially grateful to William Haenszel for his support , guid- ance, encouragement , and constructive critique since 1962 and to Steven R. Tannenbaum for helping us bridge epidemiology with laboratory science.

References 1. Kurihara, M., Aoki, K., and Hisamichi, S. Cancer mortality statistics in the

world 1950-1985. Nagoya, Japan: The University of Nagoya Press, 1989. 2. Parkin, M. D., Stjernsward, J., and Muir, C. Estimates of the worldwide

frequency of twelve major cancers. Int. J. Cancer, 41: 184-197, 1988. 3. Muir, C., Waterhouse, J., Mack, T., Powell, J., and Whelan, S. Cancer

Incidence in Five Continents, Vol. 5. Scientific Publication 88.1987. Lyon, France: International Agency for Research on Cancer, 1987.

4. Cady, B., Ross, R., and Silverman, M. Gastric adenocarcinoma. A disease in transition. Arch. Surg., 124: 303-308, 1989.

5. Blot, W. J., Devesa, S., Kneller, R., and Fraumeni, J. Rising incidence of adenocarcinoma of the esophagus and gastric cardia. JAMA, 265:1287- 1289, 1991.

6. Mufioz, N., and Connelly, R. Time trends in intestinal and diffuse types of gastric carcinoma. Int. J. Cancer, 8: 158-164, 1971.

7. Correa, P., Haenszel, W., Cuello, C., et al. Gastric precancerous process in a high risk population: cross sectional studies. Cancer Res., 50: 4731-4736, 1990.

8. Correa, P., Haenszel, W., Cuello, C., et al. Gastric precancerous process in a high risk population: cohort follow-up. Cancer Res., 50: 4737-4740, 1990.

6739

9. Correa, P. A human model of gastric carcinogenesis. Cancer Res., 48." 3854- 3860, 1988.

10. Correa, P. The new era of cancer epidemiology. Cancer Epidemiol. Biomar- kers &Prev., 1: 5-11, 1991.

11. Silva, S., and Filipe, M. I. Intestinal metaplasia and its variants in the gastric mucosa of Portuguese subjects: a comparative analysis of biopsy and gastrec- tomy material. Hum. Pathol., 17: 988-995, 1986.

12. Torrado, J., Blasco, E., Gutierrez, A., et al. Lewis system alterations in gastric carcinogenesis. Cancer (Phila.), 66:1769-1774, 1990.

13. Torrado, J., Correa, P., Ruiz, B., Zavala, D., and Bara, J. Prospective study of Lewis antigens in the gastric precancerous process. Cancer Epidemiol. Biomarkers &Prev., 1:199-205, 1992.

14. Burr, M. L., Samloff, I. M., Bates, C. J., and Holliday, R. M. Atrophic gastritis and vitamin C status in two towns with different stomach cancer death-rates. Br. J. Cancer, 56: 163-167, 1987.

15. Palli, D., Dacarli, A., Cipriani, F., et al. Plasma pepsinogens, nutrients, and diet in areas of Italy at varying gastric cancer risk. Cancer Epidemiol. Biom- arkers &Prev., 1: 45-50, 1991.

16. Miki, K., Ichinose, M., Kawamura, N., Matsuchima, M., et al. The significance of low pepsinogen levels to detect stomach cancer associated with extensive chronic gastritis in Japanese subjects. Jpn. J. Cancer Res., 80: 111-114, 1984.

17. Samloff, I. M., Varis, K., Ihamaki, T., Siurala, M., and Rolter, J. I. Rela- tionship among serum pepsinogen I, serum pepsinogen II and gastric mucosal histology. A study in relatives of patients with pernicious anemia. Gastroenterology, 83: 204-209, 1982.

18. Correa, P., Haenszel., W., Cuello, C., Arder, M., and Tannenbaum, S. R. A model for gastric cancer epidemiology. Lancet, 2: 58-60, 1975.

19. Blaser, M. J. Hypotheses on the pathogenesis and natural history of Helico- bacter pyiori-induced inflammation. Gastroenterology, 102: 1720-1727, 1992.

20. Parsonnett, J., Friedman, G., Vandersteen, D., et aL Helicobacter pylori infection and the risk of gastric carcinoma. N. Engl. J. Med., 325:1127- 1131, 1991.

21. Sierra, R., Muhoz, N., Pefia, S., et al. Antibodies to Helicobacterpylori and pepsinogen levels in children in Costa Rica. Cancer Epidemiol. Biomarkers & Prev., 1: 449-454, 1992.

22. Forman, D., Newell, D. G., Forllerton, F., et al. Association between infection with Helicobacter pylori and risk of gastric cancer: evidence from a prospective investigation. Br. Med. J., 302: 1302-1305, 1991.

23. Nomura, A., Stemmermann, G. N., Chyou, P. H., Kato, I., Perez-Perez, G. I., and Blaser, M. J. Helicobacter pylori infection and gastric carcinoma among Japanese Americans in Hawaii. N. Engl. J. Med., 325:1132-1136, 1991.

24. Talley, N. J., Zinsmeister, A. R., Weaver, A., et aL Gastric adenocarcinoma and Helicobacterpyiori infection. J. Natl. Cancer Inst., 83: 1734-1739, 1991.

25. Correa, P. Is gastric carcinoma an infectious disease? N. Engl. J. Med., 325: 1170-1171, 1991.

26. Correa, P., and Ruiz, B. Helicobacter pylori and gastric cancer. In: B. J. Rathbone and R.V. Heatley (eds.), Helicobacter pylori and Gastrointestinal Disease, Ed. 2, in press, 1992.

27. Sato, T., Fukuyama, S., Susuki, T., and Takanagi, J. The relationship between gastric cancer mortality and salted food intake in several places in Japan. Bull. Inst. Public Health, 8." 187-198, 1959.

28. Joossens, J. V., and Geboers, J. Nutrition and gastric cancer. Nutr. Cancer, 2: 250-261, 1981.

29. Tatematsu, M., Takahashi, M., Fukushima, S., Hananouchi, M., and Shirai, T. Effects in rats of sodium chloride on experimental gastric cancers induced by N-methyl-N-nitro-N-nitroso guanidine or 4-nitroquinoline-l-oxide. J. Natl. Cancer Inst., 55: 101-106, 1975.

30. Charnley, G., and Tannenbaum, S. R. Flow cytometric analysis of the effect of sodium chloride on gastric cancer risk in the rat. Cancer Res., 45: 5608- 5616, 1985.

31. Ames, B. N., and Gold, L. S. Too many rodent carcinogens: mitogenesis increases mutagenesis. Science (Washington DC), 249: 970-971, 1990.

32. Kodama, M., Kodama, T., Susuki, H., and Kondo, K. Effect of rice and salty rice diet on the structure of mouse stomach. Nutr. Cancer, 6:135-147, 1984.

33. Rojas-Campos, N., Siganin, N., Bravo, A. C., and Correa, P. Salt enhances the mutagenicity of nitrosated black beans. Nutr. Cancer, 14: 1-3, 1990.

34. You, W. C., Blot, W. J., Chang, Y. S., et al. Allium vegetables and reduced risk of stomach cancer. J. Natl. Cancer Inst., 81: 162-164, 1989.

35. Block, G. Vitamin C and cancer prevention. The epidemiologic evidence. Am. J. Clin. Nutr., 53: 2705-2825, 1991.

36. Caygiil, C. P. J. UK subgroup of ECP-EURONUT-IM study group. Plasma vitamin concentration in patients with intestinal metaplasia and in controls. Eur. J. Cancer Prev., 1: 177-186, 1992.

37. Sobala, G. M., Schorah, C. J., Sanderson, M., et al. Ascorbic acid in the human stomach. Gastroenterology, 97: 357-363, 1989.

38. Haenszel, W., Correa, P., Lopez, A., Cuello, C., Zarama, G., Zavala, D., and Fontham, E. Serum micronutrient levels in relation to gastric pathology. Int. J. Cancer, 36: 43-48, 1985.

39. Santamaria, C., Bianci, A., Ravetto, C., Arnaboldi, A., Santogati, G., and Andreoni, L. Prevention of gastric cancer induced by MNNG in rats fed supplemental carotenoids. J. Nutr. Growth Cancer, 4: 175-181, 1987.

40. Bertram, J., Hossain, M. Z., Pung, A., et al. Development of in vitro system for chemoprevention research. Prey. Med., 18." 569-573, 1984.




41. Arroyo, P. L., Hatch-Pigott, V., Mower, H. F., and Cooney, R. V. Mutage- nicity of nitric oxide and its inhibition by antioxidants. Mutat. Res., 281: 193-202, 1992.

42. Tatematsu, M., Takahashi, M., and Fukushima, S. Effects in rats of sodium chlorida on experimental gastric cancers induced by N-methyl-N-nitro-N- nitrosoguanidine and 4-nitroquinoline-l-oxide. J. Natl. Cancer Inst., 55: 101-106, 1975.

43. Fontham, E., Zavala, D., Correa, P., Rodriguez, E., Hunter, F., Haenszel, W., and Tannenbaum, S. R. Diet and chronic atrophic gastritis: a case- control study. J. Natl. Cancer Inst., 76: 621-627, 1986.

44. Kneller, R., You, W. C., Liu, D., et al. Cigarette smoking and other risk factors for progression of precancerous stomach lesions. J. Natl. Cancer Inst., 84: 1261-1266, 1992.

45. Yang, D., Tannenbaum, S. R., Buch, C., and Lee, G. C. M. 4-Chloro-6- methoxyindole is the precursor of a potent mutagen that forms during nitrosation of fava beans (Vicia faba). Carcinogenesis (Lond.), 5:1219-1224 , 1984.

46. Tiednik, H. G. M., De Haan, L. H. J., Jongen, W. M. F., and Koeman, J. H. In vitro testing and the carcinogenic potential of several nitrosated indole compounds. Cell. Biol. Toxicol., 7: 371-386., 1991.

47. Wakabayashi, K., Nagao, K., Ochiai, M., et al. A mutagen precursor in chinese cabbage, indole-3-acetonitrite, which becomes mutagenic on nitrite treatment. Mutat. Res., 143: 17-21, 1985.

48. Sierra, R., Oshima, H., Munoz, N., et al. Exposure to N-nitrosamines and other risk factors for gastric cancer in Costa Rican Children. In: I. K. O'Neill, J. Chen, and H. Bartsch (eds.), Relevance to Human Cancer of N-Nitroso Compounds, Tobacco Smoke and Mycotoxins, pp. 162-167. Lyon, France: International Agency for Research on Cancer, 1991.

49. Stillwell, W. G., Glogowski, S., Xu, H. X., et al. Urinary excretion of nitrate,

N-nitrosoproline, 3-methyladenine and 7-methylguanine in a Colombian population at high risk for gastric cancer. Cancer Res., 51: 190-194, 1991.

50. Calmels, S., Bereziat, J. C., Oshima, H., and Bartsch, H. Bacterial formation of N-nitrosocompounds in rats after omeprazole-induced achlorhydria. In: I. K. O'Neill, J. Chen, and H. Bartsch (eds.), Relevance to Human Cancer of N-Nitroso Compounds, Tobacco Smoke and Mycotoxins. Scientific Publica- tion No. 105, pp. 187-191. Lyon, France: International Agency for Research on Cancer, 1991.

51. Stemmermann, G. N., Mower, H., Price, S., et al. Mutagens in extracts of gastric mucosa. In: R. Bruc, P. Correa, M. Lipkin, S. R. Tannenbaum, and T. Wilkins (eds.), Gastrointestinal Cancer, Endogenous Factors. Banbury Rep., 7: 175-183, 1981.

52. Leaf, C. D., Wishnok, J. S., and Tannenbaum, S. R. Endogenous incorpo- ration of nitric oxide from L-arginine into N-nitrosomorpholine stimulated by E. coli lipopolysaccharide in the rat. Carcinogenesis (Lond.), 12: 537-539, 1991.

53. Nguyen, T., Brunson, D., Crespi, J. L., et al. DNA damage and mutation in human cells exposed to nitric oxide in vitro. Proc. Natl. Acad Sci. USA, 89: 3030-3039, 1992.

54. Soman, N. R., Correa, P., Ruiz, B. A., and Wogan, G. N. The TRP-MET oncogenic rearrangement is present and expressed in human gastric carcinoma and precursor lesions. Proc.. Natl. Acad Sci. USA, 88." 4892-4896, 1991.

55. Kato, K., and Nakazato, H. Gastric cancer: survival rates of "early gastric cancer". Nagoya J. Med. Sci., 38: 35-42, 1975.

56. Oshima, A., Hirata, N., Ubukata, T., et al. Evaluation of a mass screening program for stomach cancer with a case-control design. Int. J. Cancer, 38." 829-833, 1986.

6740



1992;52:6735-6740. Cancer Res Pelayo Correa Cancer Epidemiology and Prevention

First American Cancer Society Award Lecture on−−ProcessHuman Gastric Carcinogenesis: A Multistep and Multifactorial

Updated version

http://cancerres.aacrjournals.org/content/52/24/6735

Access the most recent version of this article at:

E-mail alerts related to this article or journal.Sign up to receive free email-alerts

Subscriptions

Reprints and

[email protected] at

To order reprints of this article or to subscribe to the journal, contact the AACR Publications

Permissions

Rightslink site. Click on "Request Permissions" which will take you to the Copyright Clearance Center's (CCC)

.http://cancerres.aacrjournals.org/content/52/24/6735To request permission to re-use all or part of this article, use this link



http://cancerres.aacrjournals.org/cgi/alerts

mailto:[email protected]



human gastric carcinogenesis: a multistep and ... · precancerous process, namely superficial...

Documents