Abstract
Background: Numerous studies have shown an association between Helicobacter pylori (Hp) infection and gastric cancer (GC). Study: This study was designed to determine the role of cytotoxin-associated gene A (CagA)-positive Hp infection, serum amidated gastrins and their precursor, progastrin, gastric acidity and serum pepsinogen I (PG-I) levels in gastric cancerogenesis in 74 cancer patients and in 77 age- and gender-matched controls. Serum IgG antibodies to Hp and CagA and levels of IL-8 and PG-I were measured by ELISA, while progastrin and amidated gastrin by specific radioimmunoassay. Results: The overall Hp and CagA seropositivity in GC patients were significantly higher (82 and 60%) than in matched controls (61 and 27%, respectively). Progastrin and amidated gastrin levels over their cutoff points (122 and 32 pM, respectively) were found in a significantly larger number of GC (59.4 and 44.5%) than in controls (9.0 and 16.8%, respectively). Histologically, all these GCs with increased serum progastrin and amidated gastrins were of intestinal type and showed CagA and Hp seropositivity. Serum IL-8 and gastric pH, above their cutoff points (pH >4.5), and serum PG-I level below its cutoff point (44.2 µg/l) were observed in a significantly higher number of GC patients as compared to controls. Conclusions: (1) GC patients have higher Hp and CagA seroprevalence than matched controls, confirming that CagA-positive Hp infection is associated with higher risk of GC; (2) serum levels of amidated gastrins and their precursor, progastrin, as well as IL-8 are significantly higher, while serum PG-I levels are reduced in intestinal type GC compared to controls, and (3) determination of high serum progastrin, amidated gastrins and IL-8 combined with low serum PG-I may be useful biomarkers of GC.
Journal Section:
Original Paper: Stomach
References
1.
Webb PM, Forman D: Helicobacter pylori as a risk factor for cancer. Ballieres Clin Gastroenterol 1996;9:563–582.
2.
Crespi M, Citarda F: Helicobacter pylori and gastric cancer: An overrated risk? Scand J Gastroenterol 1996;31:1041–1046.
[PubMed]
3.
Danesh J: Helicobacter pylori infection and gastric cancer: Systemic review of the epidemiological studies. Aliment Pharmacol Ther 1999;13:851–856.
[PubMed]
4.
Konturek SJ, Starzynska T, Konturek PC, Karczewska E, Marlicz K, Lawniczak M, Jaroszewicz-Heigelman H, Bielanski W, Hartwich A, Ziemniak A, Hahn EG: H. pylori and Cag A status, serum gastrin, interleukin-8 and gastric acid in gastric cancer. Scand J Gastroenterol 2002;37:891–898.
[PubMed]
5.
IARC Working Group: Monographs on the Evaluation of the Carcinogenic Risks to Humans: Schistosomes, Liver Flukes and Helicobacter pylori. Geneva, IARC, 1994, pp 177–241.
6.
Karnes WE Jr, Samloff IM, Siurala M, Kekki M, Sipponen P, Kim SW, Walsh JH: Positive serum antibody and negative tissue staining for Helicobacter pylori in subjects with atrophic body gastritis. Gastroenterology 1991;101:167–174.
[PubMed]
7.
Sakaki N, Momma K, Egawa N, Yamada Y, Kan T, Ishiwata J: The influence of Helicobacter pylori infection on the progression of gastric mucosa atrophy and occurrence of gastric cancer. Eur J Gastroenterol Hepatol 1995;7(suppl 1):S59–S62.
8.
Kikuchi S, Nakajima T, Kobayashi O, Yamazaki T, Kikuichi M, Mori K, Oura S, Watanabe H, Nagawa H, Otani R, Okamoto N, Kurosawa M, Anzai H, Kubo T, Konishi T, Futagawa S, Mizobuchi N, Kobori O, Kaise R, Sato T, Inaba Y, Wada O: Effect of age on the relationship between gastric cancer and Helicobacter pylori. Tokyo Research Group of Prevention for Gastric Cancer. Jpn J Cancer Res 2000;91:774–779.
[PubMed]
9.
Baldini L, Pretolani S, Bonvicini F, Miglio F, Epifanio G, Gentiloni Silveri N, Stefanelli ML, Bernardi M, Gasbarrini G: Effect of Helicobacter pylori infection, age and epithelial cell turnover in a general population at high risk for gastric cancer. Panminerva Med 1999;41:187–192.
[PubMed]
10.
Handa Y, Saitoh T, Kawaguchi M, Misaka R, Tsurui M, Ohno H, Morita S, Sanji T, Tani Y, Sakai Y, Umezawa H: Production of secretory component and pathogenesis of gastric cancer in Helicobacter pylori-infected stomach. J Gastroenterol 1999;34(suppl 11):37–42.
11.
Araya JC, Villaseca MA, Roa I, Roa JC: Helicobacter pylori and chronic gastritis: Relation between infection and inflammatory activity in a high risk population for gastric cancer. Rev Med Chil 2000;128:259–265.
[PubMed]
12.
Testino G, Valentini M, Cornaggia M: Helicobacter pylori and gastric cancer. Am J Gastroenterol 2000;95:2131–2133.
13.
Honig A, Witte F, Mirecka J, Binder C, Schauer A: Helicobacter pylori-induced hyperproliferation: Relevance for gastric cancer development in connection with mutagenic factors. Anticancer Res 2000;20:1641–1648.
[PubMed]
14.
Graham D: Helicobacter pylori infection is the primary cause of gastric cancer. J Gastroenterol 2000;35(suppl 12):90–97.
15.
Correa P, Haenszel W, Cuello C, Tannenbaum S, Archer M: A model for gastric cancer epidemiology. Lancet 1975;ii:58–60.
16.
Warren JR, Marshall BJ: Unidentified curved bacteria on gastric epithelium in active chronic gastritis. Lancet 1983;i:1273–1275.
17.
Cotton JP, Oglesby SD, Thompson AM, Dillon JF: Gastrin mediated expression of p53 in AGS gastric cancer cells. Gut 2001;48:A17.
18.
Konturek PC, Pierzchalski P, Konturek SJ, Meixner H, Faller G, Kirchner T, Hahn EG: Helicobacter pylori induces apoptosis in gastric mucosa through an upregulation of Bax expression in human. Scand J Gastroenterol 1999;34:375–383.
[PubMed]
19.
Peek RM Jr, Moss SF, Tham KT, Perez-Perez GI, Wang S, Miller GG, Atherton JC, Holt PR, Blaser MJ: Helicobacter pylori cagA(+) strains and dissociation of gastric epithelial cell proliferation from apoptosis. J Natl Cancer Inst 1997;89:863–868.
[PubMed]
20.
Drake IM, Mapstone NP, Schorah CJ, White KL, Chalmers DM, Dixon MF, Axon AT: Reactive oxygen species activation in Helicobacter pylori associated gastritis: Relation to gastric mucosal ascorbic acid concentrations and effect of H. pylori eradication. Gut 1998;42:768–771.
[PubMed]
21.
Feitz HR, Mobarhan S: Does vitamin C intake slow the progression of gastric cancer in Helicobacter pylori-infected population? Nutr Rev 2002;60:34–36.
22.
Watanabe T, Tada M, Nagai H, Sasaki S, Nakao M: Helicobacter pylori infection induced gastric cancer in Mongolian gerbils. Gastroenterology 1998;115:642–648.
[PubMed]
23.
Kuipers EJ, Perez-Perez GI, Meuwissen SG, Blaser MJ: Helicobacter pylori and atrophic gastritis: Importance of the cagA status. J Natl Cancer Inst 1995;87:1777–1780.
[PubMed]
24.
Blaser MJ, Perez-Perez GI, Kleanthous H, Cover TL, Peek RM, Chyou PH, Stemmermann GN, Nomura A: Infection with Helicobacter pylori strains possessing cagA associated with an increased risk of developing adenocarcinoma of the stomach. Cancer Res 1995;55:2111–2115.
[PubMed]
25.
Konturek PC, Konturek SJ, Bobrzynski A, Kwiecień N, Obtulowicz W, Stachura J, Hahn EG, Rembiarz K: Helicobacter pylori and impaired gastric secretory functions associated with duodenal ulcer and atrophic gastritis. J Physiol Pharmacol 1997;48:365–373.
[PubMed]
26.
Konturek PC, Bielanski W, Bobrzynski A, Hahn EG, Konturek SJ: Gastric mucosal expression and luminal release of growth factors in gastric carcinoma and duodenal ulcer patients before and after eradication of Helicobacter pylori. J Physiol Pharmacol 1997;48:375–382.
[PubMed]
27.
Konturek PC, Konturek SJ, Sulekova Z, Meixner H, Bielanski W, Starzynska T, Karczewska E, Marlicz K, Stachura J, Hahn EG: Expression of hepatocyte growth factor, transforming growth factor alpha, apoptosis related proteins Bax and Bcl-2, and gastrin in human gastric cancer. Aliment Pharmacol Ther 2001;15:989–999.
[PubMed]
28.
Peterson WL: Gastrin and acid in relation to Helicobacter pylori. Aliment Pharmacol Ther 11996;10(suppl 1):97–102.
29.
McColl KEL, El-Omar EM, Gillen D: The role of H. pylori infection in the pathophysiology of duodenal ulcer. J Physiol Pharmacol 1997;48:287–296.
[PubMed]
30.
Konturek JW, Bielanski W, Konturek SJ, Domschke W: Eradication of Helicobacter pylori and gastrin-somatostatin link in duodenal ulcer patients. J Physiol Pharmacol 1996;47:161–175.
[PubMed]
31.
Parsonnet J, Friedman GD, Orentreich N, Vogelman H: Risk for gastric cancer in people with CagA positive and CagA negative Helicobacter infection Gut 1997;40:297–301.
32.
Kitahara F, Kobyashi K, Sato T, Kojima Y, Araki T, Fujino MA: Accuracy for screening of gastric cancer using serum pepsinogen concentrations. Gut 1999;44:693–697.
[PubMed]
33.
Wang TC, Dangler CA, Chen D, Goldenring R, Koh TJ, Raychowdhury R, Coffey RJ, Ito S, Varro A, Dockray GJ, Fox JG: Hypergastrinemia leads to atrophy and invasive gastric cancer in transgenic mice. Gastroenterology 1999;116:G2314.
34.
Konturek PC, Bielanski W, Konturek SJ, Hartwich A, Pierzchalski P, Gonciarz M, Marlicz K., Starzyńska T, Zuchowicz M, Darasz Z, Gotze J, Rehfeld JF, Hahn EG: Progastrin and cyclooxygenase-2 in colorectal cancer. Dig Dis Sci 2002;47:1984–1991.
[PubMed]
35.
Smith AM, Watson SA: Review article; gastrin and colorectal cancer. Aliment Pharmacol Ther 2002;14:1221–1247.
36.
Varis K, Sipponen P, Laxen F, Samloff IM, Hutunen JK, Taylor PR, Heinonen OP, Albanes D, Sande N, Virtamo J, Harkonen M: Implications of serum pepsinogen I in early endoscopic diagnosis of gastric cancer and dysplasia. Helsinki Gastritis Study Group. Scand J Gastroenterol 2000;35:950–956.
[PubMed]
37.
Altman DG: Practical Statistics for Medical Research. London, Chapman & Hall, 1991.
38.
Press WH: Numerical Receipts. The Art of Scientific Computing. Cambridge, Cambridge University Press, 1992.
39.
Metz CE: Basic principles of ROIC analysis. Semin Nucl Med 1978;8:283–298.
[PubMed]
40.
Hanley JAZ, McNeil BJ: The meaning and use of area under a receiver operating characteristics (ROC) curve. Radiology 1982;143:29–36.
[PubMed]
41.
Parkin DM, Pisani P, Ferlay J: Estimates of the worldwide incidence of eighteen major cancer in 1985. Int J Cancer 1993;54:594–606.
[PubMed]
42.
Forman D, Newell DG, Fullerton F, Yarnell JW, Stacey AR, Wald N, Sitas F: Association between infection with Helicobacter pylori and risk of gastric cancer: Evidence from a prospective investigation. BMJ 1991;302:1302–1305.
[PubMed]
43.
Nomura A, Stemmermann GN, Chyou PH, Kato I, Perez-Perez GI, Blaser MJ: Helicobacter pylori infection and gastric carcinoma in a population of Japanese-Americans in Hawaii. N Engl J Med 1991;325:1132–1136.
[PubMed]
44.
Parsonnet J, Friedman GD, Vandersteen DP, Chang Y, Vogelman JH, Orentreich N, Sibley RK: Helicobacter pylori infection and the risk of gastric carcinoma. N Engl J Med 1991:325:1127–1131.
[PubMed]
45.
Forman D: Essential co-factors in gastric carcinogenesis; in Hunt RH, Tytgat GJ: (eds): Helicobacter pylori: Basic Mechanisms to Clinical Cure. London, Kluwer Academic, 1996, pp 225–261.
46.
Parsonnet J, Friedman GD, Orentreich N, Vogelman H: Risk for gastric cancer in people with CagA positive or CagA negative Helicobacter pylori infection. Gut 1997;40:297–301.
[PubMed]
47.
Marshall BJ, Armstrong JA, McGechie DB, Glancy RJ: Attempt to fulfill Koch’s postulates for pyloric campylobacter. Med J Austr 1985;142:436–439.
48.
Dooley CP, Cohen H, Fitzgibbons PL, Bauer M, Appleman MD, Perez-Perez GI, Blaser MJ: Prevalence of Helicobacter pylori infection and histologic gastritis in asymptomatic persons. N Engl J Med 1989;321:1562–1566.
[PubMed]
49.
Genta RM: The immunology of Helicobacter pylori gastritis. Semin Gastrointest Dis 1997;81:2–11.
50.
Sakaki N, Momma K, Egawa N, Yamada Y, Kann T, Ishiwata J: The influence of Helicobacter pylori infection on the progression of gastric mucosa atrophy and occurrence of gastric cancer. Eur J Gastroenterol Hepatol 1995;7:559–562.
[PubMed]
51.
Ekstrom AM, Held M, Hansson LE, Engstrand L, Nyren O: Helciobacter pylori in gastric cancer established by CagA immunoblot as a marker of past infection. Gastroenterology 2001;121:784–791.
[PubMed]
52.
Uemura N, Okamoto S, Yamamoto S, Matsumura N, Yamaguchi S, Yamakido M, Taniyama K, Sasaki N, Schlemper RJ: Helicobacter pylori infection and the development of gastric cancer. N Engl J Med 2001;345:784–789.
[PubMed]
53.
Uemura N, Mukai T, Okamoto S, Yamaguschi S, Mashiba H, Taniyama K, Sasaki N, Haruma K, Sumii K, Kajiyama G: Effect of Helicobacter pylori eradication on subsequent development of cancer after endoscopic resection of early gastric cancer. Cancer Epidemiol Biomarkers Prev 1997;6:639–642.
[PubMed]
54.
Cox AJ: Stomach size and its relation to chronic peptic ulcer. Arch Pathol 1952;54:407–422.
55.
Dockray GJ, Varro A, Dimaline R, Wang T: The gastrins: Their production and biological activities. Annu Rev Physiol 2001;63:119–139.
[PubMed]
56.
Wang TC, Koh TJ, Varro A, Cahill RJ, Dangler CA, Fox JG, Dockray GJ: Processing and proliferative effects of human progastrin in transgenic mice. J Clin Invest 1996;98:1918–1929.
[PubMed]
57.
Queiroz DM, Mendes EN, Rocha GA, Oliveira AM, Magalhaes PP, Moura SB, Cabral MM, Nogueira AM: Caga-positive Helicobacter pylori and risk for developing gastric cancer carcinoma in Brazil. Int J Cancer 1998;78:135–139.
[PubMed]
58.
Rugge M, Busatto G, Cassaro M, Shiao YH, Russo V, Leandro G, Avellini C, Fabiano A, Sidoni A, Covacci A: Patients younger than 40 years with gastric carcinoma. Helicobacter pylori genotype and associated gastritis phenotype. Cancer 1999;85:2506–2511.
[PubMed]
59.
Van Solinge WW, Rehfeld JF: Co-transcription of gastrin and cholecystokinin genes with selective transcription of gastrin mRNA in a human gastric carcinoma cell line. FEBS Lett 1992;309:47–50.
[PubMed]
60.
Watson SA, Durrant LG, Wencyk PM, Watson AL, Morris DL: Intracellular gastrin in human gastrointestinal tumor cells. J Natl Cancer Inst 1991;83:866–871.
[PubMed]
61.
Iwase K, Evers BM, Hellmich MR, Guo YS, Higashide S, Kim HJ, Townsend CM Jr: Regulation of growth of human gastric cancer by gastrin and glycine-extended progastrin. Gastroenterology 1997;13:782–790.
62.
McWilliams DF, Watson SA, Crosbee DM, Michaeli D, Seth R: Coexpression of gastrin and gastrin receptors (CCK-B and CCK-B) in gastrointestinal tumor cell lines. Gut 1998;42:795–798.
[PubMed]
63.
Watson SA, Morris TM, Varro A, Michaeli D, Smith AM: A comparison of therapeutic effectiveness of gastrin neutralization in two human gastric cancer models: Relation endocrine and autocrine/paracrine gastrin mediated growth. Gut 1999;45:812–817.
[PubMed]
64.
Konturek PC, Rembiasz K, Konturek SJ, Stachura J, Bielanski W, Galuschka K, Karcz D, Hahn EG: Gene expression of ornithine decarboxylase, cyclooxygenase-2 and gastrin in atrophic gastric mucosa infected with Helicobacter pylori before and after eradication therapy. Dis Dig Sci 2003;48:36–46.
65.
Smith A, Justin T, Watson SA: Clinical outcome of advanced colorectal cancer patients treated with the anti-gastrin immunogen, Gastrimmune. Br J Surg 1998;85:1556.
66.
Bliss PW, Healey ZV, Arebi N, Calam J: N-alpha-methyl histamine and histamine stimulate gastrin release from rabbit G-cells via histamine H2-receptors. Aliment Pharmacol Ther 1999;13:1669–1674.
[PubMed]
67.
Chowers MY, Keller N, Tal R, Barshack I, Lang R, Bar-Meir S, Chowers Y: Human gastrin: A Helicobacter pylori-specific growth factor. Gastroenterology 1999;117:1113–1118.
[PubMed]
68.
Konturek PC, Konturek SJ, Sito E, Kwiecien N, Obtulowicz W, Bielanski W, Hahn EG, Konturek SJ: Luminal Nα-methyl histamine stimulates gastric acid secretion in duodenal ulcer patients via releasing gastrin. Eur J Pharmacol 2001;412:36–46.
69.
Konturek PC, Kania J, Kukharsky V, Icker S, Hahn EG, Konturek SJ: Influence of gastrin on the expression of cyclooxygenase-2, hepatocyte growth factor and apoptosis-related proteins in gastric epithelial cells. J Physiol Pharmacol 2003;54:17–32.
[PubMed]
© 2003 S. Karger AG, Basel
Copyright / Drug Dosage / Disclaimer
Copyright: All rights reserved. No part of this publication may be translated into other languages, reproduced or utilized in any form or by any means, electronic or mechanical, including photocopying, recording, microcopying, or by any information storage and retrieval system, without permission in writing from the publisher.
Drug Dosage: The authors and the publisher have exerted every effort to ensure that drug selection and dosage set forth in this text are in accord with current recommendations and practice at the time of publication. However, in view of ongoing research, changes in government regulations, and the constant flow of information relating to drug therapy and drug reactions, the reader is urged to check the package insert for each drug for any changes in indications and dosage and for added warnings and precautions. This is particularly important when the recommended agent is a new and/or infrequently employed drug.
Disclaimer: The statements, opinions and data contained in this publication are solely those of the individual authors and contributors and not of the publishers and the editor(s). The appearance of advertisements or/and product references in the publication is not a warranty, endorsement, or approval of the products or services advertised or of their effectiveness, quality or safety. The publisher and the editor(s) disclaim responsibility for any injury to persons or property resulting from any ideas, methods, instructions or products referred to in the content or advertisements.
2004
You do not currently have access to this content.
