| [Download PDF]
|Year : 2011 | Volume
| Issue : 1 | Page : 94--98
Helicobacter pylori infection in relation to gastric cancer progression
A Venkateshwari1, D Krishnaveni1, S Venugopal1, P Shashikumar2, A Vidyasagar3, A Jyothy1,
1 Institute of Genetics and Hospital for Genetic Diseases, Osmania University, Begumpet, Hyderabad - 500 016, India
2 Sai Nikith Speciality Hospital and Laparoscopic Center, Kothapet, Hyderabad - 500 036, India
3 Department of Gastroenterology, Gandhi Hospital, Secunderabad - 500 003, India
Institute of Genetics and Hospital for Genetic Diseases, Osmania University, Begumpet, Hyderabad - 500 016
Gastric cancer is a major cause of cancer death worldwide, especially in developing countries. The incidence of gastric cancer varies from country to country, probably as a result of genetic, epigenetic, and environmental factors. H. pylori infection is considered as a major risk factor in the development of gastric cancer. However, the scenario varies in Asian countries, exhibiting a higher rate of H. pylori infection and low incidence of gastric cancer, which could be attributed to strain-specific virulence factors and host genetic makeup. In this review, we discuss the various virulence factors expressed by this bacterium and their interaction with the host factors, to influence pathogenesis.
|How to cite this article:|
Venkateshwari A, Krishnaveni D, Venugopal S, Shashikumar P, Vidyasagar A, Jyothy A. Helicobacter pylori infection in relation to gastric cancer progression.Indian J Cancer 2011;48:94-98
|How to cite this URL:|
Venkateshwari A, Krishnaveni D, Venugopal S, Shashikumar P, Vidyasagar A, Jyothy A. Helicobacter pylori infection in relation to gastric cancer progression. Indian J Cancer [serial online] 2011 [cited 2021 Jan 24 ];48:94-98
Available from: https://www.indianjcancer.com/text.asp?2011/48/1/94/75840
Gastric cancer is a major cause of morbidity and mortality worldwide. Helicobacter pylori (H. pylori) infection is one of the major causes of gastric cancer, but the exact mechanism leading to the disease is still obscure. Gastric cancer occurs when the cells in the lining of the stomach grow uncontrollably and form tumors that invade the normal tissue and result in micrometastasis. The vast majority of gastric cancers are adenocarcinomatous, a type of cancer that develops in the gastric mucosal cells, the inner most lining of the stomach. As it is asymptomatic in the early stages, it is problematic to detect or diagnose before metastasis. ,,,,
The international agency for research on cancer, in affiliation with World Health Organization, highlights the H. pylori infection as a class I carcinogen. On a global scale, gastric cancer accounts for approximately 7,00,000 deaths annually. In the US, there are 24,000 new cases and 14,000 deaths annually.  However, the prevalence of H. pylori in the Indian scenario is still obscure, despite many studies on H. pylori-related gastrointestinal disorders.
H. pylori is a microaerophilic, gram-negative, slow growing, spiral-shaped, flagellated organism that is able to grow in the human stomach. Normally the acidic microenvironment prevents the survival of viruses, bacteria, and other micro organisms. However, H. pylori has evolved to be uniquely suited to thrive in the harsh stomach environment. H. pylori secretes urease that converts urea to ammonia and carbon-di-oxide, which in turn reduces the acidity of the stomach, making it more hospitable for H. pylori. The ability to survive in the stomach helps H. pylori to coadapt in the mucosa. White blood cells that would normally recognize and attack invading bacteria are unable to cross the blood vessels to the stomach lining. Instead the ineffective white blood cells continue to respond to the site of infection where they release the nutrients for the survival of H. pylori.  The outcome of the infection may thus involve a combination of bacterial factors, host factors, as well as environmental triggers. Hence, the studies on the complex interaction of these factors are yet to be discovered.
Genetic and Non-genetic Risk Factors for Gastric Cancer
The risk factors for gastric cancer are H. pylori infection, chronic gastritis, inflammation of the stomach, pernicious anemia, intestinal metaplasia, familial adenomatous polyposis (FAP) or gastric polyps. Other risk factors are individuals with blood group A, gastric resection, consuming salt diet, preserved pickles and foods, low intake of fruits and vegetables, addiction to alcohol and smoke, familial history of stomach cancer, exposure to coal mines, processing of rubber, and nickel, abnormalities of tumor suppressor gene Tp53, overexpression, amplification, and mutations of oncogenes (c-ki-ras, HER-2/neu (aka-c-erb-b2) and c-myc, and so on. 
H. pylori Infection and Gastric Cancer
Many studies have demonstrated a link between H. pylori infection and gastric cancer. In 1994, the International Agency for Research on Cancer (IARC) classified H. pylori as a carcinogen, despite conflicting observations. Since then, colonization of the stomach with H. pylori has been increasingly accepted as an important risk factor in gastric cancer. However, this association differs in various regions of the stomach. In 2001, a combined analysis of 12 H. pylori and gastric cancer studies estimated the risk of noncardia gastric cancer to be nearly six times higher in H. pylori infected subjects than non-infected individuals. , Data reveals that H. pylori infection plays a predominant role in the development of noncardia gastric cancer, but its association with gastric cardia cancer is still obscure.
Earlier studies on the alpha-tocopheral and beta-carotene in gastric cancer revealed H. pylori as a strong risk factor for non-cardia gastric cancer and an eight-fold increased risk for the disease. In contrast, another study found that the presence of bacteria decreased the risk for cardia gastric cancer by about two-thirds.  Decline in H. pylori infection in developed countries coincided with a decline in the rates of non-cardia gastric cancer, but a rise in the rates of gastric cardia cancer and certain types of esophageal cancers was observed. Thus, the actual role of H. pylori infection in gastric cancer has to be elucidated in the Indian context.
Several studies from India failed to show a higher frequency of H.pylori infection in patients with gastric cancer than in controls, which could be correlated to the variations of the strains. Diet may play a major role in gastric carcinogenesis. In India, the southern and eastern parts experience a somewhat higher frequency of gastric cancer than the northern parts of the country, which could be due to tobacco smoking, high temperature food intake, spicy food, and rice consumption. Tobacco use and alcohol consumption are the other factors that may influence the variation in the frequency of gastric cancer.  Thus, the actual role of H. pylori in relation to the host genetic makeup and dietary and environmental factors, needs to be elucidated in the Indian scenario.
H. pylori infection is more frequent in less developed Asian countries like India, however, the frequency of gastric cancer is very low in India. The host's genetic makeup and the dietary and environmental factors might explain this mystery. Hence, studies on H. pylori in relation to genetic and environmental risk factors are urgently required.
Host factors also play an important role in the predisposition to H. pylori-induced diseases and susceptibility to a severe pathological outcome. The host factors relevant in H. pylori-induced diseases mainly include components of the gastric secretion system and the immune apparatus. Gastritis and ulcer disease that result from bacterial infection have distinct clinical profiles and are inversely associated with a high degree of acid secretion, whereas, gastric cancers are associated with a low acid secretion due to the loss of parietal cell mass. , In a recent study on the East Indian population, an association between IL-1B gene polymorphism and H. pylori-mediated duodenal ulcer risk was suggested. Differences in the risk to carcinogenesis from different geographical areas clarify the differences in their genetic makeup, suggesting the variation in host-pathogen interactions.
Virulent strains of H. pylori survive in the gastric mucosa and colonize and recolonize in high densities. Thus, bacterial adhesion is crucial in signal transduction, activation of NF kappa B, and subsequent secretion of interleukin-8, which is important in the inflammatory response during infection. Another factor that may be related to H. pylori infection susceptibility is the composition of the mucins present in the mucosal gel of the stomach. This layer protects the acid proteases, mechanical trauma, and pathogenic microorganisms. They exhibit inter-individual variation in a number of of side chains called variable number tandem repeats (VNTRs). The polymorphism in these genes result in mucin polypeptides that substantially differ in both length and glycosylation, which may further affect the protective properties of mucins and consequently lead to H. pylori infection.
In addition to the differences in the host response, the bacterial determinants also contribute to the disease outcome. H. pylori strain-specific factors may influence the pathogenecities of different H. pylori isolates.  H. pylori strains have been divided into types I and II. Type I strains express cagA and vacA, whereas, type II strains do not. It has been suggested that duodenal ulcer patients are more likely to be infected with the type I strain. ,
A strain specific H. pylori gene cagA is a component of the cag pathogenecity Island. Several genes within this island encode products that are homologs of proteins of the type IV bacterial secretion pathway.  The cagA (cytotoxin associated gene A) gene of H. pylori is the main virulence factor that leads to the development of gastric adenocarcinoma through the derangement of cellular architecture and signaling.  Severe ulceration of the stomach and duodenum is caused by cagA + strains; cagA, the effector protein product of cagA, is tyrosine phosphorylated by SRC kinases after its secretion on the intestinal mucosal surface. , Strains with multiple cagA tyrosine phosphorylation motifs are more commonly associated with gastric cancer than those with fewer cagA phosphorylation motifs, which may be associated with gastritis and the like. ,,
The cagA gene product is a highly immunogenic outer membrane protein with an appropriate molecular weight of 1, 20 ,000 - 1,40,000 Da. The cagA gene consists of an open reading frame encoding 1147 - 1181 amino acids. , The cagA gene is part of a cag pathogenecity island, a 40 kb DNA region, containing open reading frames that code a putative H. pylori secretion system that may be associated with the export of virulence factors to the extracellular compartment.  The structure of the gene reveals a 5′ highly conserved region. Variation in the size of the protein has been correlated with the presence of a variable number of repeat sequences located in the 3′ region of the cagA gene. As cagA is strongly immunogenic, it is possible that the repeats affect the host immune response.
Polymerase chain reaction (PCR) and sequencing of the PCR products led to the identification of four types of the cagA genes (types A-D) those differed in the structural organization of their primary sequences, as a result of variation and the number of different repeat regions. The repeats in the Japanese strains were designated as R1, R2, and R3. The most frequent type of cagA 3′ region was type A, whose PCR product size ranged from 642 to 651 bp. The second-most frequent type of cagA structure in Japan was type C, which contained two copies of the R3 region, with each copy being flanked by R1 regions. The combination of PCR and sequencing allowed for the distinction of four cagA types with different primary gene structures. Type A and C could be distinguished by their sizes on PCR, but types B and C had the same PCR product length and could be distinguished only by sequencing. The type B cag A gene and type D cag A gene consisted of a 756 bp PCR product, whereas, the type C cag A gene consisted of a 810 - 813 bp PCR product. It was suggested that the presence of repeat regions in the 3′ region of the cag A gene could result in proteins with different immunogenecities. It is unlikely that the presence of these repeats is useful for generating antigenic diversity, because, within the same geographic population, the primary gene sequence of these regions is significantly conserved. The presence of multiple repeats may also generate immunodominant nonprotective epitopes, which can act as carcinogens and result in H. pylori infection.
Several other proteins of the cag PAI (cag pathogenecity island) include outer membrane envelop proteins, flagellins, adhesions, neutrophil activating proteins (NAP), porins, LPS, urease, and some members of the plasticity region cluster, which probably play an important role in the inflammatory process.  Hence, further studies are required for the elucidation of these factors.
The second polymorphic H. pylori locus is vacA, which encodes the vacuolating cytotoxin. H. pylori have a single copy of the vacA (vacuolating cytotoxin A) gene encoding the VacA protein, a secreted 95 kda peptide. The vacA gene varies in its signal sequence (alleles s1a, s1b, s2) and its middle region (allele m1, m2) among different H. pylori populations. The different allotypes of the s and m regions determine the extent of cytotoxicity of the vacA. Strains with the vacA genotype s1 / m1 are more commonly associated with gastric cancer., The vacA has been shown to induce apoptosis in epithelial cells. In recent times, the VacA protein has been proposed to be a potent immunomodulatory toxin, targeting the adopted immune system, to suppress the local immune response and prolong the outcome of infection, and thus prevent the clearance by the host immune system. A recent study argues that vacA has a miniscule role as a virulence factor during cell evasion by H. pylori. The vacA null mutant of H. pylori is able to evade specific cell lines, as does its wild type.  The vacA involvement is still part of a debate on its being a true virulence factor and awaits further investigation.
Inactivation of the cagA gene had no effect on the expression of vacA or on the ability to induce IL-8. It has been suggested that cagA is only a marker for increased virulence. , Most cagA + strains also express vacuolating cytotoxin activity. Infection with cytotoxin-producing strains, as assessed by the presence of serum neutralizing antibodies, may be associated with the presence of gastric cancer. Due to the conflicting results, there is a need for further elucidation of these factors.
The babA gene encodes an outer membrane protein babA, which binds to the fucosylated lewis B blood group antigen on the gastric cells. There is significant evidence that bab A expression may influence the severity of the disease. H. pylori strains that possess babA, vacA, and cagA carry the highest risk of gastric cancer. 
Apart from cagA and vacA, a new candidate gene designated the iceA (induced by contact with the epithelium) product was suggested to have an association with peptic ulcer. ,, The iceA gene exists as two distinct genotypes iceA1 and iceA2. Carriage of iceA1 strains has been associated with peptic ulceration in some studies, but not in all. 
Immunoblast studies suggest that persons infected with cagA + strains have a high degree of gastric inflammation and epithelial cell damage than do persons from whom cagA - strains have been isolated. Infection with cagA + strains have been associated with enhanced epithelial cell injury, and injury to the surface gastric epithelial cells may promote or possibly initiate oncogenesis, via the expression of proinflammatory cytokines such as IL-1, IL-1B, and IL-8. Patients harboring cagA / vacA-positive strains of H. pylori exhibit an enhanced expression of various cytokines, thereby causing major DNA damage, which over a period leads to accumulation of mutations, resulting in gastric cancer. Hence, genotyping of H. pylori may be a useful marker in screening the individuals at an increased risk of developing malignancy. 
Thus, studies on the interaction between the host factors and pathogen virulence factors are essential for the infectivity status. Hence, the studies on host genotypes and virulence factors need to be elucidated for possible interactions in the pathogenesis of gastric cancer.
|1||Parkin DM, Bray F, Ferlay J, Pisani P. Global cancer statistics, 2002. CA Cancer J Clin 2005;55:74-108.|
|2||Beswick EJ, Suarez G, Reyes VE. H. pylori and host interactions that influence pathogenesis. World J Gastroenterol 2006;12:5599-605.|
|3||Yamaoka Y, Kodama T, Gutierrez O, Kim JG, Kashima K, Graham DY. Relationship between Helicobacter pylori iceA, cagA, and vacA status and clinical outcome: Studies in four different countries. J Clin Microbiol 1999;37:2274-9.|
|4||Akhter Y, Ahmed I, Devi SM, Ahmed N. The co-evolved Helicobacter pylori and gastric cancer: Trinity of bacterial virulence, host susceptibility and lifestyle. Infect Agent Cancer 2007;2:2-6.|
|5||Israel DA, Salama N, Arnold CN, Moss SF, Ando T, Wirth HP, et al. Helicobacter pylori strain-specific differences in genetic content, identified by microarray, influence host inflammatory responses. J Clin Invest 2001;107:611-20.|
|6||Nogueira C, Figueiredo C, Carneiro F, Gomes AT, Barreira R, Figueira P, et al. Helicobacter pylori genotypes may determine gastric histopathology. Am J Pathol 2001;158:647-54.|
|7||Tomb JF, White O, Kerlavage AR, Clayton RA, Sutton GG, Fleischmann RD, et al. The complete genome sequence of the gastric pathogen Helicobacter pylori. Nature 1997;388:539-47.|
|8||Sumathi B, Ramalingam S, Navaneethan U, Jayanthi V. Risk factors for gastric cancer in South India. Singapore Med J 2009;50:147-51.|
|9||Blaser MJ, Perez-Perez GI, Kleanthous H, Cover TL, Peek RM, Chyou PH, et al. Infection with Helicobacter pylori Strains Possessing cagA Is Associated with an Increased Risk of Developing Adenocarcinoma of the Stomach. Cancer Res 1995;55:2111-5. |
|10||Yamaoka Y ,Kodama T, Kashima K, Graham DY, Sepulveda AR. Variants of the 3' Region of the cagA Gene in Helicobacter pylori Isolates from Patients with different H. pylori-Associated Diseases. J Clin Microbiol 1998;36:2258-63.|
|11||Kamangar F, Dawsey SM, Blaser MJ, Perez-Perez GI, Pietinen P, Newschaffer CJ, et al. Opposing risks of gastric cardia and noncardia gastric adenocarcinomas associated with Helicobacter pylori seropositivity. J Natl Cancer Inst 2006;98:1445-52.|
|12||Singh K, Ghoshal UC. Causal role of Helicobacter pylori infection in gastric cancer: An asian enigma. World J Gastroenterol 2006;12:1346-51.|
|13||El-Omar EM, Oien K, El-Nujumi A, Gillen D, Wirz A, Dahill S, et al. Helicobacter pylori infection and chronic gastric acid hyposecretion. Gastroenterology 1997;113:15-24.|
|14||Hansson LE. Risk of stomach cancer in patients with peptic ulcer disease. World J Surg 2000;24:315-20.|
|15||Whittam TS, Wolfe ML, Wachsmuth IK, Orskov F, Orskov I, Wilson RA. Clonal relationships among Escherichia coli strains that cause hemorrhagic colitis and infantile diarrhea. Infect Immun1993;61:1619-29. |
|16||Censini S, Lange C, Xiang Z, Crabtree JE, Ghiara P, Borodovsky M, et al. cag, a pathogenicity island of Helicobacter pylori, encodes type I-specific and disease-associated virulence factors. Proc Natl Acad Sci USA 1996;93:14648-53.|
|17||Xiang Z, Censini S, Bayeli PF, Telford JL, Figura N, Rappuoli R, et al. Analysis of expression of CagA and VacA virulence factors in 43 strains of Helicobacter pylori reveals that clinical isolates can be divided into two major types and that CagA is not necessary for expression of the vacuolating cytotoxin. Infect Immun 1995;63:94-8.|
|18||Tummuru MK, Sharma SA, Blaser MJ. Helicobacter pylori picB, a homologue of the Bordetella pertussis toxin secretion protein, is required for induction of IL-8 in gastric epithelial cells. Mol Microbiol 1995;18:867-76.|
|19||Tummuru MK, Cover TL, Blaser MJ. Mutation of the cytotoxin-associated cagA gene does not affect the vacuolating cytotoxin activity of Helicobacter pylori. Infect Immun 1994;62:2609-13.|
|20||Oksanen A, Sipponen P, Karttunen R, Miettinen A, Veijola L, Sarna S, et al. Atrophic gastritis and Helicobacter pylori infection in outpatients referred for gastroscopy. Gut 2000;46;460-3.|
|21||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.|
|22||Hatakeyama M. Oncogenic mechanisms of Helicobacter pylori cagA protein. Nature Rev Cancer 2004;4:688-94.|
|23||Yamaoka Y, Kodama T, Kashima K, Graham DY, Sepulveda AR. Variants of the 3' region of the cagA gene in Helicobacter pylori isolates from patients with different H. pylori-associated diseases. J Clin Microbiol 1998;36:2258-63.|
|24||Azuma T, Yamakawa A, Yamazaki S, Ohtani M, Ito Y, Muramatsu A, et al. Distinct diversity of the cag pathogenicity island among Helicobacter pylori strains in Japan. J Clin Microbiol 2004;42:2508-17.|
|25||Argent RH, Kidd M, Owen RJ, Thomas RJ, Limb MC, Atherton JC. Determinants and consequences of different levels of CagA phosphorylation for clinical isolates of Helicobacter pylori. Gastroenterology 2004;127:514-23.|
|26||Covacci A, Censini S, Bugnoli M, Petracca R, Burroni D, Macchia G, et al. Molecular characterization of the 128-kDa immunodominant antigen of Helicobacter pylori associated with cytotoxicity and duodenal ulcer. Proc Natl Acad Sci 1993;90:5791-5.|
|27||Sharma SA, Tummuru MK, Miller GG, Blaser MJ. Interleukin-8 response of gastric epithelial cell lines to Helicobacter pylori stimulation in vitro. Infect Immun 1995;63:1681-7.|
|28||Tiwari SK, Manoj G, Kumar GV, Sivaram G, Hassan SI, Prabhakar B, et al. Prognostic significance of genotyping Helicobacter pylori infection in patients in younger age groups with gastric cancer. Postgrad Med J 2008;84:193-7.|
|29||Figueiredo C, Quint W, Nouhan N, Van den Munckhof H, Herbrink P, Scherpenisse J, et al. Assessment of Helicobacter pylori vacA and cagA genotypes and host serological response. J Clin Microbiol 2001;39:1339-44.|
|30||Gebert B, Fischer W, Weiss E, Hoffmann R, Haas R. Helicobacter pylori Vacuolating Cytotoxin Inhibits T Lymphocyte Activation. Science 2003;301:1099-102.|
|31||Oliveira MJ, Costa AC, Costa AM, Henriques L, Suriano G, Atherton JC, et al. Helicobacter pylori Induces Gastric Epithelial Cell Invasion in a c-Met and Type IV Secretion System-dependent Manner. J Biol Chem 2006;281:34888-96.|
|32||Xiang Z, Bugnoli M, Ponzetto A, Morgando A, Figura N, Covacci A, et al. Detection in an enzyme immunoassay of an immune response to a recombinant fragment of the 128 kilodalton protein (CagA) of Helicobacter pylori. Eur J Clin Microbiol Infect Dis 1993;12:739-45.|
|33||Crabtree JE, Xiang Z, Lindley IJ, Tompkins DS, Rappuoli R, Covacci A. Induction of interleukin-8 secretion from gastric epithelial cells by a cagA negative isogenic mutant of Helicobacter pylori. J Clin Pathol 1995;48:967-9.|
|34||Everhart JE. Recent developments in the epidemiogy of Helicobacter pylori. Gastroenterol Clin North Am 2000;29:559-78.|
|35||Peek RM, Thompson SA, Atherton JC, Blaser MJ, Miller GG. Expression of a novel ulcer-associated H. pylori gene, iceA, Following adherence to gastric epithelial cells. Gastroenterolology 1996;110:225-8.|
|36||Peek RM, Thompson SA, Donahue JP, Tham TK, Atherton JC, Blaser MJ, et al. Adherence to gastric epithelial cells induces expression of a Helicobacter pylori gene, iceA, that is associated with clinical outcome. Proc Assoc Am Phys 1998;110:531-44.|
|37||Van Doorn LJ, Figueiredo C, Sanna R, Plaisier A, Schneeberger P, De Boer W, et al. Clinical relevance of the cagA, vacA, and iceA status of Helicobacter pylori. Gastroenterology 1998;115:58-66.|
|38||Ito Y, Azuma T, Ito S, Suto H, Miyaji H, Yamazaki Y, et al. Sequence analysis and clinical significance of the iceA gene from Helicobacter pylori strains in Japan. J Clin Microbiol 2000;38:483-8.|
|39||Atherton JC, Cao P, Peek RM Jr, Tummuru MK, Blaser MJ, Cover TL. Mosaicism in vacuolating cytotoxin alleles of Helicobacter pylori: Association of specific vacA types with cytotoxin production and peptic ulceration. J Biol Chem 1995;270:17771-7.|