Review

Continuing Medical EducationNature Clinical Practice Oncology (2005) 2, 90-97
doi:10.1038/ncponc0081  
Received 18 October 2004 | Accepted 23 December 2004

Mechanisms of Disease: inflammation and the origins of cancer

Steven F Moss* and Martin J Blaser  About the authors

Correspondence *Gastroenterology Division, Department of Medicine, Brown Medical School, Rhode Island Hospital, 593 Eddy Street, APC 414, Providence, RI 02903, USA

Email Steven_Moss@brown.edu

Summary

Many common cancers develop as a consequence of years of chronic inflammation. Increasing evidence indicates that the inflammation may result from persistent mucosal or epithelial cell colonization by microorganisms; including hepatitis B virus and hepatitis C virus, which can cause hepatocellular cancer; human papilloma virus subtypes, which cause cervical cancer, and the bacterium Helicobacter pylori, which can cause gastric cancer. At present, the cause of other chronic inflammatory conditions associated with increased cancer risk, such as ulcerative colitis, is obscure. Particular microbial characteristics as well as the type of the inflammatory response contribute to clinical outcomes via influence on epithelial cell and immune responses. Persistent inflammation leads to increased cellular turnover, especially in the epithelium, and provides selection pressure that result in the emergence of cells that are at high risk for malignant transformation. Cytokines, chemokines, free radicals, and growth factors modulate microbial populations that colonize the host. Thus, therapeutic opportunities exist to target the causative microbe, the consequent inflammatory mediator, or epithelial cell responses. Such measures could be of value to reduce cancer risk in inflammation-associated malignancies.

Review criteria

The data for this review were obtained by searching the MEDLINE database for publications between the period of 1 Jan 1990 to 31 December 2004. The search terms used were "inflammation AND cancer" and "infection AND cancer" restricted to English language publications. The records identified were scrutinized, full articles thought to be potentially relevant were obtained and relevant cross-references were checked. The previous 3 years' conference proceedings of American Gastroenterology Association and American Association for Cancer Research were searched manually.

Keywords:

cancer etiology, infectious diseases, inflammation, Helicobacter pylori

Top

Introduction

Nearly 150 years ago, Rudolf Virchow speculated that the chronic inflammatory infiltrates observed in tumors reflected the origins of cancer.1, 2 The chronic inflammatory processes of wound healing and cancer are similar,3 but less is known about the role of chronic inflammation in malignant transformation. Many of the common cancers are preceded by years of chronic inflammation; examples include cancers of the lung, whereby cigarette smoking usually leads to inflammation; adenocarcinoma of the esophagus, which is usually preceded by years of inflammation caused by gastroesophageal reflux; and colon cancers, which are sometimes associated with chronic inflammatory bowel disease. For many of these inflammation-associated cancers, the initiating influence remains obscure; but for others, infectious etiologies have been identified. Colonization of the stomach by Helicobacter pylori (H. pylori) may lead to gastric cancer and lymphoma. Likewise, viral colonization by hepatitis B virus (HBV) and hepatitis C virus (HCV) can cause hepatocellular cancer, and particular subtypes of human papilloma virus (HPV) may initiate cervical cancer.4

Microbial persistence in or around epithelial cells may lead to a chronic inflammatory state resulting in increased epithelial cell turnover. The combined effects of increased inflammation and epithelial cell turnover can promote the phenotypic and genotypic changes that may ultimately progress to malignant transformation. We will review the molecular and cellular changes associated with this process by examining the role of H. pylori in gastric carcinogenesis. Discussion of the relevant mechanisms of inflammation and the role of inflammation in malignancies seen in other organs where inflammation is common may help to improve our understanding of these states and lead to novel cancer prevention and treatment strategies.

Top

Molecular mechanisms

The specific cellular and molecular pathways that link the inflammatory responses to particular microbes with malignant transformation vary depending on the microbe, target organ, and tumor subtype. In spite of these differentiating factors, several common features exist (Figure 1). Microbial presence in or near epithelia provides a stimulus for recruitment and activation of inflammatory cells from the blood stream. CYTOKINES, CHEMOKINES, and FREE RADICALS initiate and perpetuate inflammatory responses (see glossary and Table 1). Activation of inflammatory cells leads to a respiratory burst that releases free radicals. The free radicals contribute to malignant transformation by peroxidating lipids and inducing genetic mutations, which can alter proteins by chemical and post-translational modifications.5 Such damage to epithelial cells stimulates apoptotic cell death and reactive epithelial hyperproliferation that promotes further mutation.6 Accumulation of mutations in key host cell regulatory genes eventually leads to changes in cellular phenotype, at which stage eliminating the initiators of inflammation (e.g. smoking or H. pylori), or abolition of the inflammation itself cannot prevent the progression to cancer.7

Figure 1 Inflammatory-epithelial interactions in multi-step carcinogenesis.
Figure 1 : Inflammatory-epithelial interactions in multi-step carcinogenesis. Unfortunately we are unable to provide accessible alternative text for this. If you require assistance to access this image, or to obtain a text description, please contact npg@nature.com

Persistent microbial colonization by viruses, bacteria, nematodes, and other micro-organisms incite chronic inflammation. Numerous feedback and feed-forward loops then contribute to sustained tissue damage and the emergence, under this selection pressure, of populations of epithelial cells bearing survival advantages that ultimately contribute to malignant transformation.

Full figure and legend (24K)Figures & Tables indexDownload PowerPoint slide (229K)

Table 1 Host inflammatory mediators potentially important in carcinogenesis.
Table 1 - Host inflammatory mediators potentially important in carcinogenesis.
Full tableFigures & Tables indexDownload PowerPoint slide (242K)

The nature of the inflammatory response is governed initially by the dominant type of T helper (Th) lymphocyte cells recruited to the epithelium in response to inflammation. In this paradigm, the Th1 response is considered pro-inflammatory, driving cell-mediated immune responses, whereas the Th2 response is considered immunoregulatory or even anti-inflammatory, and promotes antibody-mediated immunity.8 Th1-dominated responses may not kill the causative microbe, but once cancer has developed, the immune response may be skewed to Th2, which reduces the available anti-tumor activity of cytotoxic T cells.2 Inflammation-related carcinogenesis results from inflammatory cells and mediators that act directly on epithelial cells and indirectly on stromal cells and extracellular matrix components, and by stimulating angiogenesis.9 Multiple feedback and feed-forward loops add to perpetuation of inflammation;10 the tumor cells per se and tumor-associated macrophages, in particular, modulate inflammation by secreting matrix metalloproteinases, cytokines, chemokines, and growth and angiogenic factors.2, 9

Top

H. Pylori and gastric malignancies

Gastric cancer is the second most common fatal malignancy in the world, responsible for approximately 10% of all deaths from cancer.11 Since gastric cancer usually presents clinically at an advanced stage, there is consequently high mortality highlighted by only 20% 5-year survival.12 Gastric cancer is usually preceded by decades of chronic inflammation.13 For the most common 'intestinal' subtype of gastric cancer, a preneoplastic sequence has been defined that manifests from chronic superficial gastritis through atrophic gastritis, intestinal metaplasia, ultimately leading to dysplasia. Progression through these histologic cancer precursors is accompanied by the accumulation of mutations, typical of a multi-step process of carcinogenesis. The 'diffuse' subtype of gastric cancer may also be preceded by years of chronic gastritis, although the molecular pathways and histologic changes involved are less well characterized.13, 14

A clue to the etiology of chronic inflammation preceding gastric cancer came in 1982 with the first isolation of H. pylori.15 The authors speculated, "If these bacteria are truly associated with antral gastritis...they may have a part to play in other poorly understood, gastritis-associated diseases (i.e. peptic ulcer and gastric cancer)."15 Epidemiologic, clinicopathologic and animal studies subsequently provided compelling evidence for the importance of persistent H. pylori colonization in the etiology of chronic gastritis, and in the genesis of gastric cancer16, 17, 18 Meta-analyses of seroepidemiologic studies estimate that the presence of H. pylori increases the risk by 2-fold to 5-fold for development of both histologic gastric cancer subtypes,19, 20 whereas more sensitive and strain-specific assays suggest a 20-fold increased risk.21 The majority of gastric cancers worldwide are directly attributable to H. pylori.4 Thus, H. pylori colonization—an almost universal finding in populations in the developing world22—is a more important risk factor for gastric carcinogenesis than other environmental influences, such as diet, socioeconomic status or occupation.23 For adenocarcinomas of the proximal stomach (cardia), gastroesophageal junction, and distal esophagus, the association with H. pylori is inverse, indicative of protection.17

H. pylori is usually acquired in early childhood,22 and despite producing a chronic inflammatory reaction does not cause symptoms in most cases. However, in fewer than 5% of carriers persistent colonization precipitates the development of malignancy 50 years or more later. The genotype of H. pylori acquired and particular host polymorphisms govern the inflammatory response that influences cancer risk. H. pylori virulence factors associated with increased gastric cancer risk include the following: particular polymorphisms of vacA; encoding a multimeric secreted protein that produces endosomal vacuoles in epithelial cells; babA, encoding an adhesin that binds to fucosylated Lewis B antigens on epithelial cells; and the cag island of genes.22, 24, 25 The cag gene island comprises approximately 25 open-reading frames, some of which encode a type IV bacterial secretory apparatus that injects bacterial products directly into gastric epithelial cells.26 Subsequent modulation of epithelial cell signal transduction can result in cytoskeletal alterations and the activation of inflammatory cascades and mitogenic pathways that may contribute to malignant transformation. The immunodominant CagA protein is encoded by cagA located at the 3' end of the cag island. When CagA is injected into epithelial cells, it undergoes tyrosine phosphorylation by epithelial Src-kinases, and then interacts with SHP-2, leading to anchoring on the plasma membrane and the activation of specific signal transduction pathways.27 Serum antibodies to CagA are more prevalent in subjects who develop cancer than in those who do not.21, 28, 29 The tyrosine phosphorylation motifs of CagA, encoded by the cagA gene, may vary in number in isolates from different parts of the stomach;30 strains with multiple motifs appear more highly associated with cancer.28

H. pylori infection results in development of an immune response, characterized by a proinflammatory profile of Th1-dominant cytokines such as interferon-gamma, tumor necrosis factor-alpha (TNF-alpha), and interleukin-12 (IL-12), which continuously recruit leukocytes to the gastric mucosa and activate Th1 lymphocytes31 (Figure 2). These events are, in part, initiated by H. pylori binding to epithelial cells that activate signaling through the nuclear factor-kappa B (NF-kappaB) transcription factor, with the production of specific chemokines and cytokines, including TNF-alpha, the interleukins IL-1beta, IL-6, IL-8, IL-12, and RANTES c-c motif ligand 5 (CCL5), growth-regulated oncogene-alpha, macrophage inflammatory protein-1 alpha, and monocyte chemotactic protein-1.32, 33 The upregulation of the integrin CD11b/CD18 and its receptor, intercellular-adhesion molecule-1 (also known as CD54) mediates leukocyte transmigration from the circulation to the gastric mucosa,34, 35 and stimulates gastric epithelial cell expression of the T cell co-stimulatory molecules CD80 and CD86.36 The cellular infiltration is perpetuated by sustained H. pylori presence leading to expression of class II MHC antigens by gastric epithelial cells,37 allowing continual H. pylori antigen presentation to the immune cells populating the gastric mucosa. Persistent H. pylori colonization also stimulates B lymphocytes to secrete specific anti-H. pylori antibodies, but their functional consequence is not well-defined.

Figure 2 Gastric biopsy from a patient with chronic gastritis due to H. pylori persistence.
Figure 2 : Gastric biopsy from a patient with chronic gastritis due to H. pylori persistence. Unfortunately we are unable to provide accessible alternative text for this. If you require assistance to access this image, or to obtain a text description, please contact npg@nature.com

Numerous H. pylori organisms identified by immunoperoxidase staining (A) induce an intense inflammatory response in the gastric mucosa, with neutrophils, lymphocytes and plasma cells. (B) Hematoxylin & eosin staining. (C) The many mature T lymphocytes are evident after immunostaining with the antibody CD3. Original magnifications times200. Photomicrographs courtesy of Murray Resnick, MD, PhD.

Full figure and legend (54K)Figures & Tables indexDownload PowerPoint slide (260K)

Although the immune response decreases H. pylori numbers,38 it is largely ineffectual in eliminating H. pylori, and does not confer protective immunity against reacquisition after antimicrobial therapy.39 One explanation for the failure of immunity is the ability of H. pylori to evade host adaptive and innate responses by frequent antigenic variation, and host antigen mimicry.24 However, while failing to eliminate H. pylori, the immune and inflammatory responses increase cellular damage and turnover, thereby promoting carcinogenesis.38, 40

The histologic and thus clinical consequences of the host interactions with H. pylori are determined partly by single nucleotide polymorphisms in genes encoding inflammatory cytokines involved in the inflammatory response. For example, polymorphisms of IL-1beta and its receptor, and TNF-alpha, which are associated with heightened inflammation, or polymorphisms that cause low activity of the anti-inflammatory IL-10, are associated with more severe inflammation, the development of gastric atrophy, and increased risk of gastric cancer.41, 42, 43 Combinatorial analysis of specific H. pylori strain differences with specific host cytokine polymorphisms is now being explored as an approach to estimate individual susceptibility to gastric cancer with risk ratios differing up to 90-fold.43

Despite these advances in defining host susceptibility and bacterial virulence genes, the precise molecular and cellular events responsible for the promotion of gastric cancer by H. pylori and the associated inflammatory response, are not fully defined. Chronic cellular damage from the release of reactive oxygen and nitrogen species,44, 45 increased expression of epithelial cyclooxygenase-2,46 and activation of the proinflammatory32 and oncogenic47 transcription factor NF-kappaB may all contribute to gastric cancer. Moreover, the modulation of gastric growth factors and peptides,48 and the ultimate emergence of a state of low acid secretion that encourages the growth of nitrosating non-H. pylori bacteria49 may compound these effects further. A state of increased cell turnover prior to cancer development is both frequent and prolonged, and may contribute to malignant transformation.6 The increased cell turnover, long recognized in chronic gastritis,50 is now known to reflect the impact of H. pylori colonization.51 Animal model studies suggest that H. pylori can stimulate epithelial apoptosis, and compensatory hyperproliferative responses.52 Increased cell turnover caused by continual H. pylori stimulation, together with the associated inflammatory response, provides selection pressure for the emergence of gastric epithelial cells with altered phenotypes, including resistance to apoptosis,53 which contributes to malignant transformation.7 During the cellular coevolution that occurs over the lifetime of the host, selective adaptation occurs not only in gastric epithelial cells, but also in the gastric population of H. pylori cells.24 Considerable experimental evidence indicates that specific H. pylori strain characteristics and certain cytokines released by the inflammatory response are important influences of gastric epithelial turnover,51 but their relative contributions to the gradual dysregulation of apoptosis and continued cellular proliferation that occurs during human gastric carcinogenesis remains unclear. A recent study has provided evidence that the origin of the neoplastic cells in Helicobacter-associated gastric cancer may be from recruited bone marrow-derived stem cells that then differentiate into epithelial-like cells in the inflammatory environment of the experimentally-infected mouse.54 Although the implications of this work are far-reaching, confirmation that the underlying hypothesis is correct is necessary.

Top

Therapeutic implications

Gastric adenocarcinomas

The fact that specific antibiotic therapy can reverse the histologic changes of chronic gastritis, and the evidence that gastric cancer develops rarely in the absence of H. pylori,18 suggest that gastric cancer may be largely preventable. Definitive answers may emerge from several prospective population-based clinical trials to eradicate H. pylori from populations at high risk of gastric cancer in Latin America and Asia, but full results are several years away, owing to the slow process of gastric carcinogenesis. Nevertheless, preliminary data in high-risk patients followed for several years indicate that the eradication of H. pylori can reduce the rate of progression along the gastric preneoplastic sequence.55, 56, 57 If there is a 'point of no return' in the gastric carcinogenic cascade, it may be the development of intestinal metaplasia. Preliminary analysis of a randomized controlled trial of H. pylori eradication in China showed there was a reduction in gastric cancer risk only in those patients whose most advanced lesion at the time of antibiotic therapy was chronic gastritis.58 Additional chemopreventive therapies may be necessary in those patients who have already progressed to intestinal metaplasia. Rather than an all-or-none 'point of no return', more likely there is a quantifiable risk relationship with the most favorable outcomes in populations reflecting the earliest interventions.

Gastric lymphoma

The eradication of H. pylori alone provides apparent 'cure' in most cases of early gastric lymphoma, in contrast to gastric adenocarcinomas. This unusual manifestation of H. pylori persistence represents a T cell-driven proliferation of a gastric mucosal B lymphocyte clone. Patients with these lesions who received antibiotic therapy to eradicate H. pylori have now been followed for over 10 years. The vast majority of those with early-stage disease (low grade, confined to the gastric mucosa) have had complete clinical remission.59 However, whether all the patients had malignancies, or whether some had benign monoclonal expansions, remains to be determined. The development of gastric lymphoma occurs in only a few H. pylori-positive individuals, and there is considerable geographic variability in incidence. However, because of the dramatic responses observed in patients with gastric lymphoma as a result of H. pylori eradication, this has led researchers to speculate that other lymphomas may be bacterially driven, and therefore potentially reversible with antimicrobial therapy.60

Hepatocellular carcinoma

Virus-associated cancers may be prevented by elimination of the causative agent. Liver cancer is the third most common cause of cancer-related death worldwide and is usually associated with chronic HBV or HCV infection.11 Inflammation stimulates liver cell death. Subsequent hepatic regeneration is often associated with the development of dysplastic nodules and ultimately cancer, a sequence characterized by the accumulation of molecular genetic and epigenetic alterations.61 While HBV causes cellular damage through the induction of inflammatory and immune responses rather than by its direct integration into the genome, the pathophysiology of HCV is less clear. Nevertheless, the chronic inflammation induced may again be the principal pro-oncogenic event. The universal vaccination of newborns against HBV is now common practice in endemic areas and has led to a dramatic reduction in hepatocellular carcinoma incidence.62 Progress in the prevention of HCV-associated liver cancer has been slower. The causative agent was only identified in 1988 and suitable vaccine candidates and vaccination strategies for clinical use have yet to be defined. Nonetheless, improvements in anti-HCV therapies have been rapid and current combination therapy with pegylated interferon and ribavirin are capable of achieving >50% sustained viral eradication. It is expected that such treatments will greatly reduce the progression to cirrhosis and subsequent cancer risk, but definitive data are not yet available. While there is cause for optimism in the developed world, the relative complexity and costs involved in such treatment for a largely asymptomatic condition pose substantial problems in poorer regions.

Cervical cancer

Despite the widespread use of cytology screening programs, squamous cell carcinoma of the cervix is the second most common cause of fatal cancers in women worldwide.11 The strong association between cervical cancer and HPV, especially type 16, has spurred considerable interest in the development of HPV vaccines to treat not only the genital infection but also to prevent cervical neoplasia. The development of a vaccine against HPV 16 is proof-of-principle that this prophylactic approach can prevent cervical intraepithelial neoplasia.63 The development of 'therapeutic vaccines' to boost existing cell-mediated immunity to eliminate the causative virus, and thereby prevent cancer in patients with chronic HPV, is also under investigation.64 In common with other cancers where the latency between acquisition of infection and malignant transformation can last for decades, large and long-term clinical studies will be necessary to evaluate the size of the reduction in cancer burden that may be achievable in specific populations.

Other cancers

For other poorly understood chronic inflammatory states associated with increased cancer risk, including long-standing ulcerative colitis (that predisposes to colon cancer), sclerosing cholangitis and other chronic inflammatory conditions of the biliary tract (associated with cholangiocarcinoma), the challenge is to discover whether there are cryptic causative agents, analogous to H. pylori, HPV, HBV or HCV that are responsible for the 'idiopathic' chronic inflammation. Regardless of specific causes, long-term anti-inflammatory therapies may be beneficial in reducing the cancer risk, as exemplified by some of the most promising chemopreventive, anti-inflammatory agents currently in clinical investigation to prevent a variety of cancers, such as aspirin, the COX-2 inhibitors, and certain phytochemicals.65 Therefore, even in the absence of a complete understanding of the underlying etiology, attempts to inhibit exuberant inflammation and angiogenesis may prevent or delay cancer in chronic inflammatory conditions.

Top

Conclusion

The increasing recognition of the importance of infection in multi-step carcinogenesis has validated Virchow's speculations about the inflammatory origins of cancer. While chronic inflammation secondary to persistent microbial colonization may have little clinical consequence, the mucosal colonization exerts selection pressure resulting in adaptive responses within the epithelium. The selective replacement of normal epithelial cells with variants adapted for survival caused by inflammatory states may produce cells with abnormal growth patterns and phenotypes that are more malignant. Generally, such deleterious consequences may not be selected against because they occur late in life, after the reproductive years. Because shifts in epithelial cell growth phenotypes are gradual, chemoprevention may benefit when eradication of the microbial cause is not possible. Studying the pathophysiology of chronic infection and host inflammatory responses should contribute to improved understanding of the underlying molecular and cellular pathogenesis of cancer, leading to development of useful therapeutic and chemopreventive agents. Animal models of infection and chronic inflammation, especially cancer-prone mice, may be particularly helpful. The lessons learned from studies of cytokine polymorphisms and H. pylori genotypes in relation to gastric carcinogenesis illustrate the potential importance of molecular epidemiological approaches to assessing inflammatory responses in cancer predisposition, especially in populations in which inflammation-associated cancers are prevalent.

Top
Acknowledgments

Funding support, SFM: National Institutes of Health 1P20RR17695-01. MJB: National Institutes of Health RO1 GM 63270, and the Filomena D'Agostino Foundation.

Top

References

  1. Virchow R (1863) Cellular Pathology as Based upon Physiological and Pathological Histology. Philadelphia: JB Lippincott
  2. Balkwill F and Mantovani A (2001) Inflammation and cancer: back to Virchow? Lancet 357: 539–545 | Article | PubMed | ISI | ChemPort |
  3. Dvorak HF (1986) Tumors: wounds that do not heal. Similarities between tumor stroma generation and wound healing. N Engl J Med 315: 1650–1659 | PubMed | ISI | ChemPort |
  4. Pisani P et al. (1997) Cancer and infection: estimates of the attributable fraction in 1990. Cancer Epidemiol Biomarkers Prev 6: 387–400 | PubMed | ISI | ChemPort |
  5. Hussain SP et al. (2003) Radical causes of cancer. Nat Rev Cancer 3: 276–285 | Article | PubMed | ISI | ChemPort |
  6. Preston-Martin S et al. (1990) Increased cell division as a cause of human cancer. Cancer Res 50: 7415–7421 | PubMed | ChemPort |
  7. Hahn WC and Weinberg RA (2002) Rules for making human tumor cells. N Engl J Med 347: 1593–1603 | Article | PubMed | ISI | ChemPort |
  8. Abbas AK et al. (1996) Functional diversity of helper T lymphocytes. Nature 383: 787–793 | Article | PubMed | ISI | ChemPort |
  9. DeClerck YA et al. (2004) Proteases, extracellular matrix, and cancer: a workshop of the path B study section. Am J Pathol 164: 1131–1139 | PubMed | ISI | ChemPort |
  10. Coussens LM and Werb Z (2002) Inflammation and cancer. Nature 420: 860–867 | Article | PubMed | ISI | ChemPort |
  11. Parkin DM (2001) Global cancer statistics in the year 2000. Lancet Oncol 2: 533–543 | Article | PubMed | ISI | ChemPort |
  12. Hohenberger P and Gretschel S (2003) Gastric cancer. Lancet 362: 305–315 | Article | PubMed | ISI |
  13. Correa P et al. (1975) A model for gastric cancer epidemiology. Lancet 2: 58–60 | Article | PubMed | ISI | ChemPort |
  14. Yuasa Y (2003) Control of gut differentiation and intestinal-type gastric carcinogenesis. Nat Rev Cancer 3: 592–600 | Article | PubMed | ISI | ChemPort |
  15. Warren JR and Marshall B (1983) Unidentified curved bacilli on gastric epithelium in active chronic gastritis. Lancet 1: 1273–1275 | Article | PubMed | ISI |
  16. IARC Working Group on the Evaluation of Carcinogenic Risks to Humans (1994) Schistosomes, liver flukes and Helicobacter pylori. IARC Monogr Eval Carcinog Risks Hum 61: 1–241 | PubMed |
  17. Peek RM and Blaser MJ (2002) Helicobacter pylori and gastrointestinal tract adenocarcinomas. Nat Rev Cancer 2: 28–37 | Article | PubMed | ISI | ChemPort |
  18. Uemura N et al. (2001) Helicobacter pylori infection and the development of gastric cancer. N Engl J Med 345: 784–789 | Article | PubMed | ISI | ChemPort |
  19. Huang J-Q et al. (1998) Meta-analysis of the relationship between Helicobacter pylori seropositivity and gastric cancer. Gastroenterology 114: 1169–1179 | Article | PubMed | ISI | ChemPort |
  20. Helicobacter and Cancer Collaborative Group (2001) Gastric cancer and Helicobacter pylori: a combined analysis of 12 case control studies nested within prospective cohorts. Gut 49: 347–353 | Article | PubMed | ISI |
  21. Ekstrom AM et al. (2001) Helicobacter pylori in gastric cancer established by CagA immunoblot as a marker of past infection. Gastroenterology 121: 784–791 | Article | PubMed | ChemPort |
  22. Suerbaum S and Michetti P (2002) Helicobacter pylori infection. N Engl J Med 347: 1175–1186 | Article | PubMed | ISI | ChemPort |
  23. Neugut AI et al. (1996) Epidemiology of gastric cancer. Semin Oncol 23: 281–291 | PubMed | ISI | ChemPort |
  24. Blaser MJ and Atherton JC (2004) Helicobacter pylori persistence: biology and disease. J Clin Invest 113: 321–333 | Article | PubMed | ISI | ChemPort |
  25. Aspholm-Hurtig M et al. (2004) Functional adaptation of BabA, the H.pylori ABO blood group antigen binding adhesin. Science 305: 519–522 | Article | PubMed | ISI | ChemPort |
  26. Censini S et al. (2001) Cellular responses induced after contact with Helicobacter pylori. Curr Opin Microbiol 4: 41–46 | Article | PubMed | ISI | ChemPort |
  27. Higashi H et al. (2002) SHP-2 tyrosine phosphatase as an intracellular target of Helicobacter pylori CagA protein. Science 295: 683–686 | Article | PubMed | ISI | ChemPort |
  28. Huang JQ et al. (2003) Meta-analysis of the relationship between cagA seropositivity and gastric cancer. Gastroenterology 125: 1636–1644 | Article | PubMed | ISI |
  29. Blaser MJ et al. (1995) Infection with Helicobacter pylori strains possessing cagA is associated with an increased risk of developing adenocarcinoma of the stomach. Cancer Res 55: 2111–2115 | PubMed | ISI | ChemPort |
  30. Aras RA et al. (2003) Natural variation in populations of persistently colonizing bacteria affect human host cell phenotype. J Infect Dis 188: 486–496 | Article | PubMed | ISI | ChemPort |
  31. Sommer F et al. (1998) Antrum- and corpus mucosa-infiltrating CD4(+) lymphocytes in Helicobacter pylori gastritis display a Th1 phenotype. Infect Immun 66: 5543–5546 | PubMed | ChemPort |
  32. Keates S et al. (1997) Helicobacter pylori infection activates NF-kappa B in gastric epithelial cells. Gastroenterology 113: 1099–1109 | Article | PubMed | ISI | ChemPort |
  33. Ibraghimov A and Pappo J (2000) The immune response against Helicobacter pylori—a direct linkage to the development of gastroduodenal disease. Microbes Infect 2: 1073–1077 | Article | PubMed | ChemPort |
  34. Crowe SE et al. (1995) Expression of interleukin 8 and CD54 by human gastric epithelium after Helicobacter pylori infection in vitro. Gastroenterology 108: 65–74 | PubMed | ChemPort |
  35. Hatz RA et al. (1997) Pattern of adhesion molecule expression on vascular endothelium in Helicobacter pylori-associated antral gastritis. Gastroenterology 112: 1908–1919 | PubMed | ChemPort |
  36. Ye G et al. (1997) Expression of B7-1 and B7-2 costimulatory molecules by human gastric epithelial cells: potential role in CD4+ T cell activation during Helicobacter pylori infection. J Clin Invest 99: 1628–1636 | PubMed | ChemPort |
  37. Engstrand L et al. (1989) Association of Campylobacter pylori with induced expression of class II transplantation antigens on gastric epithelial cells. Infect Immun 57: 827–832 | PubMed | ISI | ChemPort |
  38. Mohammadi M et al. (1997) Murine CD4 T-cell response to Helicobacter infection: TH1 cells enhance gastritis and TH2 cells reduce bacterial load. Gastroenterology 113: 1848–1857 | Article | PubMed | ChemPort |
  39. Ramirez-Ramos A et al. (1997) Rapid recurrence of Helicobacter pylori infection in Peruvian patients after successful eradication. Gastrointestinal Physiology Working Group of the Universidad Peruana Cayetano Heredia and The Johns Hopkins University. Clin Infect Dis 25: 1027–1031 | PubMed | ChemPort |
  40. Fox JG et al. (2000) Concurrent enteric helminth infection modulates inflammation and gastric immune responses and reduces helicobacter-induced gastric atrophy. Nat Med 6: 536–542 | Article | PubMed | ISI | ChemPort |
  41. El-Omar EM et al. (2000) Interleukin-1 polymorphisms associated with increased risk of gastric cancer. Nature 404: 398–402 | Article | PubMed | ISI | ChemPort |
  42. Machado JC et al. (2001) Interleukin 1B and interleukin 1RN polymorphisms are associated with increased risk of gastric carcinoma. Gastroenterology 121: 823–829 | Article | PubMed | ChemPort |
  43. Figueiredo C et al. (2002) Helicobacter pylori and interleukin 1 genotyping: an opportunity to identify high-risk individuals for gastric carcinoma. J Natl Cancer Inst 94: 1680–1687 | PubMed | ChemPort |
  44. Mannick EE et al. (1996) Inducible nitric oxide synthase, nitrotyrosine, and apoptosis in Helicobacter pylori gastritis: effect of antibiotics and antioxidants. Cancer Res 56: 3238–3243 | PubMed | ISI | ChemPort |
  45. Smoot DT et al. (2000) Influence of Helicobacter pylori on reactive oxygen-induced gastric epithelial cell injury. Carcinogenesis 21: 2091–2095 | Article | PubMed | ISI | ChemPort |
  46. Juttner S et al. (2003) Helicobacter pylori stimulates host cyclooxygenase-2 gene transcription: critical importance of MEK/ERK-dependent activation of USF1/-2 and CREB transcription factors. Cell Microbiol 5: 821–834 | Article | PubMed | ISI | ChemPort |
  47. Greten FR et al. (2004) IKKbeta links inflammation and tumorigenesis in a mouse model of colitis-associated cancer. Cell 118: 285–296 | Article | PubMed | ISI | ChemPort |
  48. Wang TC et al. (2000) Synergistic interaction between hypergastrinemia and Helicobacter infection in a mouse model of gastric cancer. Gastroenterology 118: 36–47 | Article | PubMed | ISI | ChemPort |
  49. Houben GM and Stockbrugger RW (1995) Bacteria in the aetio-pathogenesis of gastric cancer: a review. Scand J Gastroenterol Suppl 212: 13–18 | PubMed | ChemPort |
  50. Lipkin M et al. (1963) Cell Proliferation Kinetics in the Gastrointestinal Tract of Man. II: Cell Renewal in Stomach, Ileum, Colon, and Rectum. Gastroenterology 45: 721–729 | PubMed | ChemPort |
  51. Shirin H et al. (2001) Effects of H. pylori infection of gastric epithelial cells on cell cycle control. Front Biosci 6: E104–E118 | PubMed | ISI | ChemPort |
  52. Peek Jr, RM et al. (2000) Helicobacter pylori alters gastric epithelial cell cycle events and gastrin secretion in Mongolian gerbils. Gastroenterology 118: 48–59 | Article | PubMed | ChemPort |
  53. Shirin H et al. (2000) Chronic Helicobacter pylori infection induces an apoptosis resistant phenotype associated with decreased expression of p27kip1. Infect Immun 68: 5321–5328 | Article | PubMed | ISI | ChemPort |
  54. Houghton JM et al. (2004) Gastric cancer originating from bone marrow-derived cells. Science 306: 1568–1571 | Article | PubMed | ISI | ChemPort |
  55. Correa P et al. (2000) Chemoprevention of gastric dysplasia: randomized trial of antioxidant supplements and anti-Helicobacter pylori therapy. J Natl Cancer Inst 92: 1881–1888 | Article | PubMed | ChemPort |
  56. Ley C et al. (2004) Helicobacter pylori eradication and gastric preneoplastic conditions: a randomized, double-blind, placebo-controlled trial. Cancer Epidemiol Biomarkers Prev 13: 4–10 | PubMed | ChemPort |
  57. Leung WK et al. (2004) Factors predicting progression of gastric intestinal metaplasia: results of a randomised trial on Helicobacter pylori eradication. Gut 53: 1244–1249 | Article | PubMed | ChemPort |
  58. Wong BC et al. (2004) Helicobacter pylori eradication to prevent gastric cancer in a high-risk region of China: a randomized controlled trial. JAMA 291: 187–194 | Article | PubMed | ISI | ChemPort |
  59. Du MQ and Isaccson PG (2002) Gastric MALT lymphoma: from aetiology to treatment. Lancet Oncol 3: 97–104 | Article | PubMed | ISI | ChemPort |
  60. Lecuit M et al. (2004) Immunoproliferative small intestinal disease associated with Campylobacter jejuni. N Engl J Med 350: 239–248 | Article | PubMed | ISI | ChemPort |
  61. Coleman WB (2003) Mechanisms of human hepatocarcinogenesis. Curr Mol Med 3: 573–588 | Article | PubMed | ISI | ChemPort |
  62. Chang MH et al. (1997) Universal hepatitis B vaccination in Taiwan and the incidence of hepatocellular carcinoma in children. Taiwan Childhood Hepatoma Study Group. N Engl J Med 336: 1855–1859 | Article | PubMed | ISI | ChemPort |
  63. Koutsky LA et al. (2002) A controlled trial of a human papillomavirus type 16 vaccine. N Engl J Med 347: 1645–1651 | Article | PubMed | ISI | ChemPort |
  64. Schreckenberger C and Kaufmann AM (2004) Vaccination strategies for the treatment and prevention of cervical cancer. Curr Opin Oncol 16: 485–491 | Article | PubMed |
  65. Surh YJ et al. (2001) Molecular mechanisms underlying chemopreventive activities of anti-inflammatory phytochemicals: down-regulation of COX-2 and iNOS through suppression of NF-kappa B activation. Mutat Res 480–481: 243–268
Top
Competing interests

The authors declared no competing interests.

Top