Health knowledge made personal
Join this community!
› Share page:
Go
Search posts:

Helicobacter pylori and Cancer

Posted Feb 28 2011 10:24pm
Helicobacter pylori and Cancer

Key Points
  • Helicobacter pylori (H. pylori) is a type of bacterium that is found in the stomach of about two-thirds of the world’s population (see Questions 1 and 2 ).
  • Although H. pylori does not cause illness in most infected people, infection with this bacterium is a major risk factor for peptic ulcer disease and is responsible for the majority of ulcers of the stomach and upper small intestine (see Questions 3 and 4 ).
  • H. pylori infection is a major cause of gastric cancer. Moreover, H. pylori infection is associated with increased risk of gastric mucosa-associated lymphoid tissue (MALT) lymphoma. However, H. pylori infection may be associated with decreased risk of some other cancers, including esophageal adenocarcinoma (see Questions 68 and 1113 ).
  1. What is Helicobacter pylori?   

    Helicobacter pylori, or H. pylori, is a spiral-shaped bacterium that grows in the mucus layer that coats the inside of the human stomach, even though the stomach’s acidic environment and its secretion of antimicrobial peptides prevent the survival of most bacteria, viruses, and other microorganisms .

    To survive in this harsh environment, H. pylori secretes an enzyme called urease, which converts the chemical urea to ammonia. The production of ammonia around H. pylori neutralizes the acidity of the stomach, making it more hospitable for the bacterium. In addition, the helical shape of H. pylori allows it to burrow into the mucus layer, which is less acidic than the inside space, or lumen, of the stomach. H. pylori can also attach to the cells that line the inner surface of the stomach.

    Although immune cells that normally recognize and attack invading bacteria accumulate near sites of H. pylori infection, they are unable to reach the stomach lining. In addition, H. pylori has developed ways of interfering with local immune responses , making them ineffective in eliminating the bacteria ( 1 , 2 ).

    H. pylori has coexisted with humans for many thousands of years. Scientists had believed that the stomach was a sterile organ, and this bacterium was not discovered until the 1980s. Because H. pylori is relatively newly discovered, the complex interactions between this microbe and humans, including its risks and possible benefits, and what enables it to establish stable, long-lasting infections, are still being discovered. Some bacteria that normally live in other portions of the human gastrointestinal tract actually aid their hosts by helping in the absorption of nutrients and in defense against other, more dangerous microbes.

  2. How common is infection with H. pylori and how does it spread?   

    Human infection with H. pylori is common; the Centers for Disease Control and Prevention (CDC) estimates that approximately two-thirds of the world's population harbors the bacterium, with infection rates much higher in developing countries than in developed nations.

    H. pylori is thought to spread either through contaminated food and water or through direct mouth-to-mouth contact. In most populations, the bacterium is first acquired during childhood. Children living in crowded conditions and with a lower socioeconomic status are more likely to become infected.

  3. What are the health consequences of H. pylori infection and can it be treated?   

    People who are infected with H. pylori almost always develop chronic gastritis (stomach inflammation), frequently without symptoms. In addition, between 2 and 20 percent of people infected with H. pylori will develop peptic ulcers (ulcers of the stomach and upper small intestine). H. pylori infection is also known to cause gastric (stomach) cancer and has been reported in some studies to increase the risk of some other types of cancer. However, most people infected with H. pylori will not become ill.

    H. pylori infections usually persist unless they are treated with antimicrobial therapy. This treatment often involves the use of bismuth or a proton pump inhibitor , such as omeprazole and lansoprazole , plus two or three different antibiotics ( tetracycline , amoxicillin , clarithromycin , or metronidazole ). Efforts are also under way to develop vaccines to prevent or treat H. pylori infections.

  4. How was the relationship between H. pylori infection and peptic ulcers established?   

    In the 1980s, scientists began to notice the presence of curved bacteria, which later became known as H. pylori, in tissue samples taken from patients with peptic ulcers. Believing that bacteria could not survive in the harsh environment of the stomach, most researchers thought these mysterious bacteria had been carried into the stomach by contaminated food or might be another harmless species of bacteria similar to others found elsewhere in the gastrointestinal tract. In addition, they believed that peptic ulcers were mainly the result of stress or eating spicy food.

    However, Australian researchers Barry J. Marshall, M.D., and J. Robin Warren, M.D., were convinced that the bacteria were actually the cause of stomach ulcers. Frustrated by the lack of a good animal model of H. pylori infection and determined to prove this hypothesis, Marshall infected himself with the bacteria. He became ill, developed inflammation of the stomach, and was able to culture the bacteria from his own ulcers, thereby proving the microbe to be the cause of stomach ulcers. In 2005, Marshall and Warren were awarded the Nobel Prize in Medicine for their discovery of H. pylori and its role in peptic ulcer formation.

  5. What is peptic ulcer disease?   

    Peptic ulcers are holes in the lining of the stomach or the upper part of the small intestine (duodenum) that extend deep into the muscle layers of these organs. An ulcer forms when the stomach wall becomes inflamed and the cells of the wall die and are shed. Stomach wall inflammation can be caused by some medications, swallowing poisons or objects, surgery, certain medical conditions, and infections. In H. pylori infection, the inflammation is caused both by bacterially produced toxins that damage the cells lining the stomach and by the immune system ’s response to the infection. The resulting cellular disruption and damage also allows acid to penetrate the stomach lining, further damaging the cells.

    Approximately half a million people develop peptic ulcer disease each year in the United States ( 3 ). Stomach pain similar to heartburn is the most prevalent symptom of a peptic ulcer. Other symptoms may include indigestion, loss of appetite, and vomiting. Most cases of peptic ulcer disease are caused by H. pylori infection, although aspirin and certain other medications are also known to cause peptic ulcers.

  6. What is the evidence that H. pylori is a risk factor for certain cancers?   

    Epidemiology studies have shown that individuals infected with H. pylori have an increased risk of gastric adenocarcinoma ( 1 , 2 , 48 ) (see Question 8 ). In 1994, the International Agency for Research on Cancer (IARC) classified H. pylori as a carcinogen, or cancer-causing agent, despite conflicting results at the time. Since then, colonization of the stomach with H. pylori has been increasingly accepted as an important risk factor for stomach cancer.

    Epidemiology studies have also shown that individuals infected with H. pylori have an increased risk of gastric mucosa-associated lymphoid tissue (MALT) lymphoma, a rare cancer of the stomach.

    Conversely, risk of a type of cancer in the esophagus, esophageal adenocarcinoma, may be reduced in H. pylori-infected individuals.

  7. What is gastric cancer?   

    Gastric cancer, or cancer of the stomach, was once considered a single entity. Now, scientists divide this cancer into two main classes: gastric cardia cancer (cancer of the top inch of the stomach, where it meets the esophagus) and non-cardia gastric cancer (cancer in all other areas of the stomach).

    In each of the last 5 years, approximately 21,000 new cases of gastric cancer were diagnosed and nearly 11,000 people died of the disease in the United States. Gastric cancer is the second most common cause of cancer-related deaths in the world, killing approximately 738,000 people in 2008 ( 9 ). Gastric cancer is less common in the United States and other Western countries than in countries in Asia and South America.

    Gastric cancer incidence rates overall are decreasing. However, this decline is mainly in rates of non-cardia gastric cancer ( 10 ). Gastric cardia cancer, which was once very uncommon, now constitutes nearly half of all stomach cancers among white males in the United States.

    Infection with H. pylori is the major risk factor for gastric cancer. Other factors include chronic gastritis; older age; male sex; a diet high in salted, smoked, or poorly preserved foods and low in fruits and vegetables; tobacco smoking; pernicious anemia ; a history of stomach surgery for benign conditions; and a family history of stomach cancer ( 11 , 12 ).

  8. What evidence shows that H. pylori infection causes gastric cancer?   

    In 2001, a combined analysis of 12 studies of H. pylori and gastric cancer estimated that the risk of non-cardia gastric cancer was nearly six times higher for H. pylori-infected people than for uninfected people ( 4 ).

    Evidence for an association comes mainly from prospective cohort studies such as the Alpha-Tocopherol , Beta-Carotene (ATBC) Cancer Prevention Study in Finland, which involved nearly 30,000 male smokers who were aged 50 to 69 years at study enrollment. This study was designed to determine whether daily supplementation with alpha-tocopherol, beta-carotene, or both would reduce the number of lung or other cancers ( 13 ). H. pylori infection status was determined by analyzing blood samples obtained from each study participant at the time of enrollment in the study to see if they contained antibodies to the bacterium. Participants were enrolled during 1985 through 1988 and followed through 1999. Comparing subjects who developed gastric cancer with noncancer control subjects, the researchers found that H. pylori-infected individuals had a nearly eightfold increased risk for non-cardia gastric cancer ( 14 ).

  9. Can treatment to eradicate H. pylori infection reduce gastric cancer rates?   

    Only a few clinical trials have been conducted to determine whether eradicating H. pylori infection with antimicrobial therapy will reduce the incidence of gastric cancer. The total number of gastric cancers that have developed in those studies is too small to make definitive statements. However, a meta-analysis of six randomized trials suggests that eradication may lead to a modest reduction in gastric cancer risk ( 15 ).

  10. What is gastric mucosa-associated lymphoid tissue (MALT) lymphoma?   

    Gastric MALT lymphoma is a rare type of non-Hodgkin lymphoma that is characterized by the slow multiplication of B lymphocytes , a type of immune cell, in the stomach lining. This cancer represents approximately 12 percent of the extranodal (outside of lymph nodes) non-Hodgkin lymphoma that occurs among men and approximately 18 percent of extranodal non-Hodgkin lymphoma among women ( 16 ). During the period 1999–2003, the annual incidence of gastric MALT lymphoma in the United States was about one case for every 100,000 persons in the population.

    Normally, the lining of the stomach lacks lymphoid (immune system) tissue, but development of this tissue is often stimulated in response to colonization of the lining by H. pylori ( 2 ). However, only in rare cases does this tissue give rise to MALT lymphoma.

  11. What evidence shows that H. pylori infection increases the risk of gastric MALT lymphoma?   

    Nearly all patients with gastric MALT lymphoma show signs of H. pylori infection, and the risk of developing this tumor is over six times higher in infected people than in uninfected people ( 17 , 18 ). Furthermore, up to 80 percent of patients with gastric MALT lymphoma achieve complete remission of their tumors after treatment with H. pylori-eradicating antimicrobial therapy ( 2 , 18 ).

  12. What is the evidence that H. pylori infection may reduce the risks of some cancers?   

    The ATBC cohort study revealed the risk of gastric cardia cancer among H. pylori-infected individuals to be one-third the risk among uninfected individuals ( 14 ). Several other studies have also detected an inverse relationship between H. pylori infection and gastric cardia cancer ( 1921 ), although the evidence is not entirely consistent ( 22 ). The possibility of an inverse relationship between the bacterium and gastric cardia cancer is supported by the correspondence between the decrease in H. pylori infection rates in Western countries during the past century—the result of improved hygiene and widespread antibiotic use—and the increase in rates of gastric cardia cancer in these same regions.

    Similar epidemiologic evidence suggests that H. pylori infection may be associated with a lower risk of esophageal adenocarcinoma. For example, a large case-control study in Sweden showed that the risk of esophageal adenocarcinoma in H. pylori-infected individuals was one-third that of uninfected individuals ( 21 ). A meta-analysis of 13 studies, including the Swedish study, found a 45 percent reduction in risk of esophageal adenocarcinoma with H. pylori infection ( 23 ). Moreover, as with gastric cardia cancer, dramatic increases in esophageal adenocarcinoma rates in several Western countries parallel the declines in H. pylori infection rates.

  13. How might H. pylori infection decrease the risk of some cancers while increasing the risk of other cancers?   

    Although it is not known for certain how H. pylori infection increases the risk of gastric cancer, some researchers speculate that the long-term presence of an inflammatory response predisposes cells in the stomach lining to become cancerous. This idea is supported by the finding that increased expression of a single cytokine ( interleukin-1-beta ) in the stomach of transgenic mice causes sporadic gastric inflammation and cancer ( 24 ). The increased cell turnover resulting from ongoing cellular damage could increase the likelihood that cells will develop harmful mutations .

    One hypothesis that may explain reduced risks of gastric cardia and esophageal adenocarcinoma in H. pylori-infected individuals relates to the decline in stomach acidity that is often seen after decades of H. pylori colonization. This decline would reduce acid reflux into the esophagus, a major risk factor for adenocarcinomas affecting the upper stomach and esophagus.

  14. What is cagA-positive H. pylori and how does it affect the risk of gastric and esophageal cancers?   

    Some H. pylori bacteria use a needle-like appendage to inject a toxin produced by a gene called cytotoxin -associated gene A (cagA) into the junctions where cells of the stomach lining meet ( 25 , 26 ). This toxin (known as CagA) alters the structure of stomach cells and allows the bacteria to attach to them more easily. Long-term exposure to the toxin causes chronic inflammation. However, not all strains of H. pylori carry the cagA gene; those that do are classified as cagA-positive.

    Epidemiologic evidence suggests that infection with cagA-positive strains is especially associated with an increased risk of non-cardia gastric cancer and with reduced risks of gastric cardia cancer and esophageal adenocarcinoma. For example, a meta-analysis of 16 case-control studies conducted around the world showed that individuals infected with cagA-positive H. pylori had twice the risk of non-cardia gastric cancer than individuals infected with cagA-negative H. pylori ( 27 ). Conversely, a case-control study conducted in Sweden found that people infected with cagA-positive H. pylori had a statistically significantly reduced risk of esophageal adenocarcinoma ( 21 ). Similarly, another case-control study conducted in the United States found that infection with cagA-positive H. pylori was associated with a reduced risk of esophageal adenocarcinoma and gastric cardia cancer combined, but that infection with cagA-negative strains was not associated with risk ( 28 ).

    Recent research has suggested a potential mechanism by which CagA could contribute to gastric carcinogenesis . In three studies, infection with CagA-positive H. pylori was associated with inactivation of tumor suppressor proteins, including p53 ( 2931 ).

  15. Is H. pylori infection associated with any other cancer?   

    A possible association between H. pylori infection and pancreatic cancer was suggested by several small epidemiology studies that found an increased risk of pancreatic cancer among patients who had been treated with surgery for peptic ulcer disease up to 20 years earlier. Furthermore, in the ATBC cohort study, individuals infected with H. pylori at the time of study enrollment were approximately twice as likely to develop pancreatic cancer as those without the infection ( 32 ). However, this association between H. pylori infection and pancreatic cancer was not confirmed in another study that involved 128,992 adults. When the participants who developed pancreatic cancer were compared with control subjects, no evidence was found that individuals infected with H. pylori at study enrollment were more likely to develop pancreatic cancer than those who were not infected ( 33 ).

  16. Who should seek diagnosis and treatment of an H. pylori infection?   

    According to the CDC, people who have active gastric or duodenal ulcers or a documented history of ulcers should be tested for H. pylori, and, if they are infected, should be treated. (More information is available on the CDC Web site at http://www.cdc.gov/ulcer/keytocure.htm#tested .) Testing for and treating H. pylori infection is also recommended after resection of early gastric cancer and for low-grade gastric MALT lymphoma. However, most experts agree that the available evidence does not support widespread testing for and eradication of H. pylori infection.

Selected References

  1. Atherton JC. The pathogenesis of Helicobacter pylori-induced gastro-duodenal diseases. Annual Review of Pathology 2006; 1:63–96. [ PubMed Abstract ]   

  2. Kusters JG, van Vliet AH, Kuipers EJ. Pathogenesis of Helicobacter pylori infection. Clinical Microbiology Reviews 2006; 19(3):449–490. [ PubMed Abstract ]   

  3. Ramakrishnan K, Salinas RC. Peptic ulcer disease. American Family Physician 2007; 76(7):1005–1012. [ PubMed Abstract ]   

  4. Helicobacter and Cancer Collaborative Group. Gastric cancer and Helicobacter pylori: a combined analysis of 12 case control studies nested within prospective cohorts. Gut 2001; 49(3):347–353. [ PubMed Abstract ]   

  5. Parsonnet J, Friedman GD, Vandersteen DP, et al. Helicobacter pylori infection and the risk of gastric carcinoma. New England Journal of Medicine 1991; 325(16):1127–1131. [ PubMed Abstract ]   

  6. Huang JQ, Sridhar S, Chen Y, Hunt RH. Meta-analysis of the relationship between Helicobacter pylori seropositivity and gastric cancer. Gastroenterology 1998; 114(6):1169–1179. [ PubMed Abstract ]   

  7. Eslick GD, Lim LL, Byles JE, Xia HH, Talley NJ. Association of Helicobacter pylori infection with gastric carcinoma: a meta-analysis. American Journal of Gastroenterology 1999; 94(9):2373–2379. [ PubMed Abstract ]   

  8. Uemura N, Okamoto S, Yamamoto S, et al. Helicobacter pylori infection and the development of gastric cancer. New England Journal of Medicine 2001; 345(11):784–789. [ PubMed Abstract ]   

  9. Ferlay J, Shin HR, Bray F, et al. Estimates of worldwide burden of cancer in 2008: GLOBOCAN 2008. International Journal of Cancer 2010; 127(12):2893–2917. [ PubMed Abstract ]   

  10. Anderson WF, Camargo MC, Fraumeni JF, et al. Age-specific trends in incidence of noncardia gastric cancer in U.S. adults. Journal of the American Medical Association 2010; 303(17):1723–1728. [ PubMed Abstract ]   

  11. Forman D, Burley VJ. Gastric cancer: global pattern of the disease and an overview of environmental risk factors. Best Practice & Research Clinical Gastroenterology 2006; 20(4):633–649. [ PubMed Abstract ]   

  12. Brenner H, Rothenbacher D, Arndt V. Epidemiology of stomach cancer. Methods in Molecular Biology 2009; 472:467–477. [ PubMed Abstract ]   

  13. The ATBC Cancer Prevention Study Group. The alpha-tocopherol, beta-carotene lung cancer prevention study: design, methods, participant characteristics, and compliance. Annals of Epidemiology 1994; 4(1):1–10. [ PubMed Abstract ]   

  14. Kamangar F, Dawsey SM, Blaser MJ, et al. Opposing risks of gastric cardia and noncardia gastric adenocarcinomas associated with Helicobacter pylori seropositivity. Journal of the National Cancer Institute 2006; 98(20):1445–1452. [ PubMed Abstract ]   

  15. Fuccio L, Zagari RM, Eusebi LH, et al. Meta-analysis: can Helicobacter pylori eradication treatment reduce the risk for gastric cancer? Annals of Internal Medicine 2009; 151(2):121–128. [ PubMed Abstract ]   

  16. Wu XC, Andrews P, Chen VW, Groves FD. Incidence of extranodal non-Hodgkin lymphomas among whites, blacks, and Asians/Pacific Islanders in the United States: anatomic site and histology differences. Cancer Epidemiology 2009; 33(5):337–346. [ PubMed Abstract ]   

  17. Parsonnet J, Hansen S, Rodriguez L, et al. Helicobacter pylori infection and gastric lymphoma. New England Journal of Medicine 1994; 330(18):1267–1271. [ PubMed Abstract ]   

  18. Sagaert X, Van Cutsem E, De Hertogh G, Geboes K, Tousseyn T. Gastric MALT lymphoma: a model of chronic inflammation-induced tumor development. Nature Reviews Gastroenterology & Hepatology 2010; 7(6):336–346. [ PubMed Abstract ]   

  19. Hansen S, Melby KK, Aase S, Jellum E, Vollset SE. Helicobacter pylori infection and risk of cardia cancer and non-cardia gastric cancer. A nested case-control study. Scandinavian Journal of Gastroenterology 1999; 34(4):353–360. [ PubMed Abstract ]   

  20. Ramakrishna BS. Helicobacter pylori infection in India: the case against eradication. Indian Journal of Gastroenterology 2006; 25(1):25–28. [ PubMed Abstract ]   

  21. Ye W, Held M, Lagergren J, et al. Helicobacter pylori infection and gastric atrophy: risk of adenocarcinoma and squamous-cell carcinoma of the esophagus and adenocarcinoma of the gastric cardia. Journal of the National Cancer Institute 2004; 96(5):388–396. [ PubMed Abstract ]   

  22. Kamangar F, Qiao YL, Blaser MJ, et al. Helicobacter pylori and oesophageal and gastric cancers in a prospective study in China. British Journal of Cancer 2007; 96(1):172–176. [ PubMed Abstract ]   

  23. Islami F, Kamangar F. Helicobacter pylori and esophageal cancer risk: a meta-analysis. Cancer Prevention Research 2008; 1(5):329–338. [ PubMed Abstract ]   

  24. Tu S, Bhagat G, Cui G, Takaishi S, et al. Overexpression of interleukin-1beta induces gastric inflammation and cancer and mobilizes myeloid-derived suppressor cells in mice. Cancer Cell 2008; 14(5):408–419. [ PubMed Abstract ]   

  25. Wen S, Moss SF. Helicobacter pylori virulence factors in gastric carcinogenesis. Cancer Letters 2009; 282(1):1–8. [ PubMed Abstract ]   

  26. Bagnoli F, Buti L, Tompkins L, Covacci A, Amieva MR. Helicobacter pylori CagA induces a transition from polarized to invasive phenotypes in MDCK cells. Proceedings of the National Academy of Science USA 2005; 102(45):16339–16344. [ PubMed Abstract ]   

  27. Huang JQ, Zheng GF, Sumanac K, Irvine EJ, Hunt RH. Meta-analysis of the relationship between cagA seropositivity and gastric cancer. Gastroenterology 2003; 125(6):1636–1644. [ PubMed Abstract ]   

  28. Chow WH, Blaser MJ, Blot WJ, et al. An inverse relation between cagA+ strains of Helicobacter pylori infection and risk of esophageal and gastric cardia adenocarcinoma. Cancer Research 1998; 58(4):588–590. [ PubMed Abstract ]   

  29. André AR, Ferreira MV, Mota RM, et al. Gastric adenocarcinoma and Helicobacter pylori: correlation with p53 mutation and p27 immunoexpression. Cancer Epidemiology 2010; 34(5):618–625. [ PubMed Abstract ]   

  30. Wei J, Nagy TA, Vilgelm A, et al. Regulation of p53 tumor suppressor by Helicobacter pylori in gastric epithelial cells. Gastroenterology 2010; 139(4):1333–1343. [ PubMed Abstract ]   

  31. Tsang YH, Lamb A, Romero-Gallo J, et al. Helicobacter pylori CagA targets gastric tumor suppressor RUNX3 for proteasome-mediated degradation. Oncogene 2010; 29(41):5643–5650.[ PubMed Abstract ]   

  32. Stolzenberg-Solomon RZ, Blaser MJ, et al. Helicobacter pylori seropositivity as a risk factor for pancreatic cancer. Journal of the National Cancer Institute 2001; 93(12):937–941. [ PubMed Abstract ]   

  33. de Martel C, Llosa AE, Friedman GD, et al. Helicobacter pylori infection and development of pancreatic cancer. Cancer Epidemiology Biomarkers and Prevention 2008; 17(5):1188–1194.[ PubMed Abstract ]   

Related NCI materials and Web pages:


How can we help?

We offer comprehensive research-based information for patients and their families, health professionals, cancer researchers, advocates, and the public.

Post a comment
Write a comment:

Related Searches