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Cancer is one of the greatest health care problems facing society today, and gastric cancer is currently the 4th most prevalent type. The discovery of Helicobacter pylori 25 years ago has been a hugely important advancement in the understanding of the cause of gastric cancer. Aim: to carry out effective database searches of current literature on this subject, and use a selection of the studies found to confirm the link between infection with this bacterium and the later development of gastric cancer. Method: database searches were carried out using a range of keywords, and the number of studies reduced by using exclusion criteria. From this three theories were reviewed using the studies collected. Results: 22 studies were found using the keywords and exclusion criteria for the review. From this 3 were selected for further analysis. Each provided conclusive data on the link between Helicobacter pylori infection and gastric cancer. Interestingly, however, the 3 studies varied greatly in their area of research. Conclusion: the literature analysed in this review presents a variety of possible reasons why Helicobacter pylori infection leads to gastric cancer in some people. From the available information this review has drawn the conclusion that Helicobacter pylori must be recognised as an important risk factor in the development of gastric cancer. What this review was unable to conclusively say is the reason behind this link, and it has instead put forward the ideas at the forefront of current research. Helicobacter pylori's role in the onset of cancer will continue to be a vital area of research if the prevalence of gastric cancers is to be reduced.
History of Helicobacter pylori
There have been numerous infectious diseases emerging over the last 30 years, but few discoveries earn the pioneers in their field a Nobel Prize within 25 years of their discovery. However this is exactly what happened for Robin Warren and Barry Marshall, who were awarded the Nobel Prize for Medicine and Physiology in 2005 for their discovery of a "curved bacillus lining the gastric epithelium of patients with gastritis and ulceration"1 in 1984ÂÂ - later named Helicobacter pylori (H. pylori).
The discovery of this bacterium revolutionised the treatment of not only gastritis and peptic ulcers, but more amazingly of gastric cancer. Before this, the stomach was considered an almost sterile environment due to its very low pH, and the main cause of peptic ulcers was thought to be stress or spicy foods1. These theories about the causes of ulcers were well established, and so Marshall put himself at risk of serious discomfort to prove Koch's third postulate, and show that H. pylori was not simply "an opportunistic colonizer of pre-existing lesions"2. To prove Koch's third postulate, H. pylori cultured from ulcers would need to cause ulceration in animals or humans. At the point of discovery, Marshall and Warren had been unable to cause H. pylori in laboratory animals (although since this time, different species of the Helicobacter bacterium have been used to further studies, for example Helicobacter felis, which can be used to produce ulcers in laboratory rats), and so Marshall volunteered himself for infection with the bacterium3. Marshall had an endoscopy prior to drinking the H. pylori culture, confirming there were no lesions present before the study. Two weeks after ingesting H. pylori, a second endoscopy showed areas of inflammation of the stomach mucosa, and a biopsy confirmed H. pylori had colonised these areas. This was a great risk for his science; at the time there was no known antibiotic combination that would cure H. pylori infection, however Marshall recovered from the infection, and he and Warren went on to win the Nobel Prize for their important discovery.
H. pylori epidemiology
Figure 1: World Map showing epidemiological spread of H. pylori4What Warren and Marshall discovered is now known as H. pylori, a gram-negative bacterium found lining the epithelium of the stomach in more than half of the world's population. It is thought to be mostly acquired through ingestion of contaminated food and water. This theory is backed up by the epidemiology of the bacterial infection, as statistics show although an estimated 50% of the world's adult population is infected with H. pylori, this is not equally distributed4. As shown in Figure 1, developed countries have relatively low levels of infection: on average 20% under 40s and 50% over 60s are affected by H. pylori infection. In contrast, Figure 14 shows extremely high levels of infection in developing countries in Africa, Asia and South America.
Recently, studies have linked standards of living and hygiene levels to the risk of H. pylori infection. One study in India, concentrated on the relationship between the clean water index (CWI) and H. pylori infection, with results showing greater numbers of infected individuals in families with low CWI (indicating drinking un-boiled water from wells and lower standards of personal hygiene)5. Families in lower socioeconomic classes generally had dirtier water sources as they often had no access to tap water, which supports the theory of transmission through contaminated water sources5. Transmission through unsanitary living conditions and poor hygiene is also demonstrated by the overall decline in H. pylori infected individuals. Standards of living and sanitation levels have increased worldwide due to new technology, and for developing countries increased aid from western countries has also contributed. In both developed and developing countries the decline in H. pylori infection can be noted, suggesting that there are links to transmission of the bacteria via unsanitary conditions6.
Studies have also shown, however, a high prevalence of H. pylori in the saliva of contaminated individuals, suggesting the bacteria can also be passed on through mouth-to-mouth contact7.
H. pylori pathophysiology and pathogenicity
Figure 2: An electron micrograph of H. pylori8 H. pylori finds its niche in the stomach by remaining near gastric mucosal cells, as the conditions are less acidic here than the lumen of the stomach. H. pylori has a variety of ingenious adaptations which allow it to survive in the stomach's low pH environment. It senses the pH gradient of the mucosa by chemotaxis and moves towards areas of higher pH, further into the mucus layer, and sometimes to the gastric epithelium, aided by the use of flagella. H. pylori can also produce adhesions which allow the bacterium to attach to epithelial cells; however the most important adaptation of the bacterium is the production (both inside and as a surface protein) of urease2. Urease breaks down urea in the stomach, forming carbon dioxide and ammonia. Each bacterium is then surrounded by an ammonia layer, which neutralises the highly acidic gastric juices on contact9. H. pylori's production of urease is therefore vital for its continued survival in the harsh acidic conditions of the stomach2.
Figure 3: Diagram demonstrating how H. pylori causes inflammation and ulceration9The ammonia produced by the breakdown of urea is also important to the pathogenicity of the bacterium, as it is in part how H. pylori causes gastritis and peptic ulcers. Infection with H. pylori causes chronic gastritis, an inflammation of the stomach lining, in all cases. Many individuals are asymptomatic, however, and it is only over time as the gastritis causes ulceration the infection is apparent. H. pylori causes inflammation of the gastric mucosa because ammonia, as well as other factors such as the virulence factors cagA and vacA10, and increased levels of free radicals around the bacterium11 cause damage and irritation of the mucosal lining. However, they also stimulate an immune response by the host, and white blood cells and antibodies flood to the stomach lining to fight the infection. The host's own inflammatory response damages the delicate gastric mucosa, reducing the effectiveness of its protection against the low pH environment of the stomach. Over time, this will cause to increasingly severe damage, leading to gastric and duodenal ulcers.
Clinical Signs and Tests
As previously mentioned, for many people H. pylori infection is asymptomatic, however for around 3 in 20 the chronic gastritis will develop into duodenal or gastric ulcers12, the type depending on factors such as stomach acid pH and where the infection is localised. Duodenal ulcers are characterised by confinement of gastritis to the antrum and higher levels of acid secretion, meaning a lower pH in the stomach13. High levels of inflammation of the lining of the corpus, however, will cause higher pH gastric acid, as acid secretion occurs in parietal cells in this region, and damage to them caused by inflammation will reduce the amount of gastric acid secreted. This will lead instead to the development of gastric ulcers13.
H. pylori infection is usually diagnosed using a urea breath test14. Individuals with symptoms of H. pylori infection are given a 'drink' of radioactively labelled urea (C14 urea), after 6 hours of fasting. As the urease produced by H. pylori breaks down the urea into carbon dioxide and ammonia, labelled CO2 will be exhaled. Samples of breath are taken at 20-minute intervals and checked for the presence of C14, indicating a H. pylori infection14. Other methods of diagnosis include checking of stool samples for H. pylori bacteria, checking blood samples for the antigen against H. pylori and even through samples taken upon endoscopy15, although the urea breath test is by far the most common.
Further Complications and H. pylori as a Carcinogen
There have been numerous studies which show strong links between H. pylori and an increased risk of gastric cancer, so much so that in 1994 the International Agency for Research on Cancer (IARC) concluded there was "sufficient evidence to classify H. pylori as a 'Group 1 = Definite' human carcinogen16". It is the studies based around these links with cancer that will be further investigated in the discussion of this review, as the ability to treat H. pylori infection with antibiotics could in some people eradicate the biggest risk for gastric cancer and its pre-cursors.
It is H. pylori and its role as a carcinogen which is arguably the most important discovery related to this bacterium, and so is the factor further questioned in this review. To select studies to review, several different databases were utilised: Scopus, Medline and PubMed. A manageable number of searches were found by using keywords and search criteria, only studies and reviews published:
in the last 3 years
were included. The word infection was added after the original search of "Helicobacter pylori", removing most of the studies related to the bacterium itself rather than the pathogenicity and infection of it. Results were further reduced by concentrating on the link to gastric cancer. Also, depending on the structure of the database used, findings were reduced by the use of built in refining tools, e.g. only including Health and Life Sciences results (Scopus).
Helicobacter pylori infection
Helicobacter pylori infection AND cancer
Helicobacter pylori infection AND gastric cancer
Helicobacter pylori infection AND gastric cancer link
The results were then sorted by title relevance by each database, and selected for discussion firstly by reading the titles. This eliminated several studies, which were mainly aimed at studying complex genetic interactions, which involved too much background reading given the time constraints for this review. From the remaining articles 3 were selected by reading the abstracts. These articles were picked to give a breadth of research based their on strong results and conclusions .Information gathered during attendance at an Inaugural Lecture on ongoing research on this topic has also been used in the discussion.
Since its classification as a Group 1 carcinogen, there has been a huge amount of research further investigating whether this was a correct decision by discovering how H. pylori causes the development of gastric cancer, as well as the effect H. pylori eradication has on the progression and regression of precancerous gastric lesions.
It is firstly important to research the pathogenicity of H. pylori in relation to development of cancerous and pre-cancerous lesions is identified. Development of gastric cancer follows a multistep sequence, from superficial gastritis to atrophic gastritis, intestinal metaplasia and finally dysplasia, before developing into a cancerous gastric adenocarcinoma. However the precise mechanism of this process is still not understood.
One of the most common theories is that the cagA protein plays a vital role in the sequelae of H. pylori infection. CagA is a virulence factor produced by H. pylori, cytotoxin-associated gene, produced by the Cag pathogenicity island (CagPAI)9. CagPAI codes for the production of a Type IV secretion system which H. pylori uses to inject the host cells with cagA10. H. pylori which can produce this virulence factor stimulate a stronger inflammatory response and alter signalling pathways at the "C-terminal" of the protein17. There are two different strains of H. pylori, categorised depending on whether they have the cagA protein production capabilities or not. There have been many studies18,19 investigating the significance of cagA-positive H. pylori, dating back over a decade, confirming that this is an important factor in the link between the bacterium and cancer.
A recent study20 has investigated this further, and suggested cagA-positive H. pylori can be categorised further depending on the polymorphism of specifically the C-terminal found on cagA. The results of this study suggest a strong link between specific types of C-terminal polymorphism (specifically the strain of H. pylori with the cagA EPIYA-ABD genotype) - 100% of the cancer patients who volunteered for the study were found to have a cagA EPIYA-ABD type H. pylori infection20.This study clearly shows that H. pylori does have a strong link with gastric cancer, however it seems to indicate only certain strains of the bacterium will actually cause progression of the initial gastritis to gastric cancer. The study was restricted to patients from South Korea due to the huge prevalence of infection, which limits its application in western countries as there are differences between H. pylori found in the east and west. It also used a fairly small sample of 254 patients, and only 11.8% of these presented with gastric cancer20. Although the study showed 100% of the patients with the same C-terminal type, this does only represent 30 patients overall, however it does show statistical significance, and is a clear indicator that further research is required to establish why this is the case.
There is also ongoing research considering the importance of gastrin to the development of gastric cancer due to H. pylori infection. It has been shown that H. pylori causes an increase in gastrin levels in the stomach, and the combination of increased gastrin and H. pylori colonisation location affect where gastric ulcers present13, however, gastrin is also known to inhibit apoptosis21. This is important in the development of cancerous lesions as reduced apoptosis will increase the chance of mutation of epithelial cells, leading eventually to cancerous growth21.
Research using animal models has confirmed this, as results from various studies have shown the development of precancerous lesions at 20 months after infection with Helicobacter felis, compared with the onset of gastric cancer 6 months after infection in mice with increased gastrin secretion (INS-GAS mice)22. At 20 months old rats are fairly old relative to their average life span, and so pre-cancerous lesions at this age may be expected, even without infection using H. felis. 6 months is a very early stage for the development of cancerous lesions, and suggests that H. felis infection becomes an increasingly important factor when combined with increased levels of gastrin in a subject22. Animal models are very useful for investigating the link between H. pylori and gastric cancer, as bacterium such as H. felis are very similar to the human H. pylori infection, meaning conclusions drawn using animal models can on the whole be reliably applied to draw the same conclusions when considering the effect on a human host. Studies using human subjects are, however, very important in confirming discoveries using animal models, and so there is a current research study being carried out to show the importance of H. pylori and gastrin, involving 2000 volunteers who are receiving gastroscopy23. This study should be extremely useful in the future, as it uses a wide volunteer base, although it must be remembered when considering such a study that for obvious ethical issues patients cannot be infected with H. pylori. Those volunteering already require investigation for various gastric ailments, and so there will be other cofounders in this study which may influence the results.
Although the exact reason that H. pylori infection can lead to gastric cancer is unknown, evidence does seem to show that the link, as outlined by the IARC in 1994, is definitive. One way of continuing to strengthen this link is to research the effect of eradicating H. pylori infection in patients with pre-cancerous lesions. A recent meta-analysis focused on studies based on the eradication of H. pylori and the effect this had on gastric histology24 by compiling data from studies on the effect of eradicating H. pylori in patients with gastric atrophy and intestinal metaplasia, studying patients with lesions at both anatomical sites of infection and analysing the data for each site separately. As these are pre-cancerous lesions and are part of the sequence of gastric cancer development, regression after the eradication of H. pylori infection would suggest that the bacterium does play a role in the development of gastric adenocarcinoma. The results of the study24 lead to the conclusion that H. pylori eradication is beneficial in reversing early stages of gastric cancer sequelae (gastric atrophy) but there was little benefit in most studies if the lesion had progressed to intestinal metaplasia. This is an interesting result, as it could indicate there is a "point of no return" in the progression of this cancer, meaning if it is caught early H. pylori eradication could become important in the prevention of gastric cancer. The regression of gastric atrophy found using the meta-analysis24 is also important in the case for H. pylori's significance in development of gastric cancer, as regression at this stage is still a positive indication that H. pylori infection is a vital element and a notable risk factor for gastric cancer.
Overall this can be used to support the opinion that there is a link between H. pylori and gastric cancer, however it does have its disadvantages. As a meta-analysis, the results of many different studies have been pooled in an attempt to achieve an overall conclusion on the subject. Although this has the advantage of giving an increased overall sample size, which should make conclusions drawn more reliable as they are consistent, the quality of the original studies used must be considered to determine how useful the results and thus the conclusions it draws are. This is something which cannot be easily identified without critically analysing every study used in the meta-analysis. Reading the method of selection for this meta-analysis24, however, it seems the authors have done everything possible to prevent selection of inaccurate studies. The most up to date, published studies available have been used, and the meta-analysis itself was published in a good journal, all of which suggests the conclusions drawn using it are viable.
The studies reviewed above provide current evidence of the link between H. pylori infection and gastric cancer. All provide strong, statistically significant results, and use reliable methods of research to collect this data and draw their conclusions. It is evident, however, from all the studies read during this review that although the link with cancer has been shown, the reasons behind this link are still up for debate. This review has only presented a selection of the most currently relevant and common theories behind H. pylori's role in gastric cancer development, however the field of research on this topic is incredibly widespread.
As an emerging infectious disease, there is still much to be understood about H. pylori. It is and will continue to be a subject on which there will be much research and discussion in the future. Reading the most current journal articles on the subject will allow for continued education and understanding of the pathogenicity of the bacterium, as well as keeping up to date on new developments in treatment, and especially the links with gastric cancer development and whether eradication of the bacterium upon its discovery continues to be method of best practice.
This review has been limited by the huge amount of information available on the subject; this provided a great wealth of knowledge, but made finding the best and most relevant information for use arduous and time consuming. Also, as this is a subject that is still relatively new, much of the material is very advanced, making it difficult to utilise all of the resources available without a much more in depth knowledge, especially of subjects such as biochemistry and genetics.