Download gastric cancer in humans and helicobacter pylori: mechanisms

GASTRIC CANCER IN HUMANS AND HELICOBACTER PYLORI: MECHANISMS
UNDERLYING CARCINOGENESIS
Gerardo Nardone
Gastroenterology Unit, Department of Clinical and Experimental Medicine
University of Naples Federico II
Via Pansini 5 80131 Napoli
Phone ++39 081 7462158
Fax
++39 081 7464293
[email protected]
Gastric cancer (GC) is still a major health problem worldwide due to its frequency, poor prognosis
and limited treatment options. According to the International Gastric Cancer Society, more than 1
million people are affected by GC every year and up to 800,000 people have succumbed to GC (1).
In 2006 in the United States alone, of 22,280 patients diagnosed with GC 11,430 died (2). The 5year relative survival rate for cases in the US from 1995 to 2001 was only 23% and in Europe in
1991-1994 it was 21% (3.4). GC is often resistant to radiotherapy and chemotherapy thus, surgery
represents the only potentially treatment to cure GC. However, two-thirds of Western GC patients
are still diagnosed in advanced stages when surgery can be only palliative.
One of the primary objectives of The World Health Organization and researchers is to plan
programs for GC prevention. However, to be successful, this strategy depends on the understanding
of aetiological factors and molecular mechanisms underlying gastric carcinogenesis. Currently,
according to Online Mendelian Inheritance in Man (OMIM database) 90% of GC patients are
considered sporadic, 10% hereditary of whom less than 2% show an autosomal dominant pattern of
inheritance (5,6).
Thus, environmental rather than genetic inheritance is implicated in gastric carcinogenesis. The
most important environmental factor implicated in gastric carcinogenesis is Helicobacter pylori (H.
pylori) infection classified in 1994, just after few years from its accidental discovery, as first class
carcinogen, by International Agency for Research on Cancer (IARC) (7).
The causal link between H. pylori and the development of GC has been postulated to exist mainly
on the basis of epidemiological investigations (retrospective, case-control and prospective clinical
trial) and animal model studies (8-10). According to a recent meta-analysis, concurrent or previous
H. pylori infection is associated with an increased risk of GC in respect to uninfected people (OR
3.0 95% CI 2.3-3.8); the risk is stronger when blood samples for H. pylori serology are collected ten
years before cancer diagnosis (OR 5.9; 95% CI 3.4-10.3) (11).
Helicobacter pylori colonises the gastric epithelium inducing an inflammatory reaction that may
persist throughout the patient’s life despite a strong local immune reaction (12). The extent and
severity of gastric mucosal inflammation, as well as the clinical outcome of the infection depend on
a number of factors including the virulence of the bacterium, host genetic susceptibility, immune
response, age at the time of initial infection and environmental factors (12). The complexity
interplay between these factors may explain why only a minority (<1%) of those infected ultimately
develop GC (13).
H. pylori-related inflammatory gastric mucosal reaction locally induces the generation of reactive
oxygen species (ROS) and the release of nitric oxide (NO) synthase that in turn hampers epithelial
DNA and causes molecular and cellular alterations leading to cell proliferation and apoptosis
imbalance (14). Indeed, long-standing H. pylori-induced gastric inflammation often leads to
excessive cell loss and atrophic gastritis which is considered the first important step in the
histogenesis of GC (13-15). The risk of GC is greatest among the subjects with moderate or severe
gastric atrophy involving both antrum and body (16).
Gastric atrophy, particularly when it affects a large part of the gastric body, is associated with acid
hyposecretion and low pepsinogen levels.41 The modified gastric microenvironment may promote
the development of carcinogenic factors, i.e., N-nitroso formation and transformation of gastric
epithelial cells. Indeed, chronic atrophic gastritis is often associated with intestinal metaplasia (IM).
This cascade of events has been recognised by many studies that have shown both lesions closely
related to H. pylori infection and the risk of GC significantly higher in H. pylori-positive patients
with gastric atrophy and IM than in those H. pylori-negative without gastric atrophy and IM (1316).
The cascade of phenotypic events follows the underlying molecular alteration. Indeed from a
molecular view point GC may be considered as the end result of a progressive accumulation of
genotypic changes (17-18). Two mechanisms have been implicated in the cancer-related molecular
alterations: genetic and epigenetic (19). Genetic alterations are associated with changes in DNA
sequence, whereas epigenetic alterations do not induce changes in DNA sequence. A distinguishing
feature of epigenetic changes versus genetic changes is that they are reversible. Mounting evidence
shows that, in tumour cells, hereditable alterations are 90% of epigenetic nature versus the 10%
genetic (19). The list of genes altered by epigenetic mechanisms is rapidly expanding to date and,
more than 600 genes have been reported to be modified in cancer ( Human Epigenome Project)
(20).
Epigenetic changes include histone modification and DNA methylation, which work in close
contact and play a key role in tumour suppressor silencing, oncogene activation, chromosomal
instability, loss of imprinting, chromatin structure and remodelling (21). The most important
mechanism of epigenetic changes is methylation of the promoter region of the gene in areas called
CpG islands (an addition of a methyl group to the carbon 5 position of the cytosine ring within the
CpG dinucleotide) (21). Methylation is needed for the normal cell development and is restricted to
physiologic situations such as embryogenesis, balance between pluripotent and committed cells and
cell differentiation. However, aberrant methylation gives a selective growth advantage resulting in
cancerous proliferation (21).
The stomach is one of the organs that frequently undergoes to the DNA epithelial cell methylation
of CpG islands, and GC is estimated to be a tumour with a high frequency of CpG island
methylation (22,23). The cause remains unclear, but it may be related to the easy accessibility of
the tissue from exogenous agents such as H. pylori infection (22, 23). Indeed, H. pylori through the
release of inflammatory mediators or affecting directly DNA-methyl transferase activity can cause
the methylation of CpG islands leading to activation of oncogenes and inactivation of tumour
suppressor genes (22). The number of methylated genes increases during the multistep process of
H. pylori-related gastric carcinogenesis (22,24). Furthermore, it appears that epigenetic alterations
may resolve if H. pylori infection is treated within a reasonable time instead it may persist and may
even evolve to genetic alterations irrespective of eradication therapy if infection is long-standing
(25,26). In conclusion, H. pylori, acting through inflammatory mediators, may play a key role in
the development of cellular and molecular alterations underlying gastric carcinogenesis. In the last
years, much has been learnt but much remains to be learned to combat gastric cancer, which is one
of the most frequent and lethal neoplasias worldwide. The study of epigenetic alterations
underlying gastric carcinogenesis offers greats potential for the identification of biomarkers that can
be used to detect and diagnose cancer in its earliest stages, accurately to assess individual risk, and
to act as a target for chemotherapeutic strategies.
Currently, the most realistic outcome achieved with H. pylori eradication is disappearance of
inflammation, elimination of the DNA damage exerted by ROS and NO, reduction in cell turnover,
and increase in acid output and ascorbic acid secretion into the gastric juice. Thus, it is useful to
search for and treat H. pylori in high-risk areas of GC, in offspring of patients with GC and in
patients with chronic atrophic gastritis and IM. In this latter group, if atrophy and IM persists a
careful follow-up (upper endoscopy with multiple bioptic sample or serum pepsinogens profile)
have to be scheduled irrespective of H.pylori eradication.
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