Helicobacter pylori Infection and Gastric Adenocarcinoma


cytotoxin-associated gene cagA and the vacuolating cytotoxin gene vacA. The cagA gene is present in about 60% of strains isolated in developed countries and in almost all strains from East Asian countries,20


and is a marker of the cag pathogenicity island.21 This island


is a 40kb locus that encodes a type IV secretion system and several proteins, including CagA, an oncoprotein. On contact with host epithelial cells, H. pylori utilizes the type IV secretion system to inject CagA into epithelial cells, beginning a series of changes that lead to morphologic alterations of the host cells, disruption of intercellular junctions, and loss of cell polarity. Infection with cagA-positive strains increase cancer risk compared with infection with cagA-negative strains.10,22


The gene vacA is present in all H. pylori strains and encodes VacA, a bacterial toxin that induces vacuolation in epithelial cells. The gene presents three regions of great diversity (s, signal terminus; m, mid-region; i, intermediate region) and the combination of different alleles determines the vacuolating activity.23,24


Our studies in Colombia, a country with high rates of gastric cancer, show that H. pylori isolates from the high altitude Andes Mountains population have ~90% prevalence of such markers (cagA-positive vacA s1m1), compared with ~70% in isolates from the Pacific coast.25


Such


difference is significant but may not fully explain the big difference in cancer rates—25-times higher in the mountains than on the coast. Recently developed techniques of multi-locus sequence typing have allowed us to trace the ancestral origin of Colombian cagA-positive, vacA s1m1 H. pylori isolates. All isolates analyzed from the high-risk area (Andes Mountains) population (n=35) display European ancestry. Other investigators have shown that when populations of European ancestry are mixed with populations of Asian ancestry, the original H. pylori strains of Amerindian genotype are replaced by European strains.26


In our study


in Colombia, isolates analyzed from the coastal region (n=29) have a heterogeneous ancestry. Approximately one-third have European ancestry, probably reflecting the same phenomenon just described for the high-risk area isolates. The rest have African ancestral markers.27


It


would appear that the low virulence H. pylori strains in Africa prevailed in the Colombian Pacific coastal inhabitants after their ancestors migrated several centuries ago. Our preliminary results in Colombia indicate that the ancestral origin of the H. pylori strains may, at least partially, determine their carcinogenicity potential, independently of the classical virulence markers cagA and vacA. Other investigators have shown that H. pylori isolates from modern African-Americans retain traces of African roots, despite the multiple generations since their ancestors were taken from West Africa.28


Among the mechanisms of carcinogenesis associated with inflammation, one hypothesis postulates that oxidative and nitrosative stress permanently alter the DNA molecules of the gastric epithelial cells. This mechanism is supported by our preliminary findings studying gastric mucosa biopsy samples of Colombian subjects. H. pylori isolates from inhabitants of the Andes Mountains (with high risk for gastric cancer) induce higher levels of inducible nitric oxide synthase and spermine oxidase, enzymes involved in nitrosative and oxidative stress, than isolates from the coastal region.29


These experiments were conducted


with cagA-positive, vacA s1m1 H. pylori isolates from both regions, indicating that other components of the H. pylori genome, not yet


US GASTROENTEROLOGY & HEPATOLOGY REVIEW


elucidated, may have carcinogenic potential. In addition, preliminary findings indicate that cagA-positive, vacA s1m1 H. pylori isolates from the mountains increase the expression of the CagA protein when cultured in a broth medium with high-salt concentration (John T Loh, unpublished data, 2010).


Another hypothesis postulates that bone marrow-derived cells contribute to the development of gastric cancer in Helicobacter-infected gastric mucosa. Experiments in mice reconstituted with labeled bone marrow and infected with H. felis (the mouse-adapted Helicobacter species) demonstrated that bone marrow-derived cells travel to, and engraft in, gastric mucosa with chronic inflammation and progress to adenocarcinoma.30


Epidemiologic Studies


Classic case-control studies have yielded inconsistent messages about causation. It seems clear now that these discrepancies can be explained by the temporality bias: the infection is mostly acquired during childhood and persists for years, but it tends to disappear when advanced atrophy and intestinal metaplasia extend, creating an unfavorable environment for H. pylori colonization, but increasing the cancer risk. Several studies have supported the role of this temporality bias. Fukuda et al.31


conducted a


case-control study to evaluate the role of H. pylori infection in gastric cancer. No overall association was detected, but when the comparisons were limited to younger patients, early cancers, or small tumors, significant associations were found. Also, when the degree of atrophy was evaluated by serum pepsinogen (PG) levels (PGI/PGII ratio) the association with H. pylori infection was significantly elevated.31 reported by Ohata et al.32


Similar results were in a cohort study of 4,655 subjects followed up


by an average of 7.7 years. Patients with negative serology for H. pylori but with extensive atrophy (evaluated by serum pepsinogen levels) had higher gastric cancer risk than those who remained infected. It does appear that the oncogenic potential of the H. pylori infection persists after the infection is lost.32


61


Figure 2: Histologic Section of Human Gastric Mucosa Colonized by Helicobacter pylori


Abundant micro-organisms (black staining) are seen attached to the epithelial cells and surrounding mucus layer (modified Steiner silver stain, x400).


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