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(ESCC) and esophageal adenocarcinoma (EAC). CagA-negative strains, H. pylori strains that harbor the
Tobacco smoking and alcohol consumption are the two CagA pathogenicity islands (PAI) are associated with a
major risk factors in ESCC, [27] with a risk of heavy signifi cantly increased risk of distal gastric cancer. After
[40]
smokers/drinkers for 50 times greater in the induction attached to gastric epithelial cells, H. pylori CagA-positive
[28]
of ESCC. Tobacco smoking and alcohol consumption strains eject the CagA protein directly into the gastric
have been associated with the fi eld of cancerization epithelial cells. After translocation, CagA undergoes
in the upper aerodigestive tract. For example, Oka tyrosine phosphorylation by Src and Abl kinases and the
[29]
et al. demonstrated that tobacco smoking was tyrosine phosphorylated-CagA binds to the Src homology
likely to induce global DNA hypomethylation and 2 (SHP-2) domain, leading to morphologic alterations
[41]
site-specifi c CpG island promoter hypermethylation such as cell scattering and elongation. Furthermore,
in the normal-appearing esophageal mucosa. Both CagA-activated SHP-2 deregulates the MAP kinase
[42]
these mutations are representative of DNA methylation signaling cascade. The CagA protein of certain
alterations occurring in cancer cells. In addition, we also H. pylori strains can stimulate expression of IL-8 by
[43]
previously reported that global DNA hypomethylation activating NF-κB, thereby contributing to neutrophil
in normal esophageal mucosa was observed in ESCC infi ltration in the gastric mucosa. In addition, chronic
patients who habitually smoked, suggesting epigenetic infl ammation caused by H. pylori infection contributes
[30]
fi eld defected after exposure to risk factors. Recently, to neoplastic transformation by establishing a positive
defi ciency in the enzyme aldehyde dehydrogenase feedback loop via the signal transducer and activator
2 (ALDH2), which causes the so-called alcohol fl ushing of transcription (STAT) 3-dependent COX-2 induction,
response, has been revealed to increase the risk of which in turn infl uences STAT3 regulation via IL-6. [44]
alcohol-related ESCC. [31] In East Asian populations, Another mechanism of H. pylori-induced gastric
there is a variant of ALDH2 in which the glutamate carcinogenesis is genomic alteration and gene mutation.
at position 487 is replaced with lysine, resulting in an For example, prevalence of the TP53 mutation in gastric
inactive protein. Consumption of hot beverages is also cancer is, on average, approximately 40%. Previous
[32]
[45]
suspected to cause chronic infl ammation in esophageal studies have shown that various genetic alterations
squamous cell mucosa. In addition, the infl uence of occur in the gastric mucosa during chronic gastritis, [46,47]
[33]
human papillomavirus in increasing ESCC risk is still suggesting an importance of the accumulated genomic
under debate. [34]
mutations induced by H. pylori infection in the
Gastroesophageal refl ux disease (GERD), cigarette development of gastric cancer. Activation-induced
smoking and obesity are all risk factors in EAC. EAC cytidine deaminase (AID), a member of the cytidine
[35]
develops through chronic exposure to gastroesophageal deaminase family that functions to edit genomic DNA,
refl ux, Barrett’s esophagus, dysplasia and adenocarcinoma is an enzyme essential for somatic hypermutation and
[48]
as a sequence. [36,37] Increased exposure of the esophagus class-switch recombination in immunoglobulin genes.
epithelium to refl uxed gastric and bile acid, particularly However, inappropriate AID expression acts as a genomic
deoxycholic acid, has a critical role in promoting the mutagen to contribute to tumorigenesis. [49,50] Infection
development of Barrett’s esophagus and EAC. NF-κB is with CagA PAI-positive H. pylori ectopically induced
a key regulator of the infl ammatory process that has been high expression of AID via NF-κB activation in human
shown to be activated in EAC. Several studies report gastric epithelial cells, leading to multiple mutations
that NF-κB was activated by bile acid components and in the host genome, such as those found in TP53. The
subsequently involved in the development of metaplasia accumulation of nucleotide alterations will lead to the
of Barrett’s esophagus and cancer. [25] development of gastric cancer. [51]
Gastric Cancer Recently, exciting data showed an association of
H. pylori infection with cancer stem cell population.
Gastric adenocarcinoma is the second leading cause The leucine-rich repeat-containing G-protein coupled
of cancer-related death in the world. H. pylori receptor (Lgr5) is known as the stem cell marker of GI
[38]
causes chronic gastritis, and the relationship between cancers, including gastric cancer. Lgr5-positive epithelial
H. pylori-induced chronic infl ammation and cancer is one cells have higher levels of oxidative DNA damage than in
of the best-elucidated factors. Indeed, H. pylori induces Lgr5-negative cells from patients with H. pylori-positive
active chronic gastric infl ammation, which progresses gastric cancer, indicating that H. pylori specifi cally
to gastric adenocarcinoma, resulting in approximately targets Lgr5-positive epithelial cells. [52]
660,000 worldwide new cases of gastric cancer Other infl ammatory risk factors that either act
per year. However, only a few percentage of infected independently of H. pylori infection or further enhance
[39]
persons do develop neoplasia.
its effects have been also identifi ed. For example,
Several recent studies described that cytotoxin chronic gastritis caused by bile refl ux can cause
associated gene A (CagA)-positive H. pylori strains were intestinal metaplasia as a neoplastic precursor lesion in
identifi ed to be particularly carcinogenic. Compared to gastric cancer. Moreover, T-cell-mediated autoimmune

140 Journal of Cancer Metastasis and Treatment ¦ Volume 1 ¦ Issue 3 ¦ October 15, 2015 ¦