Carcinoma of The Stomach: A Review of Epidemiology, Pathogenesis, Molecular Genetics and Chemoprevention

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doi:10.4251/wjgo.v4.i7.156 © 2012 Baishideng. All rights reserved.
EDITORIAL
Carcinoma of the stomach: A review of epidemiology,

pathogenesis, molecular genetics and chemoprevention
Siddavaram Nagini
Siddavaram Nagini, Department of Biochemistry and Biotech- and hygiene, screening and treatment of H. pylori in-
nology, Faculty of Science, Annamalai University, Annamalaina- fection, and follow-up of precancerous lesions. The fact
gar-608 002, Tamil Nadu, India that diet plays an important role in the etiology of gas-
Author contributions: Nagini S solely contributed to this paper. tric cancer offers scope for nutritional chemoprevention.
Supported by A Grant from the Department of Biotechnology,
Animal models have been extensively used to analyze
New Delhi, India under the 7th FP of the Indo-EU Joint Collab-
orative Project on “FUNCFOOD” the stepwise evolution of gastric carcinogenesis and to
Correspondence to: Siddavaram Nagini, Professor, Depart- test dietary chemopreventive agents. Development of
ment of Biochemistry and Biotechnology, Faculty of Science, multitargeted preventive and therapeutic strategies for
Annamalai University, Annamalainagar-608 002, Tamil Nadu, gastric cancer is a major challenge for the future.
India. [email protected]
Telephone: +91-4144-239842 Fax: +91-4144-238145 © 2012 Baishideng. All rights reserved.
Received: November 11, 2011 Revised: June 4, 2012
Accepted: June 12, 2012 Key words: Chemoprevention; Diet; Epidemiology; Epi-
Published online: July 15, 2012
genetic changes; Gastric cancer; Genetic alterations;
Helicobacter pylori ; Risk factors
Peer reviewer: Jian-Kun Hu, MD, PhD, Associate Professor,

Abstract Department of Gastrointestinal Surgery, West China Hospital,
Sichuan University, Chengdu 610041, Sichuan Province, China
Carcinoma of the stomach is still the second most com-
mon cause of cancer death worldwide, although the in-
Nagini S. Carcinoma of the stomach: A review of epidemiology,
cidence and mortality have fallen dramatically over the
pathogenesis, molecular genetics and chemoprevention. World J
last 50 years in many regions. The incidence of gastric
Gastrointest Oncol 2012; 4(7): 156-169 Available from: URL:
cancer varies in different parts of the world and among
http://www.wjgnet.com/1948-5204/full/v4/i7/156.htm DOI:
various ethnic groups. Despite advances in diagnosis
http://dx.doi.org/10.4251/wjgo.v4.i7.156
and treatment, the 5-year survival rate of stomach
cancer is only 20 per cent. Stomach cancer can be clas-
sified into intestinal and diffuse types based on epide-
miological and clinicopathological features. The etiology
of gastric cancer is multifactorial and includes both INTRODUCTION
dietary and nondietary factors. The major diet-related Adenocarcinoma of the stomach, a leading cause of can-
risk factors implicated in stomach cancer development
cer death worldwide is the second and fourth most com-
include high content of nitrates and high salt intake.
mon cancer in males and females respectively[1,2]. Glob-
Accumulating evidence has implicated the role of Heli-
cobacter pylori (H. pylori ) infection in the pathogenesis ally, gastric cancer accounts for 989 600 new cases and
of gastric cancer. The development of gastric cancer is 738 000 deaths annually. The case-fatality ratio of gastric
a complex, multistep process involving multiple genetic cancer is higher than for common malignancies like co-
and epigenetic alterations of oncogenes, tumor sup- lon, breast, and prostate cancers[3]. Despite advances in
pressor genes, DNA repair genes, cell cycle regulators, diagnosis, the disease is usually detected after invasion of
and signaling molecules. A plausible program for gastric the muscularis propria, because most patients experience
cancer prevention involves intake of a balanced diet vague and nonspecific symptoms in the early stages and
containing fruits and vegetables, improved sanitation the classic triad of anemia, weight loss, and refusal of
WJGO|www.wjgnet.com 156 July 15, 2012|Volume 4|Issue 7|

Nagini S. Gastric cancer, molecular pathogenesis and chemoprevention
meat-based foods is seen only in advanced stages. Fur- living in the same region; African-Americans, Hispanics
thermore, surgery and chemotherapy have limited value and Native Americans are affected more than Caucasians
in advanced disease and there is a paucity of molecular in the United States. High frequency of gastric cancer has
markers for targeted therapy. Since cancer of the stom- been documented in Maoris of New Zealand[16]. Howev-
ach has a very poor prognosis and the 5-year survival rate er, the geographical distribution of gastric cancer cannot
is only around 20 per cent, a new look at the results of be ascribed to racial differences alone. For example, na-
epidemiological and experimental studies is important to tives of Japan and China living in Singapore have higher
establish strategies for primary prevention. This review rates than their counterparts in Hawaii. Furthermore,
discusses what is currently known about the pathology, people who migrate from high incidence areas such as
epidemiology, etiology, genetic and epigenetic alterations, Japan to low-incidence regions such as the United States
and chemoprevention of stomach cancer. were found to have reduced gastric cancer risk[9,16].
EPIDEMIOLOGY PATHOLOGY
Age, sex and site distribution Stomach cancer refers to any malignant neoplasm that
Stomach cancer incidence is known to increase with age arises from the region extending between the gastro-
with the peak incidence occurring at 60-80 years. Cases in esophageal junction and the pylorus. Approximately
patients younger than 30 years are very rare[4,5]. In India, 95 per cent of stomach tumours are epithelial in origin
the age range for stomach cancer is 35-55 years in the and designated as adenocarcinomas. Adenosquamous,
South and 45-55 years in the North. The disease shows squamous, and undifferentiated carcinomas are however
a male preponderance in almost all countries, with rates rare[17]. The World Health Organization and Lauren’s clas-
two to four times higher among males than females[3,6]. sification system have described two histological types
Gastric cancer can develop both in the proximal and of gastric cancer that are clinically and epidemiologically
the distal region. Distal gastric cancers predominate in distinct entities- intestinal and diffuse. The well-differen-
tiated intestinal-type, which contains cohesive neoplastic
developing countries, among blacks, and in the lower
cells, forms gland-like tubular structures that frequently
socio-economic groups. Dietary factors and Helicobacter
ulcerate whereas the poorly differentiated diffuse-type
pylori (H. pylori) infection are major risk factors for the
is characterized by infiltration and thickening of the
development of distal tumors. Proximal tumors are more
stomach wall (“leather bottle appearance”) without the
common in developed countries, among whites, and in formation of a discrete mass. The intestinal-type, more
higher socio-economic classes. The major risk factors for common in men, older people in high-risk regions, and in
proximal cancers are gastroesophageal reflux disease and African-Americans, is of the epidemic type and has a bet-
obesity. Distal tumors continue to predominate in Japan ter prognosis. It arises from precancerous lesions such as
in contrast to the increasing prevalence of proximal tu- gastric atrophy and intestinal metaplasia, and is influenced
mors in the rest of the world[7]. by environmental factors such as H. pylori infection, obe-
sity, and dietary factors. The diffuse-type represents the
Geographic distribution major histological type in endemic areas, is more frequent
The steady decline in the incidence and mortality of in women and younger patients, and is associated with
stomach cancer in most affluent countries has been at- blood group A, indicating genetic susceptibility. Mixed
tributed to changes in dietary pattern, food storage, and gastric carcinomas composed of intestinal and diffuse
control of H. pylori infection. The incidence of gastric components have also been identified[18,19].
cancer varies in different parts of the world with highest The development of invasive gastric carcinoma in-
incidence rates documented in Eastern Asia, Eastern Eu- volves a stepwise evolution through a cascade of precan-
rope, and South America, while North America and Af- cerous lesions. Sequential histopathological changes take
rica show the lowest recorded rates[3,8-10]. Stomach cancer place in the gastric mucosa including atrophic gastritis
is the fifth most common cancer in Europe with 159 900 with loss of parietal cell mass, intestinal metaplasia, and
new cases and 118 200 deaths reported in 2006[11]. The dysplasia that eventually lead to carcinoma. The meta-
population of Linxian, China is known to have one of plasia/dysplasia/carcinoma sequence is more relevant
the highest rates of oesophageal/gastric cardia cancer in for the intestinal-type gastric cancer that develops by a
the world[12]. In India, the incidence of gastric carcinoma cumulative series of genetic alterations similar to those in
is higher in the southern and north-eastern states with colorectal cancer[20].
Mizoram recording an age-adjusted rate of 50.6 and 23.3
for men and women respectively[13,14]. A recent assess-
ment of 556 400 deaths due to cancer in India in 2010 ETIOLOGY
based on a nationally representative survey found that Although the etiology of gastric cancer is multifactorial,
stomach cancer with a mortality rate of 12.6% is the sec- more than 80% of cases have been attributed to H. pylori
ond most common fatal cancer[15]. infection. In addition, diet, lifestyle, genetic, socioeco-
Significant variations in the incidence of gastric can- nomic and other factors contribute to gastric carcinogen-
cer have been observed between different ethnic groups esis.

H. pylori cancer of both intestinal and diffuse types, but not the
H. pylori, a Gram-negative microaerophilic, spiral bacterium risk of cardia cancer. The CagA protein is delivered into
found in the gastric mucosa in patients with severe gastritis gastric epithelial cells where it undergoes tyrosine phos-
and chronic atrophic gastritis, has been recognized as an phorylation by SRC family kinases. Phosphorylated CagA
important risk factor for gastric cancer[2,21]. The results of specifically binds to and activates SHP2, a phosphatase
several meta-analyses concluded that H. pylori infection is that transmits positive signals for cell growth and motil-
associated with an approximately two-fold increased risk ity. Thus H. pylori acting via cagA activates growth factor
of developing gastric cancer[22]. In a prospective study receptors, increases proliferation, inhibits apoptosis, and
involving 1526 Japanese patients who had duodenal ul- promotes invasion and angiogenesis[33].
cers, gastric ulcers, gastric polyps or non-ulcer dyspepsia, Gene expression profiling of gastric antral mucosa
2.9% of H. pylori infected patients subsequently developed samples from H. pylori infected patients by microarray
gastric cancer while none of the uninfected patients de- analysis followed by quantitative real-time PCR assays
veloped tumors[23]. In 1994, the International Agency for have revealed differential expression of 38 genes, indi-
Research on Cancer categorized H. pylori as a “Group 1 cating that H. pylori infection leads to evasion of host
human carcinogen” based on a plethora of studies[24]. defense, enhanced inflammatory and immune responses,
Currently, approximately 50 per cent of the world’ activation of NF-κB and Wnt/β-catenin signaling path-
s population is infected by H. pylori. The prevalence of ways, perturbation of metal ion homeostasis, and induc-
H. pylori infection varies markedly in different countries tion of carcinogenesis[34].
in Asia with seroprevalence rates higher in developing
countries than in industrialized, developed nations[25]. Dietary factors
The identification of H. pylori as a risk factor for gas- A survey of literature on the role of diet in the pathogen-
tric carcinogenesis has stimulated extensive research on esis of gastric cancer using PubMed as a search platform
the mechanisms by which H. pylori induces carcinogen- has revealed over 2000 epidemiological and experimental
esis. A combination of a virulent organism, a permissive studies. Populations at high risk for stomach cancer have
environment, and a genetically susceptible host is consid- been shown to consume diets rich in starch and poor in
ered essential for H. pylori-induced gastric cancer. H. pylori protein quality, and are not inclined to eat fresh fruits and
has been suggested to trigger a cascade of events that vegetables. Both high starch and low protein diet may
promote the sequential progression of normal gastric favor acid-catalyzed nitrosation in the stomach and cause
epithelium through atrophic gastritis, intestinal metapla- mechanical damage to the gastric mucosa[35-37]. Using an
sia, and dysplasia to carcinoma[26-28]. The bacterium se- ecological approach, Park et al[38] found a negative asso-
cretes several products that cause gastric mucosal damage ciation between refrigerator use, fruit intake, and gastric
such as urease, protease, phospholipase, ammonia, and cancer mortality and positive associations between salt/
acetaldehyde. H. pylori disrupts gastric barrier function via sodium intake and gastric cancer mortality and incidence
urease-mediated myosin Ⅱ activation[29]. in Korea.
Generation of oxidative stress is recognized as a viru- Both epidemiological and experimental studies
lence factor in H. pylori-infected hosts. H. pylori infection strongly support the role of excessive salt intake in gastric
induces the production of reactive oxygen and nitrogen carcinogenesis. D’Elia et al[39] reported a direct correla-
species and suppresses the host antioxidant defense tion between dietary salt intake and risk of gastric cancer
mechanisms, leading to oxidative DNA damage. How- with progressively increasing risk across consumption
ever, H. pylori, which is endowed with a variety of anti- levels based on a meta-analysis of prospective studies.
oxidant enzymes is spared from oxidative stress and the Consumption of large amount of salted fish, soy sauce,
damage is solely restricted to the gastric mucosa of the pickled vegetables, cured meat and other salt-preserved
susceptible host[30]. H. pylori although not directly muta- foods enhances H. pylori colonization, and increases the
genic, has been suggested to favor the formation of mu- risk of gastric cancer through direct damage to the gas-
tagenic substances through inflammatory mediators or by tric mucosa resulting in gastritis. Salt is also known to
impairing the mismatch repair pathway[26,31]. Kim et al[26] induce hypergastrinemia and endogenous mutations, pro-
demonstrated that H. pylori infection promotes gastric moting epithelial cell proliferation which eventually leads
carcinogenesis by increasing endogenous DNA damage to parietal cell loss and gastric cancer progression[40,41].
whilst decreasing repair activities and by inducing muta- Reports from this laboratory as well as by other workers
tions in the mitochondrial and nuclear DNA. Aberrant have demonstrated that saturated sodium chloride
DNA methylation induced by H. pylori infection has been (S-NaCl) promotes the development of N-methyl-N’-
found to be a significant risk factor for gastric cancer[32]. nitro-N-nitrosoguanidine (MNNG)-induced rat gastric
Epidemiological evidence suggests that H. pylori carcinomas[42,43].
strains containing the cag pathogenicity island (cagPAI) Dietary nitrates are found either naturally in foods
are more virulent. The cagPAI is a 40-kb genome seg- such as cabbage, cauliflower, carrot, celery, radish, beets,
ment that encodes approximately 30 genes including the and spinach or added during preservation. In addition,
cytotoxin-associated gene A (cagA). The virulent cagA the nitrate content of fertilizers, soil, and water also con-
positive strains increase the risk of non-cardia gastric tribute to dietary nitrate. Nitrite, nitrate, and nitrosating

agents can be synthesized endogenously by reactions environment and have similar socioeconomic status.
mediated by bacteria and/or activated macrophages. Ni- These risk factors act independently or in conjunction
trosation of a number of naturally occurring guanidines with genetic factors thereby increasing the risk of stom-
and L-arginine-containing polypeptides produces mu- ach cancer.
tagenic compounds. Dietary nitrate is converted to car-
cinogenic N-nitroso compounds (NNC) by gastric acid Occupations
thereby increasing gastric cancer risk. Small quantities of A positive correlation has been recognized between
preformed NNC and nitrosamines may also be present increased stomach cancer risk and a number of occupa-
in some foods including cured meats, dried milk, instant tions including mining, farming, refining, and fishing as
soups, and coffee dried on direct flame[44-46]. well as in workers processing rubber, timber, and asbes-
In addition to specific components of the diet, cer- tos[58,59]. Occupational exposure to dusty and high tem-
tain cooking practices are also associated with increased perature environments such as in cooks, wood process-
risk of gastric cancer. These include broiling of meats, ing plant operators, food and related products machine
roasting, grilling, baking, and deep frying in open furnac- operators was associated with a significant increased risk
es, sun drying, salting, curing, and pickling, all of which of gastric cancer of the diffuse subtype[60]. A German
increase the formation of NNC. Polycyclic aromatic uranium miner cohort study however found a positive
hydrocarbons such as benzo[a]pyrene formed in smoked statistically non-significant relationship between stomach
food have been incriminated in many areas of the world cancer mortality and occupational exposure to arsenic
with high stomach cancer rates[47,48]. dust, fine dust, and absorbed dose from α and low-linear
energy transfer radiation[61].
Lifestyle
Alcohol, a gastric irritant is an important risk factor for GENETIC AND EPIGENETIC
gastric cancer. Zaridze et al[49] have reported an increased
risk of stomach cancer in men and women who regularly ALTERATIONS IN STOMACH CANCER
consume strong alcoholic beverages. A direct correlation The development of gastric cancer is a complex, mul-
was observed between consumption of alcohol and to- tistep process involving multiple genetic and epigenetic
bacco and the risk of gastric cancer in a population-based alterations in oncogenes, tumor suppressor genes, DNA
prospective cohort study[50]. A study from this labora- repair genes, cell cycle regulators, and signaling mol-
tory demonstrated a positive correlation between alcohol ecules. The catalogue of gene alterations in gastric cancer
consumption and cigarette smoking with the blood lipid is expanding rapidly[62,63]. An average of 4.18 genomic
profile in gastric cancer patients[51]. The European Pro- alterations has been suggested to be necessary for the
spective Investigation into Cancer and Nutrition (EPIC) development of gastric cancer[64]. Gastric carcinoma is
project found a significant association between the inten- characterized by genomic instability that could be either
sity and duration of cigarette smoking and gastric cancer microsatellite instability (MSI) or chromosomal instability
risk[52]. Smoking history was found to be a significant (CIN)[65].
independent risk factor for death from gastric cancer
in patients who had undergone curative surgical resec- CIN
tion[53]. Smoking is known to decrease prostaglandins that CIN, recognized as the most common instability occurring
maintain gastric mucosal integrity[54]. Tobacco smoke has in sporadic gastric tumors, may manifest as gain or loss
been reported to induce the development of precursor of whole chromosomes (aneuploidy) or parts of chro-
gastric lesions such as gastritis, ulceration, and intestinal mosomes [loss of heterozygosity (LOH), translocations,
metaplasia. Smokers tend to have a higher incidence of and amplifications][65]. Comparative genomic hybridiza-
H. pylori infection and gastroduodenal inflammation than tion analysis has revealed numerous DNA copy number
non-smokers[55]. variations with gains in chromosomal regions 6p21, 9p34,
11q23, 17p13, 19p13, and 22q13, especially in younger
Family history patients[66]. Using laser microdissection, Tsukamoto et al[67]
Gastric cancer is a known manifestation of inherited can- demonstrated DNA copy number variations in gastric
cer predisposition syndromes similar to hereditary nonpol- cancer patients with a high frequency of 20q13 chromo-
yposis colon cancer and Li-Fraumeni syndrome. Accord- some gain as well as upregulation of 114 candidate genes
ing to the OMIM database, 90 per cent of gastric cancers in the regions of amplification, and downregulation of 11
are sporadic, whereas 10 per cent are hereditary. The first genes in the regions of deletion. LOH at chromosomes
documented report of familial predisposition to gastric 1p, 2q, 3p, 4p, 5q, 6p, 7p, 7q, 8p, 9p, 11q, 12q, 13q, 14q,
cancer was described for Napoleon Bonaparte’s family 17p, 18q, 21q, and 22q that are possible sites of tumor
(OMIM_192090) with Napoleon, his father, grandfather, suppressor genes is believed to play a crucial role in gas-
brother, and three sisters, all dying of stomach cancer at tric carcinogenesis. A high frequency of LOH was found
a relatively early age[56]. The Scandinavian twin study in in the adenomatous polyposis coli (APC), p53, nm23
the Swedish, Danish, and Finnish twin registries found and Rb loci[65,68]. Several factors have been suggested to
an increased risk of stomach cancer in the twin of an af- contribute to CIN in gastric cancer patients including
fected person[57]. Family members usually share the same aberrations in chromosome segregation, DNA damage

response, cell cycle regulation, H. pylori infection, tobacco, tric cancer. Overexpression of cyclin E and CDK together
and dietary nitrates. with aberrant p53 expression and downregulation of p27,
a common event in gastric cancer, is associated with in-
MSI creased aggressiveness and poor prognosis[80,81]. A meta-
MSI, resulting from errors in DNA replication is seen in analysis of cell proliferation-related genetic polymor-
15-20 per cent of gastric cancers with a higher frequency phisms revealed a significantly higher risk of diffuse-type
in familial cases. The high frequency of MSI associated of stomach cancer in individuals harboring TP5372Pro
with advanced, invasive, intestinal-type gastric cancer has polymorphisms[82]. Immunohistochemistry and TUNEL
been suggested to be due to epigenetic inactivation of staining performed on tissue array slides containing 293
the mismatch repair gene hMLH1, whereas mutations in gastric carcinoma specimens showed a positive correla-
transforming growth factor-β (TGF-β) RII, insulin-like tion between the expression of cyclin D1, p21, or p27 with
growth factor Ⅱ (IGFⅡ) R, and BAX genes in sporadic early pTNM stages, tumor cell proliferation and good
gastric tumors with MSI display a decreased tendency for prognosis, but an inverse correlation with lymph node me-
invasion and nodal metastasis[65,69,70]. Cytosine-adenine tastasis. However, p27 expression inversely correlated with
repeat instability, LOH of the APC, and deleted in colon the apoptosis index indicating that these cell cycle regula-
cancer genes have been documented in well-differentiated tors may serve as candidate molecular markers for early
tumors[71]. gastric carcinoma[83]. High levels of circulating cell-free
human telomerase reverse transcriptase mRNA in gastric
Oncogenes cancer patients suggests that this molecule may be useful
Mutational activation and/or amplification of several on- as a noninvasive diagnostic and prognostic marker[84].
cogenes has been documented in gastric cancer. The K-ras Several growth factors and cytokines produced by the
oncogene was found to be mutated (codon-12) in intesti- gastric tumor microenvironment regulate differentiation,
nal-type cancer and its precursor lesions, intestinal meta- activation, and survival of multiple cell types. Extensive
plasia, and adenoma, but not in diffuse-type cancer[72]. changes in the expression profiles of the components of
Overexpression of c-erbB2 a cell surface receptor of the the TGF-β signaling pathway and its downstream targets
tyrosine kinase family is more common in intestinal-type occur during the sequential progression of the normal
gastric cancer, whereas in diffuse-type gastric cancers, epithelium through chronic atrophic gastritis and dys-
amplification of c-met, a transmembrane tyrosine kinase plasia to carcinoma. These changes include a progressive
receptor, and aberrations in the FGFR2/ErbB3/PI3 increase in the expression of TGFB1/2, TGFBR1, MYC
kinase pathway have been frequently documented[63,73]. and TP53, enhanced expression of SMAD4, CDKN1A,
A high correlation was observed between EZH2 the hu- SMAD1/2/3, SMAD2/3 and CDKN1B in dysplasia
man homolog of the Drosophila protein ‘‘Enhancer of that decreased in carcinoma, and enhanced expressed of
Zeste’’, with intestinal-type cancer and the risk of distant TGFBR2, SMAD7, RELA, and CDC25A both in dyspla-
metastasis[74]. sia and carcinoma[85]. A systematic review and meta-anal-
ysis of interleukin (IL)-1B cluster gene polymorphisms at
Tumor suppressor genes positions -511, -31, and +3954 and the receptor IL-1RN
Alterations in a number of TSGs have been documented variable number tandem repeat (VNTR) polymorphisms
in the pathogenesis of stomach cancer. The p53 gene revealed that IL-1B -511 T allele and IL-1 RN*2 VNTR
is frequently inactivated in gastric carcinomas as well as are significantly associated with an increased risk of de-
in precursor lesions by LOH, missense mutations, or veloping gastric carcinoma especially the non-cardia or
frameshift deletions[63,65,72]. GC-AT transitions of the p53 intestinal-type and among Caucasians[86].
gene are common in diffuse-type gastric cancer induced
by carcinogenic N-nitrosamines produced from dietary Invasion and angiogenesis
amines and nitrates[72,75]. LOH and mutations of PTEN Mutational inactivation and downregulation of genes
on chromosome 10q23.31 were observed in gastric can- encoding cell-adhesion molecules that function as tumor
cers as well as in precancerous lesions[76]. The RUNX3 suppressors have been documented in gastric cancer. In-
gene, a tumor suppressor, is also involved in the complex activation of E-cadherin, a product of the CDH1 gene
process of gastric oncogenesis[77]. Hypermethylation of has been suggested to play an important role in cell motil-
RUNX3 promoter in chronic gastritis, intestinal meta- ity, growth, and invasion of gastric cancer[87]. Rare genetic
plasia, and gastric adenomas, suggests that this gene is a alterations of IQ motif-containing GTPase-activating
target for epigenetic gene silencing in stomach cancer[78]. protein 1 gene, also called p195 (locus 15q26), a negative
Hypermethylation of nuclear retinoic acid receptor β has regulator of cell-cell adhesion at adherens junctions were
been documented in intestinal-type gastric cancers but found to occur in diffuse gastric cancers[88].
not in the diffuse-type[79]. Expression of the proangiogenic vascular endothelial
growth factor (VEGF) was demonstrated to correlate
Cell cycle regulators, growth factors and cytokines with poor survival in gastric cancer patients[89]. VEGF-A
Gene abnormalities and aberrant expression of cell cycle was found to be a significant marker for the presence of
regulators play a pivotal role in the pathogenesis of gas- tumor cells in the bone marrow, whereas VEGF-D is a

useful predictor of the lymphatic spread of tumor cells of dysplasia. Gene expression profiles by Affymetrix
in gastric cancer patients indicating that the metastatic technology and quantitative polymerase chain reaction
spread of gastric cancer could be determined, in part, by and in situ hybridization on tissue microarrays revealed
the profile of VEGF family members expressed in the that the majority of alterations associated with early gas-
primary tumour of gastric cancer patients[90]. Using hu- tric cancer are retained in advanced gastric cancer, with
man gastric cancer specimens, in vitro cell experiments, additional gene expression changes in AGC compatible
and in vivo animal experiments, Lee et al[91] demonstrated with a progression model of gastric carcinogenesis. Mo-
that hypoxia-independent promotion of the AKT-HIF- lecular characterization of 8 primary gastric carcinomas,
1α-VEGF pathway contributes to gastric cancer tumori- corresponding xenografts, and 2 novel gastric carcinoma
genesis and angiogenesis. cell lines revealed comparable histological features and
expression of several markers as revealed by immunohis-
Microribonucleic acids (miRs) tochemistry, copy number, and hypermethylation of up
miRNAs located within regions of LOH, amplification, to 38 genes[99].
fragile sites, and in other cancer-associated genomic Comprehensive protein profiling of paired surgi-
regions regulate a number of important biological pro- cal specimens of primary gastric adenocarcinomas and
cesses relevant to carcinogenesis including proliferation, non-tumor mucosae from Japanese patients by 2-D gel
apoptosis, differentiation, angiogenesis, metastasis, and electrophoresis and liquid chromatography-electrospray
immune response and they function as both oncogenes ionic tandem mass spectrometry revealed increases in
and tumor suppressor genes. miR dysregulation plays manganese dismutase and nonhistone chromosomal pro-
a key role in the pathogenesis of gastric cancer. Stud- tein HMG-1 with decreases in carbonic anhydrases Ⅰ and
ies have shown that miRs that function as oncogenes, Ⅱ, glutathione-S-transferase and foveolin precursor (gas-
such as miR-21, miR-106a and miR-17, were upregulated, trokine-1) (FOV), an 18-kDa stomach-specific protein
whereas miRs that function as tumor suppressors, in- with putative tumor suppressor activity. RT-PCR analysis
cluding miR-101, miR-181, miR-449, miR-486, let-7a, were also revealed significant downregulation of FOV mRNA
downregulated in gastric cancer[92]. In addition, genetic expression in tumor tissues, underscoring its potential
polymorphism of miR-196a-2 that interfers with its nor- use as an effective biomarker for diagnosis and molecular
mal binding with target mRNA such as homeobox gene target for chemotherapy[100].
cluster and annexin A1 was associated with a significantly
increased risk of gastric cancer[93]. H. pylori infection was Epigenetic changes
demonstrated to induce dysregulation of cancer-associ- Although the role of genetic alterations in gastric cancer
ated miRNAs including oncogenic (miR-106b) and tumor has long been recognized, global changes in the epigenetic
suppressor (let-7) miRNAs with hypermethylation of the landscape with reference to DNA methylation, histone
tumor suppressor miRNAs miR-124a-1, miR-124a-2 and methylation and histone acetylation have only been re-
miR-124a-3[94,95]. cently documented. While global hypomethylation leads to
activation of oncogenes and genomic instability, promoter
Gene and protein expression profiling hypermethylation is associated with transcriptional silenc-
The advent of genomics, proteomics, and transcriptomics ing of TSGs and DNA mismatch repair genes[101]. Diverse
has enabled successful detection of the comprehensive CpG island methylator phenotypes have been identified in
molecular alterations that occur during neoplastic trans- gastric cancer that serve as good prognostic indicators[102].
formation of the gastric mucosa. In Japan, a genome- Meta-analysis indicated aberrant methylation of 77 genes
wide linkage study identified chromosome 2q33-35 as in gastric cancer, suggesting the potential clinical value
a potential susceptibility locus for proximal gastric can- of DNA methylation as a marker for risk prediction and
cer[96]. Analysis of the microarray gene-expression data of prognosis[103]. Hypermethylation of promoters of genes
54 paired gastric cancer and adjacent noncancerous gas- involved in cell cycle control, metabolism of essential
tric tissues identified gene signatures of different grades nutrients, and production of inflammatory mediators, has
and different stages of gastric cancer. While a 19-gene been described in H. pylori infection as well as in gastric
signature distinguished between high- and low-grade cancer[104].
gastric cancers, an expanded 198-gene panel allowed the E-cadherin, a member of the APC pathway, and
stratification of cancers into four grades plus control and CDH4 (encoding R-cadherin), are hypermethylated in
a 10- and 9-gene signature enabled classification of early- gastric tumors. In particular CDH4 methylation is an ear-
and advanced-stage cancer respectively[97]. Sun et al[98] ana- ly diagnostic marker for gastrointestinal tumorigenesis[105].
lysed multiple gene expression patterns and their exact Epigenetic inactivation by hypermethylation of the RAS-
roles in gastric carcinogenesis using high-throughput tis- related gene, RASSF1A isoform, a negative effector of
sue microarray technique. The results showed that while K-ras, and activation of the R-RAS oncogene by hypo-
p53 was useful for distinguishing low-grade dysplasia methylation has been reported in gastric carcinomas[106].
from high-grade dysplasia, high-level expression of cyclin Histone acetylation and deacetylation catalyzed by his-
E might be an indicator for malignant transformation tone acetyltransferases and histone deacetylases (HDACs)

play an important role in chromatin remodeling. His- 477 312 subjects including 683 gastric adenocarcinoma
tone H4 acetylation in both the promoter and coding patients with 11 years of follow-up found that intake
regions of the p21WAF1/CIP1 gene in cells expressing of fresh fruits and citrus fruits protected against the
dominant-negative p53 was significantly reduced in gas- risk of diffuse and cardia gastric cancer respectively[112].
tric cancer cells expressing wild-type p53[107]. Epigenetic The EPIC study also reported a positive correlation be-
modifications also play an important role in miRNA de- tween consumption of red meat and gastric cancer risk,
regulation in gastric cancer[95]. whereas high plasma vitamin C, some carotenoids, retinol
Thus, genetic and epigenetic alterations can lead to and α-tocopherol, high intake of cereal fibre, and adher-
perturbations in normal cellular homeostasis eventually ence to the Mediterranean diet exhibited inverse associa-
culminating in neoplastic transformation of the gastric tion[113,114]. Dietary modification by reducing the intake of
mucosa. In particular, disruption in a number of regula- salt and salted food, as well as by increasing the intake of
tory pathways, evasion of apoptosis and increased pro- fruits and vitamin C is thus considered a practical strat-
gression through the cell cycle could create a permissive egy to prevent gastric cancer[37-40]. Both green and black
environment for genomic instability, invasiveness, and tea consumption has been reported to be associated with
metastasis. reduced risk of stomach cancer in epidemiological and
experimental studies[115,116].
Results from epidemiological and experimental studies
PREVENTION STRATEGIES point to a major influence of antioxidant nutrients in the
Correa et al[108] have suggested a plausible program for prevention of gastric carcinogenesis. Low plasma levels
gastric cancer prevention that involves screening and of the antioxidants ascorbic acid and vitamin E have
treatment of H. pylori infection, endoscopic and histolog- been reported in high-risk regions[113]. Studies from this
ic surveillance of precancerous lesions, improved sanita- laboratory have demonstrated that patients with gastric
tion and hygiene, restriction of dietary salt, and intake of cancer are more susceptible to reactive oxygen species-
a balanced diet containing fresh fruits and vegetables rich induced lipid peroxidation as a consequence of insuf-
in antioxidants. ficient antioxidant potential[117]. In particular, vitamin C is
Eradication of H. pylori infection is regarded as a pri- reported to prevent gastric cancer development by inhib-
mary chemoprevention strategy for reducing the incidence iting the conversion of nitrates into NNC and to delay
of gastric cancer[109]. American and European guidelines tumour induction in experimental animals[118]. Ascorbic
recommend H. pylori eradication in all patients with atro- acid has been demonstrated to attenuate the mutagenic
phy and/or intestinal metaplasia and in all first-degree rel- potency of MNNG in S. typhimurium and in gastric mu-
atives of gastric cancer patients in addition to endoscopic cosal cells[119].
and histological surveillance. The Asian Pacific Gastric Results from intervention trials confirm that subjects
Cancer Consensus has recommended population-based at high risk of developing stomach cancer can be pro-
screening and treatment of H. pylori infection in regions tected by supplementation with antioxidants. The finding
with an annual gastric cancer incidence above 20/100 000 of a reduction in cancer mortality among those receiving
to reverse H. pylori-induced biochemical, genetic, and antioxidant supplements in Linxian, China, was the first
epigenetic changes. In several intervention trials, H. pylori large intervention study that stimulated basic research in
eradication has prevented the progression of precancer- this area[120].
ous lesions. Intervention studies in Japan have demon- Dietary antioxidants may exert their inhibitory effects
strated significant prophylactic effects of H. pylori eradi- on gastric carcinogenesis by any one or a combination of
cation on the development of gastric cancer. The value the following mechanisms- preventing metabolic activation
of early eradication therapy in preventing gastric cancer of procarcinogens, inactivating carcinogens, enhancing
development was also confirmed in animal models[109,110]. DNA repair mechanisms, decreasing protooncogene ex-
Modulation of dietary patterns and changes in cook- pression, activating tumor suppressor genes, inhibiting cell
ing practices are believed to significantly reduce gastric proliferation, angiogenesis and inflammation, inducing dif-
cancer risk[108]. Refrigeration of food that obviates the use ferentiation and apoptosis, stimulating immune response,
of salt as a preservative, reduces the possibility of molds and modulating transcription factors and aberrant signaling
overgrowing in food, and renders conversion of nitrates pathways[121].
into NNC more difficult in cured and pickled foods[38].
Several studies have demonstrated the protective effect
of high intake of raw vegetables and fruits against the EXPERIMENTAL CHEMOPREVENTION
risk of gastric cancer. A EPIC study that recruited a total IN ANIMAL MODELS OF STOMACH
of 521 457 subjects in 23 centers across 10 European
countries found a positive association between high in-
CARCINOGENESIS
take of dietary antioxidants and reduced risk of gastric The fact that diet plays an important role in the etiology
cancer[111]. Reanalysis of the beneficial effects of fruit and of gastric cancer offers scope for nutritional chemopre-
vegetables in a continuation of the EPIC study involving vention. Chemoprevention, a promising approach for

controlling cancer, involves the use of specific natural or contrast, intragastric intubation of MNNG either in sin-
synthetic chemical agents to reverse, suppress or prevent gle or multiple doses is reported to produce forestomach
premalignancy from progressing to invasive cancer. Many tumours[131].
dietary agents, medicinal plants and their constituent phy- Experimental gastric tumours induced by the ad-
tochemicals have received growing attention as potential ministration of MNNG in Wistar rats show a number
chemopreventive agents over the past few years[122]. How- of similarities to human stomach cancer. The major risk
ever, it is essential to test the chemopreventive efficacy of factors associated with human stomach cancer such as
a putative agent in an animal model of gastric carcinogen- ethanol, high salt, low protein, diet and H. pylori were also
esis before embarking on clinical trials. found to promote or enhance MNNG-induced gastric
Various chemical carcinogens such as NNCs, nitro carcinogenesis[132,133]. Overexpression of HSP27, Bcl-2
compounds, aliphatic/aromatic hydrocarbons and ha- and COX-2, as well as H-ras and p53 gene mutations have
logenated hydrocarbons have been reported to induce been documented in both human and MNNG-induced
gastric tumours in experimental animals. A review of the gastric tumours[134,135]. Chen et al[136] have reported upregu-
National Toxicology Program database and the Carcino- lation of 11 proteins and downregulation of 2 proteins
genic Potency Database revealed that at least 26 chemicals in MNNG-induced gastric tumour tissue. The identified
induced gastric neoplasms in rodents of which N-methyl- proteins include cytoskeletal proteins, stress-associated
N-nitrosourea (MNU) and MNNG are the most com- proteins, and proteins involved in signal transduction, cell
monly used[123]. Animal models have been extensively proliferation, differentiation, and metabolism. Abe et al[137]
used to investigate the mechanisms of gastric carcinogen- reported that MNNG-induced rat stomach carcinomas
esis and to test chemopreventive agents[124]. possessed infiltration capacity and had lost differentiated
Tatematsu et al[125,126] induced glandular stomach tu- phenotypes for the stomach, in the same way as human
mors in BALB/c and C3H mice using MNU. Oshima stomach carcinomas, and could be used as a good model
and Oshima[127] constructed a series of mouse models from the viewpoint of molecular expression profile. A
to investigate the role of oncogenic pathways in gastric number of dietary agents have been tested for chemopre-
tumorigenesis. While Wnt activation in gastric epithelial ventive efficacy in the MNNG model, some of which are
cells suppressed differentiation, and induced preneo- listed in Table 1.
plastic lesions, induction of the PGE-2 pathway induced Studies from this laboratory have demonstrated
development of spasmolytic polypeptide-expressing the inhibitory effects on the development of MNNG-
metaplasia and promoted gastric hamartoma develop- induced rat forestomach tumours of extracts of black tea
ment when bone morphogenetic protein signaling was polyphenols as well as the dietary phytochemicals S-allyl-
suppressed. Simultaneous activation of the Wnt and cysteine, an organosulfur constituent of garlic, lycopene,
PGE-2 pathways led to dysplastic gastric tumor develop- a tomato carotenoid, and eugenol, a phenolic constituent
ment. found in clove oil[42,116,138-140]. In addition, curcumin, epi-
The Mongolian gerbil model that develops histo- gallocatechin gallate, folic acid, genistein and naringenin
pathological changes such as gastric atrophy, intestinal have been reported to exert chemopreventive effects in
metaplasia, dysplasia, and adenocarcinoma emulates the the MNNG model. Several of these agents act through
stages seen in human gastric cancer development. Gastric multiple mechanisms to exert their chemopreventive ef-
adenocarcinomas were successfully induced in Mongolian fects. These include inhibition of genotoxicity and oxida-
gerbils using MNNG and MNU as well as H. pylori infec- tive stress, modulation of signal transduction pathways
tion. The dose-dependent promoting effect of salt was and genes involved in the control of cell proliferation,
also demonstrated in this model. The Mongolian gerbil cell cycle, apoptosis, invasion, angiogenesis, and transcrip-
has emerged as the most relevant animal model for ana- tion regulation[141-145].
lyzing gastric cancer development and progression as well
as for chemoprevention trials[124,128]. MOLECULAR TARGETS FOR
Sugimura et al[129] in 1967 first demonstrated that high
yields of gastric tumours could be induced in Wistar rats CHEMOPREVENTION AND THERAPY
using MNNG. MNNG, a model direct-acting alkylat- Novel molecular targets are being discovered and used
ing agent produces several hundred-fold greater alkyla- to design drugs for gastric cancer. Most of the strategies
tion than other alkylating agents. MNNG is known to for testing the efficacy of gene therapy for gastric cancer
methylate all oxygen and most nitrogen atoms of DNA. have involved the use of adenoviral vectors. Some of
The major mutagenic lesion induced by MNNG is O6- the adenovirus-mediated approaches include transfer of
methylguanine that results in G:C to A:T transition muta- p53, Bax, truncated dominant negative IGF-Ⅰ receptor,
tions by mispairing during DNA replication[130]. MNNG enhancement of the c-Jun NH2-terminal kinase to re-
induces both glandular and forestomach carcinomas, duce the level of P-glycoprotein, transduction of soluble
depending on the concentration and route of adminis- VEGF receptors Flt-1 in peritoneal mesothelial cells to
tration. When administered in drinking water, MNNG inhibit the dissemination of gastric cancer in vivo and to
predominantly induces glandular stomach tumours. In increase the survival of treated animals[146-150].

Table 1 Dietary agents demonstrated to possess chemopreventive potential in the N-methyl-N’-nitro-N-nitrosoguanidine-induced

gastric carcinogenesis model
Agent Mechanism of action Targets Ref.

Curcumin Inhibition of cell proliferation, angiogenesis and COX-2 VEGF, COX-2, PCNA [141]
signaling
Eugenol Inhibition of NF-κB signaling, induction of apoptosis, NF-κB, IκB, Bcl-2, Bcl-xL, Bax, Apaf-1, cytochrome [139,140]
inhibition of cell proliferation and angiogenesis C, caspase-9, caspase-3, MMP-2, MMP-9, RECK,
TIMP-2, VEGF, VEGFR1
Folic acid Inhibition of cell proliferation PCNA [142]
Genistein Inhibition of cell proliferation and induction of apoptosis PCNA, Bcl-2, Bax [143]
Lycopene Modulation of biotransformation enzymes and antioxidant Glutathione redox cycle antioxidants, Bcl-2, Bax, Bim, [42,138]
defenses, induction of apoptosis caspase-8, caspase-3
Naringenin Modulation of biotransformation enzymes and antioxidant Glutathione redox cycle antioxidants [144]
defenses
S-allylcysteine Modulation of biotransformation enzymes and antioxidant Glutathione redox cycle antioxidants, Bcl-2, Bax, Bim, [42,138]
defenses, induction of apoptosis caspase-8, caspase-3
Induction of apoptosis
Tea polyphenols Modulation of antioxidant defenses, inhibition of oxidative PCNA, GST-pi, VEGF, Bcl-2, Bax, cytochrome C, [116,145]
and EGCG DNA damage, cell proliferation and angiogenesis, and caspase-3
induction of apoptosis
MNNG: N-methyl-N’-nitro-N-nitrosoguanidine; VEGF: Vascular endothelial growth factor; VEGFR: VEGF receptors; COX-2: Cyclooxygenase-2; PCNA:
Proliferating cell nuclear antigen; NF-κB: Nuclear factor κB; MMP: Matrix metalloproteinase; TIMP: Tissue inhibitor of matrix metalloproteinase; EGCG:
Epigallocatechin-3-gallate.
DNA methylating and histone deacetylating markers attractive approach to optimize therapeutic regimens and
have assumed significance in recent years for risk assess- minimize adverse side effects. Multitargeted preventive
ment, detection, prognostic evaluation, and as therapeutic and therapeutic strategies for gastric cancer are a major
targets. In particular, the use of HDAC inhibitors that can challenge for the future.
reactivate transcriptionally silenced genes to induce cell
differentiation, apoptosis, and growth suppression is an
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S- Editor Wang JL L- Editor Hughes D E- Editor Zheng XM

Carcinoma of The Stomach: A Review of Epidemiology, Pathogenesis, Molecular Genetics and Chemoprevention

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Carcinoma of The Stomach: A Review of Epidemiology, Pathogenesis, Molecular Genetics and Chemoprevention

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com/1948-5204office World J Gastrointest Oncol 2012 July 15; 4(7): 156-169

Carcinoma of the stomach: A review of epidemiology,

Peer reviewer: Jian-Kun Hu, MD, PhD, Associate Professor,

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Table 1 Dietary agents demonstrated to possess chemopreventive potential in the N-methyl-N’-nitro-N-nitrosoguanidine-induced

Agent Mechanism of action Targets Ref.

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Agren A, Martinez C, Dorronsoro M, Barricarte A, Tormo 244-251

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