Nutrition and gastric cancer risk: an update.

Abstract

Data from epidemiologic, experimental, and animal studies indicate that diet plays an important role in the etiology of gastric cancer. High intake of fresh fruits and vegetables, lycopene and lycopene-containing food products, and potentially vitamin C and selenium may reduce the risk for gastric cancer. Data also suggest that high intake of nitrosamines, processed meat products, salt and salted foods, and overweight and obesity are associated with increased risk for gastric cancer. However, current data provide little support for an association of beta-carotene, vitamin E, and alcohol consumption with risk for gastric cancer.

Full text

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Lead Article
Nutrition and gastric cancer risk: an update
Chun Liu and Robert M Russell
Data from epidemiologic, experimental, and animal studies indicate that diet plays
an important role in the etiology of gastric cancer. High intake of fresh fruits and
vegetables, lycopene and lycopene-containing food products, and potentially
vitamin C and selenium may reduce the risk for gastric cancer. Data also suggest that
high intake of nitrosamines, processed meat products, salt and salted foods, and
overweight and obesity are associated with increased risk for gastric cancer.
However, current data provide little support for an association of 8-carotene,
vitamin E, and alcohol consumption with risk for gastric cancer.
© 2008 International Life Sciences Institute
INTRODUCTION?
and allium vegetables and citrus fruits.71 Meta-analyses
have shown that the inverse association is stronger for
fruits than for vegetables, but it was weaker in cohort
studies than in case-control studies.711 In the 2003 report
of the International Agency for Research on Cancer
(IARC), the summary relative risks comparing high to
low categories for fruits were 0.63 (95% confidence inter-
val [CI] 0.58-0.69) from 37 case-control studies and 0.85
(95% Cl 0.77-0.95) from 11 cohort studies! Regarding
vegetables, the summary relative risks comparing high to
low categories were 0.66 (95% Cl 0.61-0.71) from 20
case-control studies and 0.94 (95% Cl 0.84-1.06) from 5
cohort studies.' Several case-control studies included in
the IARC meta-analysis also showed that the association
between intake of fruits and vegetables and gastric cancer
risk was similar by gastric anatomic site.' In the 2005
meta-analysis of cohort studies, the summary relative
risks of gastric cancer were 0.82 (95% Cl 0.73-0.93) for
fruits and 0.88 (95% CI 0.69-1.13) for vegetables.'0
?
Recently, two large European cohort studies reported
the results on fruit and vegetable consumption and
?
gastric cancer risk by anatomic site. In the prospective
analysis of the Alpha-Tocopherol, Beta-Carotene (ATBC)
Cancer Prevention Study,among 29 1133 male smokers
high consunption of fruits was assdciated with'a lower
risk of gastricnon-cardia cancer, but not with gastric
cardiá cancer.' However, consumtion of vegetabIe w
Gastric cancer is the fourth most frequent cancer and the?
second leading cause of cancer death worldwide.' Gastric?
cancer is relatively uncommon in the United States,?
ranking 14th among both incident cancers and cancer?
deaths, with approximately 22,280 new cases and 11,430?
deaths reported in 2006.2 The death rate from gastric?
cancer has gradually declined over the last several?
decades in the United States 2 and worldwide,' indicating?
that environmental factors (e.g. diet) play a critical role in?
the etiology of this malignancy. Mounting evidence mdi-?
cates that gastric cardia (the part of the stomach nearest?
to the esophagus) and non-cardia (the middle or lower?
part of the stomach) cancer differ in etiology.' The mci-?
dence of gastric cardia cancer has risen in the United?
States'-' and in European countries,' whereas the mci-?
dence of gastric non-cardia cancer has steadily de-?
creased.' The rising rate of obesity has been suggested to?
contribute to this increase in gastric cardia cancer.'
FRUITS AND VEGETABLES
The association betweenintake 'of fruits and vegetables?
and risk for gastric cancer hs bedn'èváluated extensively?
in observational epideniologic tudie. The studies gen-?
erally suggest an' inverse association, particularly for raw?
Affiliations: C Liu and RM Russell are with the Jean Mayer United States Department of Agriculture Human Nutrition Research Center on..
Aging, Tufts University, Boston, Massachusetts, YS.? .?
Correspondence: C Lit, Nutrition and Cancer Biology Laboratory, Jean Mayer United States Department of Agriculture Human Nutrition'
Research Center on-Aging at Tufts University, 711 -Washington Street, Boston, MA 02111, USA. E-mail: chun.liu@tufts.edu, Phone:,.
+1-617-556-3174, Fax: +1-617-556-3344,
.
Key words: gastric cancer, nutrition,
Nu
doi:1 0.1111/j.1753-4887.2008.00029.x
Nutrition Reviews Vol. 66(5):237-249
?
237

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not associated with risk for either gastric cardia or non-
cardia cancer in the ATBC Cancer Prevention Study.' The
results from the European Prospective Investigation into
Cancer and Nutrition (EPIC) cohort study, conducted
among 521,457 men and women living in 10 European
countries, showed no significant association of consump-
tion of fresh fruits, total vegetables, or specific groups of
vegetables with risk for gastric cancer regardless of ana-
tomic site, although a non-significant inverse association
was observed for citrus fruits or onion and garlic and risk
for gastric cardia cancer only.'
ANTIOXIDANT NUTRIENTS
Recent systemic reviews and meta-analyses of random-
ized trial data revealed that antioxidant supplements of
f3-carotene, vitamin A, and vitamin E, with the potential
exception for selenium and vitamin C, had no significant
effect on the incidence of gastrointestinal cancers;' 1,12 on
the contrary, f3-carotene, vitamin A, and vitamin E may be
associated with increased mortality. 13 To date, no ran-
domized trials have evaluated the effect of lycopene,
cc-carotene, lutein/zeaxanthin, or J3-cryptoxanthin on the
prevention of gastric cancer.
Carotenoids
Carotenoids are lipid-soluble compounds that are rich in
fruits and vegetables and responsible for the color of
many fruits and vegetables.' 4 u-Carotene, 3-carotene,
lycopene, lutein/zeaxanthin, and -cryptoxanthin are the
most abundant carotenoids from the diet and in the cir-
culation of humans.'4 Several carotenoids (such as
u-carotene, n-carotene, and 3-cryptoxanthin) present in
fruits and vegetables can be partially metabolized to
retinol.'5
Experimental studies. Carotenoids (lycopene, lutein, and
3-carotene) and retinoids have been shown to inhibit the
incidence and growth of the chemically induced gastric
tumors in laboratory animal studies.'6-'8 Experimental
and animal studies suggest several potential mechanisms
by which carotenoids may affect gastric carcinogenesis.
Carotenoids can act as antioxidants to do the following:
neutralize reactive oxygen species, thereby protecting
DNA from oxidative damage;' 7"9 decrease cell prolifera-
tion and induce apoptosis;'6'2° modify cell-cell communi-
cation;" enhance host immunologic functions; 2' and
reduce Helicobacter pylori bacterial load and gastric
inflammation by shifting the T-lymphocyte response
from a predominant Thl-response dominated by
y-interferon to a Thl/Th2-response with 'y-interferon and
interleukjn (IL)-4.22 In addition, in several human cross-
sectional studies, plasma lycopene and other carotenoid
concentrations have been inversely associated with
inflammatory markers. 23-25
Using the ferret animal model, the effects of lycopene
supplementation on cigarette-smoke-induced changes in
protein levels of p53 tumor suppressor gene, p53 target
genes (p2lWf/CIPI and Bax-1), cell proliferation, and apo-
ptosis in the gastric mucosa were examined .21 p2lwaf/6P
(a CDK inhibitor) is a key component in the cell cycle
arrest in GI, and Bax is a pro-apoptotic member of the
Bcl-2 family. p2lwaf/c•PI and Bax-1 function as mediators
to promote p53-dependent apoptosis. 26 In that study,
ferrets were assigned to cigarette smoke exposure or to no
cigarette smoke exposure and to low-dose, or high-dose
lycopene supplementation, or to no lycopene for nine
weeks. Lycopene concentrations were significantly
elevated in a dose-dependent manner in the gastric
mucosa of ferrets supplemented with lycopene alone, but
were markedly reduced in ferrets supplemented with
lycopene and exposed to smoke. It was also found that
total p53 and phosphorylated p53 levels were higher in
ferrets exposed to smoke alone than in all other groups.
However, smoke-elevated total p53 and phosphorylated
p53 were markedly attenuated by both doses of lycopene.
p2l'
apoptosis) were substantially decreased, whereas cell pro-
liferation indices like cyclin Dl and proliferating cellular
nuclear antigen (PCNA) were increased in ferrets
exposed to smoke alone, while lycopene prevented
smoke-induced changes in p21afP), Bax-1, cleaved
caspase 3, cyclin Dl, and PCNA in a dose-dependent
fashion.2° p53 phosphorylation, especially at serine 15, is
an early cellular response to various genotoxic carcino-
gens and stresses that produce reactive oxygen species,
and facilitates both the accumulation and functional acti-
vation of p53.27 Our data indicate that lycopene may
prevent smoke exposure-induced changes in p53, p53
phosphorylation, p53 target genes, cell proliferation, and
apoptosis in the gastric mucosa of ferrets, suggesting that
lycopene may protect against the development of gastric
cancer by modulating p53-dependent cell cycle control
and apoptosis.
P' ), Bax-1, and cleaved caspase 3 (an index for
Observational epidemiologic studies and randomized tri-
als. Observational epidemiologic data, albeit not entirely
consistent, have shown that high intake of tomato and
tomato-based products (major sources of lycopene) and
high intake or plasma levels of lycopene are associated
with reduced risk for gastric cancer (Table 1).2832
However, the results for u-carotene, j3-carotene, lutein/
zeaxanthin, and 3-cryptoxanthin, and retinol have been
conflicting.8'3'35
Randomized trials also have not yielded consistent
evidence for the efficacy of J3-carotene or combination of
238
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Nutrition Reviews ® Vol. 66(5):237-249

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0-carotene with other antioxidants on gastric cancer
prevention . 36-40 Daily 3-carotene supplementation
(30 mg) for six years among individuals with multifocal
nonmetaplastic atrophy and/or intestinal metaplasia
(premalignant lesions) significantly ihcreased the rates of
regression in the Columbia trial.39 In the General Popu-
lation Trial of Linxian, China, among 29,584 high-risk
individuals with suboptimal nutritional status, random-
ized daily treatment for 5.25 years with supplements con-
taining 3-carotene (15 mg), a-tocopherol (30 mg), and
selenium from yeast (50 tg) resulted in a non-significant
reduction in both the incidence of and mortality from
gastric cardia and non-cardia cancer. 36 Two randomized
trials in well-nourished Western populations, however,
found no beneficial effect of 3-carotene for reducing the
risk for gastric cancer .3738 Although the number of gastric
cancers was small in one of these studies, the results
showed that 50 mg of 3-carotene supplementation every
other day for 12 years did not affect the risk for gastric
cancer among 22,071 apparently healthy US male physi-
cians.37 In the ATBC Cancer Prevention Study, random-
ized daily treatment with 3-carotene (20 mg) or with
combined 3-carotene (20 mg) and a-tocopherol (50 mg)
for five to eight years led to a non-significant, increased
risk for gastric cancer among 29,133 Finnish male smok-
ers;39 however, it had no influence on the occurrence of
neoplastic changes of the stomach in male smokers with
atrophic gastritis.4'
Vitamin C
Experimental, studies. Vitamin C (ascorbic acid) is a
water-soluble antioxidant that is abundant in fruits and
vegetables and can regenerate vitamin E from its oxidized
form.42 The effect of vitamin C on experimentally in-
duced gastric cancer in laboratory rodents is conflicting,
with studies showing an inhibitory effect, 43 no effect '44 or
a promoting effect.45 A few studies reported a promoting
effect of vitamin C on forestomach carcinogenesis when it
was coadministrated with sodium nitrite following pre-
treatment with chemical carcinogens, whereas vitamin C
itself had ni'o influence on forestomach or glandular
stomach carcinogenesis.46
Data frbm experimental and animal studies indicate
several potential mechanisms by which vitamin C may
affect gastric carcinogenesis, including the following:
vitamin C reduces gastric mucosal oxidative stress and
DNA damage 41.4' and gastric inflammation 47 by scaveng-
ing reactive oxygen species; it inhibits gastric nitrosation
reaction for the formation of N-nitroso compounds by
reducing nitrous acid to nitric oxide and producing
dehydro- ascorbicacid in the stomach; 41.41.11 it enhances
host immunologic functions;2142 it has a direct effect on
H. pylori growth and virulence;42 and it inhibits gastric
cell proliferation and induces apoptosis.42
Observational epidemiologic studies and randomized
trials. Case-control studies have consistently reported an
inverse association between vitamin C and gastric cancer
risk.50 Most of the prospective cohort studies have also
shown an inverse association. In the Basel Study, serum
vitamin C levels were inversely associated with mortality
from gastric cancer. 5' In the EPIC cohort, plasma vitamin
C levels were associated with reduced risk for gastric
cancer, and this inverse association was similar according
to anatomic site (cardia vs. non-cardia), histologic
subtype (diffuse vs. intestinal), or H. pylori infection.52 Use
of vitamin C supplements was also associated with
reduced mortality from gastric cancer in the American
Cancer Society Cancer Prevention Study II cohort. 53 In
the cohort analysis of the ATBC Cancer Prevention
Study, high vitamin C intake was associated with reduced
risk for gastric non-cardia cancer but not for gastric
cardia cancer.' However, the Netherlands Cohort Study
found no association between vitamin C intake and risk
for gastric cancer.33
The results from several randomized trials that have
assessed the efficacy of vitamin C in the prevention of
gastric cancer are not entirely consistent (Table 2). One
randomized trial in Japan among individuals with
chronic gastritis reported that vitamin C slowed the pro-
gression of gastric mucosal atrophy, a precancerous
lesion of gastric cancer.54 In that trial, daily treatment with
50 mg or 500 mg of vitamin C for five years significantly
reduced the ratio of serum pepsinogen I/Il, a marker of
gastric atrophy.54 In an Italian trial among patients with
intestinal metaplasia (premalignant lesions) on the
gastric mucosa following H. pylori eradication, vitamin C
supplementation (500 mg/day) for six \pionths signifi-
cantly increased the rate of regression of intestinal meta-
plasia.55 In the Columbia trial, individuals with multifocal
non-metaplastic atrophy and/or intestinal metaplasia
(premalignant lesions) assigned to vitamin C supple-
ments (1 g twice a day) also had significantly increased
rates of regression over six years of treatment. 39 However,
supplementation with combined vitamin C (250 mg),
vitaiin E (100 IU),and selenium from' yeast (37.5 .tg)
twic dáilfor 7.3 years did not lower the.jirevalence of
precancerous gastric lesions and the incidence of gastric
cancers in the Linqu trial in China.40 Randomized daily
treatment with combined vitamin C (120 mg) and
molybdenum supplements for 5.25 years also had no sig-
nificant effect on both incidence and mortality from
gastric cardia and iion-ardia cancer in the General
Population Trial of Linxian, China.36
In human studies, treattheiit with high-dose vitamin
C (5 g daily for 4 weeks) eradicated H. pylon infection.56
Vitamin C supplementation (1 g twice daily for 4-12
months) reduced the formation of nitrot'yrosine, a nitrat-
ing product, among patients with H. 'pyloni non-atrophic
240?
Nutrition Reviews? Vol. 66(5):237-249

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Nutrition Reviews* Vol. 66(5):237-249?
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