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A Higher Dietary Ratio of Long-Chain Omega-3 to Total Omega-6 Fatty Acids for Prevention of COX-2-Dependent Adenocarcinomas

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Compelling evidence that daily low-dose aspirin decreases risk for a number of adenocarcinomas likely reflects the fact that a modest but consistent inhibition of cyclooxygenase-2 (COX-2) activity can have a meaningful protective impact on risk for such cancers. The cancer-promoting effects of COX-2 are thought to be mediated primarily by prostaglandin E2 (PGE2), synthesized from arachidonic acid. The long-chain omega-3s eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA), abundant in many fatty fish, can interfere with the availability of arachidonate to COX-2 by multiple complementary mechanisms; moreover, the PGE3 produced by COX-2 from EPA is a competitive inhibitor of the receptors activated by PGE2. These considerations have given rise to the hypothesis that a high dietary intake of EPA/DHA, relative to omega-6 (from which arachidonate is generated), should lessen risk for a number of adenocarcinomas by impeding PGE2 production and activity-while not posing the risk to vascular health associated with COX-2-specific nonsteroidal antiinflammatory agents. Analyses that focus on studies in which the upper category of fish consumption (not fried or salt-preserved) is 2 or more servings weekly, and on studies that evaluate the association of long-term fish oil supplementation with cancer risk yields a number of findings that are consistent with the hypothesis. Further studies of this nature may help to clarify the impact of adequate regular intakes of long-chain omega-3 on cancer risk, and perhaps provide insight into the dose-dependency of this effect.
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A Higher Dietary Ratio of Long-Chain Omega-3 to
Total Omega-6 Fatty Acids for Prevention of COX-2-
Dependent Adenocarcinomas
James J. DiNicolantonioa, Mark F. McCartyb, Subhankar Chatterjeec, Carl J. Lavied & James
H. O’Keefee
a Mid America Heart Institute at Saint Luke's Hospital, Kansas City, Missouri, USA
b Catalytic Longevity, Carlsbad, California, USA
c R. G. Kar Medical College & Hospital, Kolkata, India
d John Ochsner Heart and Vascular Institute, Ochsner Clinical School, The University of
Queensland School of Medicine, New Orleans, Louisiana, USA and Pennington Biomedical
Research Center, Baton Rouge, Louisiana, USA
e Mid America Heart Institute at Saint Luke's Hospital, Kansas City, Missouri, USA and
University of Missouri-Kansas City, Kansas City, Missouri, USA
Published online: 30 Oct 2014.
To cite this article: James J. DiNicolantonio, Mark F. McCarty, Subhankar Chatterjee, Carl J. Lavie & James H. O’Keefe
(2014): A Higher Dietary Ratio of Long-Chain Omega-3 to Total Omega-6 Fatty Acids for Prevention of COX-2-Dependent
Adenocarcinomas, Nutrition and Cancer, DOI: 10.1080/01635581.2014.956262
To link to this article: http://dx.doi.org/10.1080/01635581.2014.956262
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A Higher Dietary Ratio of Long-Chain Omega-3 to Total
Omega-6 Fatty Acids for Prevention of COX-2-Dependent
Adenocarcinomas
James J. DiNicolantonio
Mid America Heart Institute at Saint Luke’s Hospital, Kansas City, Missouri, USA
Mark F. McCarty
Catalytic Longevity, Carlsbad, California, USA
Subhankar Chatterjee
R. G. Kar Medical College & Hospital, Kolkata, India
Carl J. Lavie
John Ochsner Heart and Vascular Institute, Ochsner Clinical School, The University of Queensland
School of Medicine, New Orleans, Louisiana, USA and Pennington Biomedical Research Center, Baton
Rouge, Louisiana, USA
James H. O’Keefe
Mid America Heart Institute at Saint Luke’s Hospital, Kansas City, Missouri, USA and University
of Missouri-Kansas City, Kansas City, Missouri, USA
Compelling evidence that daily low-dose aspirin decreases risk
for a number of adenocarcinomas likely reflects the fact that a
modest but consistent inhibition of cyclooxygenase-2 (COX-2)
activity can have a meaningful protective impact on risk for such
cancers. The cancer-promoting effects of COX-2 are thought to
be mediated primarily by prostaglandin E2 (PGE2), synthesized
from arachidonic acid. The long-chain omega-3s eicosapentaenoic
acid (EPA) and docosahexaenoic acid (DHA), abundant in many
fatty fish, can interfere with the availability of arachidonate to
COX-2 by multiple complementary mechanisms; moreover, the
PGE3 produced by COX-2 from EPA is a competitive inhibitor of
the receptors activated by PGE2. These considerations have given
rise to the hypothesis that a high dietary intake of EPA/DHA,
relative to omega-6 (from which arachidonate is generated),
should lessen risk for a number of adenocarcinomas by impeding
PGE2 production and activity—while not posing the risk to
vascular health associated with COX-2-specific nonsteroidal
antiinflammatory agents. Analyses that focus on studies in which
the upper category of fish consumption (not fried or salt-
preserved) is 2 or more servings weekly, and on studies that
evaluate the association of long-term fish oil supplementation
with cancer risk yields a number of findings that are consistent
with the hypothesis. Further studies of this nature may help to
clarify the impact of adequate regular intakes of long-chain
omega-3 on cancer risk, and perhaps provide insight into the
dose-dependency of this effect.
There is considerable evidence that cyclooxygenase-2
(COX-2) activity often plays a mediating role in the induction
and progression of a range of cancers, most notably adenocar-
cinomas (1–8). Epidemiology correlating regular nonsteroidal
anti-inflammatory drug use with decreased risk for various
adenocarcinomas is consistent with this proposition (9). Yet,
the most compelling evidence in this regard is a meta-analysis
by Rothwell and colleagues examining cancer mortality in
subjects randomized to receive daily aspirin for at least 4 yr in
8 large clinical trials originally designed to assess aspirin’s
impact on cardiovascular events (10). Deaths attributed to can-
cer were recorded in each of these trials, and for 3 of these tri-
als a follow up of 20 yr was achieved. The impact of aspirin
assignment on total mortality from solid cancers during at least
10 years of follow-up was dramatic—cancers death were
Submitted 22 December 2013; accepted in final form 27 July 2014.
Address correspondence to James J. DiNicolantonio, Saint Luke’s
Mid America Heart Institute, 4321 Washington Street, Suite 2100,
Kansas City, MO 64111. E-mail: jjdinicol@gmail.com
1
Nutrition and Cancer, 0(0), 1–6
Copyright Ó2014, Taylor & Francis Group, LLC
ISSN: 0163-5581 print / 1532-7914 online
DOI: 10.1080/01635581.2014.956262
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roughly 25% lower in comparison to subjects who received
placebo [hazard Ratio (HR) D0.75, 95% confidence interval
(CI): 0.67–0.84, P<.0001, among patients followed for
20 yr]. This benefit primarily reflected lower deaths from
adenocarcinomas of gastrointestinal or non-gastrointestinal
origin, which were about a third less likely over 20 yr in those
randomized to aspirin. Cancer sites in which prevention of
cancer death reached statistical significance included esoph-
ageal, colorectal, pancreatic, and lung; the protection afforded
from lung and esophageal cancers was specific to adenocarci-
nomas. A trend toward prevention of prostate cancer deaths
over 20 yr did not achieve statistical significance (HR D0.83,
95% CI: 0.61–1.06, PD0.12). Unfortunately, owing to the
fact that the large majority of subjects enrolled in these trials
were male, information on female-specific cancers was sparse
and was not reported.
As might be expected, this effect showed considerable
latency, with significant cancer prevention not emerging until
over 5 years of follow-up. Also in line with expectation, those
asked to take aspirin for at least 7.5 yr achieved greater long-
term cancer prevention than those taking aspirin for shorter
periods. Remarkably, no dose-dependency was observed—
75 mg aspirin daily was found to be as protective as higher
doses.
Aspirin’s capacity to inhibit cyclooxygenase activity, even
in doses as low as 75 mg daily, reflects the fact that it causes
permanent inhibition of this enzyme (both COX-1 and COX-
2) by inducing covalent acetylation of its active site (11).
There is good reason to suspect that the inhibition of COX-2
in preneoplastic lesions or early cancers was primarily respon-
sible for the protective benefit reported by Rothwell et al.
(10). Previous epidemiological analyses focusing specifically
on colorectal cancer have found that regular aspirin use
reduces risk for, and death from, colorectal cancers that
express COX-2; no impact of aspirin was found on the occur-
rence or clinical course of colorectal cancers lacking COX-2
(12,13). It is unlikely that aspirin’s ability to inhibit platelet
aggregation via COX-1 inhibition could have been responsible
for prevention of cancer mortality, because the Women’s
Health Study, in which subjects received 100 mg aspirin every
other day, failed to find any impact on cancer incidence or
mortality during 10 years of follow up (14)—and yet such a
regimen is sufficient for effective platelet stabilization. [Anal-
ogously, 325 mg aspirin every other day failed to influence
colorectal cancer risk in the Physicians’ Health Study (15).] In
concert with the ample evidence that COX-2 often plays a key
role in the genesis and progression of cancer—notably adeno-
carcinomas—these considerations strongly suggest that COX-
2, either in transformed cells or adjoining stroma, is the key
target of aspirin’s cancer protective activity.
It can be concluded that COX-2-derived prostanoids play a
key role in driving the genesis and progression of human
adenocarcinomas. Considerable evidence indicts prostaglandin
E2 (PGE2) as the most prominent mediator in this regard. Via
activation of membrane receptors—of four isotypes, EP1–
EP4—it can exert autocrine and paracrine effects that work in
a variety of complementary ways to aid the survival and
spread of neoplastic or pre-neoplastic lesions (16–26). In vari-
ous cancers, activation of these receptors has been reported to
oppose apoptosis by such effects as increased Bcl-2 expres-
sion, decreased expression of pro-apoptotic Bax or Bim, inhib-
itory Bad phosphorylation, and Akt activation; inhibition of
apoptosis in initiated preneoplastic cells is a key mechanism
whereby cancer promoters increase cancer risk (27). These
receptors can also promote proliferation and invasive spread
in certain cancers, promote angiogenesis, and inhibit the can-
cer-killing efficacy of cytotoxic T cells as well as natural killer
cells. Furthermore, in breast tissue, COX-2/PGE2 activity, act-
ing via EP2/EP4 and cyclic AMP, promotes induction of aro-
matase in stroma and in breast cancer cells (28–31); breast
stromal aromatase activity is believed to be a key determinant
of risk for estrogen-positive breast cancer post-menopausally.
(32,33)
AN ALTERNATIVE STRATEGY FOR SUPPRESSING COX-2
ACTIVITY: INCREASING OMEGA-3 INTAKE
As is well known, strong and persistent inhibition of COX-
1 commonly leads to gastrointestinal bleeding and nephropa-
thy. Aspirin has a higher affinity for COX-1 than for COX-2,
and yet most people tolerate low-dose aspirin well. This evi-
dently reflects the fact that such regimens achieve only a very
partial and transitory inhibition of COX-1, and hence also of
COX-2. Unfortunately, it is now known that strong specific
inhibition of COX-2 is attended by an elevation of cardiovas-
cular risk that would be unacceptable in the general population
(34). Nonetheless, as adjuncts or alternatives to low-dose aspi-
rin, various safe measures with potential for limiting COX-2
expression can be expected to have utility for cancer preven-
tion, as reviewed recently (35). Thus, in certain cancer-prone
epithelia, induction of COX-2 can be opposed by high-normal
vitamin D status, agents which downregulate oxidative stress
(such as phase 2 inducer dietary phytochemicals and possibly
spirulina), soy isoflavones (via activation of estrogen receptor-
beta), and measures that decrease systemic IGF-I bioactivity,
such as quasivegan diets and active lifestyles that promote
leanness and muscle insulin sensitivity (35). In addition, meas-
ures that modulate COX-2’s access to its key substrate, arachi-
donic acid, can be expected to influence cancer induction and
spread.
The long-chain omega-3 fatty acids eicosapentaenoic acid
(EPA, 20:5n3) and docosahexaenoic acid (DHA, 22:6n3),
richly supplied by many fatty fish, can act to displace arachi-
donic acid from membrane phospholipids, in part because they
compete for the desaturase enzymes which generate arachido-
nate from linoleic acid (36–39). In addition, EPA and DHA
can act as a competitive inhibitors of arachidonate’s binding to
the active site of COX-2, and EPA acts as an alternative
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substrate for this enzyme (40). The prostanoid PGE3 derived
from COX-2’s action on EPA not only fails to activate PGE2’s
receptors, but also acts as a competitive inhibitor in this regard
(41). Other prostanoids that EPA or DHA can give rise to tend
to have antiinflammatory effects, in marked contrast to the
often proinflammatory impacts of arachidonate products (42).
The membrane content of arachidonic acid can also be
decreased by minimizing dietary intakes of omega-6 fatty
acids, which can give rise to arachidonate by desaturation and
elongation reactions, and by minimizing intake of preformed
arachidonate (as with plant-based food choices). Hence, it is
reasonable to predict that a diet rich in EPA/DHA, although
relatively low in omega-6 fatty acids (including arachidonic
acid), could decrease the cancer-supportive activity of COX-2
by limiting its access to arachidonic acid. A corollary of this is
that—other factors being equal—such a diet could be expected
to provide protection from a range of adenocarcinomas. A
summary of the mechanisms whereby long-chain omega-3s
can oppose COX-2 activity is offered in Table 1.
Such a prediction, of course, omits from consideration the
possibility that the omega-3/omega-6 ratio of the diet might
act in ways other than modulation of COX-2 activity to influ-
ence cancer induction and spread. Because omega-3-derived
mediators tend to have antiinflammatory actions, it perhaps is
reasonable to expect that any ancillary effects of omega-3
nutrition will more likely be protective than harmful with
respect to cancer risk. Nonetheless, it clearly is appropriate to
examine the epidemiological evidence pertinent to the propo-
sition that a relatively high dietary omega-3/omega-6 ratio can
provide protection from adenocarcinomas. Moreover, epide-
miology may provide some insight into the dose-dependency
of any protection afforded by long-chain omega-3s.
It seems reasonable to suspect that EPA/DHA intakes of at
least several grams daily, in the context of modern diets that
are typically laced with omega-6-rich oils, would be required
to have a functionally significant impact on eicosanoid produc-
tion. In this regard, a recent placebo-controlled study demon-
strating that 2 g EPA daily could reduce polyp number and
size in patients with familial adenomatous polyposis, to an
extent similar to that seen with COX-2 inhibitors, may provide
insight regarding the omega-3 intake that might be useful for
prevention of adenocarcinomas (43). Also illuminating is a set
of studies demonstrating that ingestion of 4.4 g of fish oil
omega-3s per day can slow epithelial proliferation and PGE2
release from rectal biopsy specimens ex vivo—but not if a diet
rich in omega-6 is ingested concurrently (44,45). It is notable
that the average daily American intake of EPA CDHA is said
to be only about 100 mg (46). The proposition that EPA and/
or DHA have cancer-preventive potential can only be assessed
fairly on epidemiological studies which quantify cancer risk in
subjects who consume fatty fish multiple times weekly, and/or
that supplement with significant doses of fish oil on a daily
basis, in the context of a diet of moderate omega-6 content.
One would not expect meta-analyses incorporating studies
from low-omega-3-intake populations to confirm this
proposition.
PERTINENT EPIDEMIOLOGICAL DATA
The impact of omega-3 consumption on cancer risk can be
appropriately evaluated in Italy, where the staple oil used in
cooking and as salad dressing, olive oil, is quite low in omega-
6 (about 12%), and fish is a staple food for a significant propor-
tion of the population. In this regard, a summary of case-con-
trol studies conducted in northern Italy between 1983 and
1996 is particularly illuminating (47). Among the 7,990
patient controls employed in these studies, 23% ate fish at least
2 times weekly. Subjects who consumed fish at least 2 times
weekly, as compared to those who ate fish less than once a
week, were found to be at significantly lower risk for ovarian
[odds ratio (OR) D0.7), endometrial (OR D0.8), pharyngeal
(OR D0.5), esophageal (OR D0.6), gastric (O R D0.7),
colonic (OR D0.6), rectal (OR D0.5), and pancreatic (OR D
0.7) cancers. No apparent protection was seen for breast or
prostate cancers. Although this report did not specify the his-
tology of the cancers observed, it can be presumed that a high
proportion of the cancers for which fish-related protection was
observed were adenocarcinomas.
A search for other epidemiological studies in which the top
category of fish consumption was two or more servings weekly
yielded a Swedish case-control study in which fatty fish con-
sumption in the upper intake group, relative to the lowest
intake group (median 0.2 servings weekly), was associated
with a significantly lower risk for endometrial cancer: multi-
variate OR D0.6, 95% CI: 0.5–0.8; Pfor trend, 0.0002 (48).
In contrast, consumption of lean fish was not associated with
risk. In a Polish case-control study, focusing on colorectal can-
cer, the upper intake group was defined as over 2 servings
weekly, and marked protection was observed: adjusted OR D
0.56; 95% CI: 0.39–0.86; a lesser but still significant degree of
protection was seen in those eating 1–2 fish servings weekly
(49).
The Swedish study raises the point that the nature of fish—
whether or not it is fatty—and the way in which fish is pre-
served or cooked, can skew the outcomes of epidemiological
TABLE 1
How long-chain omega-3 opposes Cox-2 activity
Competition for desaturase enzymes which convert linoleic
acid to arachidonic acid (37,38)
Competition with arachidonate for incorporation into
membrane phospholipids (36)
Competition with arachidonate for access to the active site of
cox-2 (40)
PGE3, synthesized from EPA, acts as a competitive inhibitor
of PGE2 receptors for EP2/EP4 (41)
OMEGA-3/OMEGA-6 RATIO, COX-2, AND ADENOCARCINOMAS 3
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studies evaluating fish consumption. Salt-preserved fish (as
opposed to fresh or frozen) is commonly consumed in many
cultures and may be laced with mutagens (50,51); hence, some
studies find a positive association between consumption of
such fish and risk for cancers, particularly those of the upper
gastrointestinal tract (52–56). Fried fish, as opposed to baked
or boiled fish, fails to associate with protection in some stud-
ies, or is even associated with increased risk (55,57–60) frying
can reduce the total omega-3 content, while notably increasing
the omega-6/omega-3 ratio of the fish, particularly if a polyun-
saturated oil is employed (61,62). Moreover, high-temperature
cooking of fish, such as frying, can promote production of
mutagenic heterocyclic amines, as it does in other flesh foods
(owing to reactions involving creatine) (63–66). In the VITa-
mins And Lifestyle (VITAL) study (cited below), nonfried fish
consumption was associated with reduced risk for pancreatic
cancer (0.62; 95% CI: 0.40, 0.98; P-trend D0.08), but con-
sumption of fried fish did not associate with protection (60).
Farmed fish, such as much marketed tilapia and salmon, tend
to have a higher omega-6/omega-3 ratio than wild fish, as they
are often fed with grains; the long-chain omega-3s in fish are
not synthesized de novo but rather stem from unicellular
organisms at the base of their natural food chain (67–69).
Hence, studies examining populations in which habitual fish
intake is low, lean, or farmed fish is preferred, or in which con-
sumption of salt-preserved or fried fish is common, may not be
appropriate for evaluating the impact of long-chain omega-3
intake on cancer risk. These considerations are summarized in
Table 2.
FISH OIL SUPPLEMENTATION AND CANCER RISK
Another approach to evaluating the potential of omega-3 to
decrease cancer risk—which overcomes these obstacles—is to
examine risk for adenocarcinomas in individuals who have
consumed fish oil capsules on a regular basis for years.
Although a raft of epidemiological studies have attempted to
correlate fish consumption—which tends to be sporadic—with
cancer risks, very few to date have examined regular fish oil
supplementation—which can readily provide 1 or more grams
of long-chain omega-3 daily—as a correlate of cancer risk.
This approach was taken recently by Kantor and colleagues,
using data from the prospective VITAL study, which queried
68,109 Washington residents, aged 50–76, on their lifestyle
habits, including diet and supplement usage, in 2000–2002
(70). These researchers focused on a group of subjects who
claimed to have used fish oil supplements at least 4 days a wk
for at least 3 yr. In comparison to subjects in the trial who did
not supplement with fish oil, the fish oil users were found to be
at notably lower subsequent risk for colorectal cancer (HR D
0.51, 95% CI: 0.26–1.00) after multivariate adjustments that
included an estimate of omega-6 consumption (adjustment for
only age and sex also observed protection: HR D0.48, 95%
CI: 0.26–0.87).
In another analysis of the VITAL cohort, current use of fish
oil supplements was associated with reduced breast cancer
risk: HR D0.68, 95% CI: 0.50–0.92, after multivariate adjust-
ment (71). Assessed 10-yr average use of fish oil supplements
showed a trend toward protection (Ptrend D0.09). An analy-
sis of prostate cancer risk in this population failed to observe
any correlation with fish oil use (OR D0.98) (72). A recent
analysis of an Icelandic cohort, however, reported that fish oil
supplementation during later life was associated with a marked
reduction in risk for advanced prostate cancer: HR D0.43,
95% CI: 0.19–0.95 (73). These findings are actually in reason-
able accord with a meta-analysis of fish consumption and pros-
tate cancer; whereas fish consumption did not clearly associate
with incidence of prostate cancer (it emerged as protective in
case-control studies, but not in prospective cohort studies), it
was associated with a highly significant 63% reduction in risk
for prostate cancer mortality (74). With respect to endometrial
cancer, a recent case-control study in Connecticut found that
fish oil consumption was associated with a significantly lower
risk after multivariate adjustment: OR D0.63, 95% CI:
0.71–0.88 (75).
Very recently, a further analysis of the VITAL cohort has
appeared, focusing on global mortality, including total cancer
mortality. Total daily intake of EPA CDHA from both diet
and supplements was associated inversely with total mortality;
comparing the fourth with the first quartile, and adjusting for
multiple potentially confounding variables, including arachi-
donic acid intake, HR D0.82, 95% CI: 0.73, 0.93. An inverse
association between omega-3 intake and total cancer mortality
was also observed: HR D0.77, 95% CI: 0.64, 0.92 (76). The
cogency of these findings may reflect the fact that total omega-
3 intake, from both diet and supplements, was assessed.
Additional studies examining cohorts in which a significant
fraction of subjects are heavy regular consumers of fatty fish
(not fried or salt-preserved), or regular users of fish oil supple-
ments, preferably correcting for concurrent intake of omega-6
fats, may give us further insight into the potential of fish oil
consumption to prevent adenocarcinomas, and perhaps also
TABLE 2
Why many epidemiological studies fail to correlate fish intake
with reduced cancer risk
Relatively low fish intake among the high-intake category
High concurrent intake of omega-6-rich oils
Predominant consumption of lean fish, low in omega-3
Farmed fish, such as tilapia, often has a relatively high omega-
6/omega-3 ratio (67–69)
Salted/preserved fish often contain mutagens such as
nitrosamines (50,51)
Fried fish has an increased omega-6/omega-3 ratio (61,62)
Fish cooked at high heat (e.g., frying) has heterocyclic amines
and other mutagens (63–66)
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the dose-dependency of such an effect. In addition, the ran-
domized placebo-controlled Vitamin D and Omega-3 Trial,
which plans to follow 20,000 middle-aged US men and
women, half of whom will receive a supplement providing 1 g
of EPACDHA daily, for 5 yr, may offer a useful assessment
of the cancer preventive potential of fish oil, in a modest but
consistent daily dose (77).
REFERENCES
1. Saukkonen K, Rintahaka J, Sivula A, Buskens CJ, Van Rees BP, et al.:
Cyclooxygenase-2 and gastric carcinogenesis. APMIS 111, 915–925,
2003.
2. Piazuelo E, Jimenez P, and Lanas A: COX-2 inhibition in esophagitis,
Barrett’s esophagus and esophageal cancer. Curr Pharm Des 9,
2267–2280, 2003.
3. Glover JA, Hughes CM, Cantwell MM, and Murray LJ: A systematic
review to establish the frequency of cyclooxygenase-2 expression in nor-
mal breast epithelium, ductal carcinoma in situ, microinvasive carcinoma
of the breast and invasive breast cancer. Br J Cancer 105, 13–17, 2011.
4. Hoellen F, Kelling K, Dittmer C, Diedrich K, Friedrich M, et al.: Impact
of cyclooxygenase-2 in breast cancer. Anticancer Res 31, 4359–4367,
2011.
5. Ohno S, Ohno Y, Suzuki N, Inagawa H, Kohchi C, et al.: Multiple roles
of cyclooxygenase-2 in endometrial cancer. Anticancer Res 25,
3679–3687, 2005.
6. Kraus S, Naumov I, and Arber N: COX-2 active agents in the chemopre-
vention of colorectal cancer. Recent Results Cancer Res 191, 95–103,
2013.
7. Sandler AB and Dubinett SM: COX-2 inhibition and lung cancer. Semin
Oncol 31, 45–52, 2004.
8. Hussain T, Gupta S, and Mukhtar H: Cyclooxygenase-2 and prostate car-
cinogenesis. Cancer Lett 191, 125–135, 2003.
9. Moran EM: Epidemiological and clinical aspects of nonsteroidal anti-
inflammatory drugs and cancer risks. J Environ Pathol Toxicol Oncol 21,
193–201, 2002.
10. Rothwell PM, Fowkes FG, Belch JF, Ogawa H, Warlow CP, et al.: Effect
of daily aspirin on long-term risk of death due to cancer: analysis of indi-
vidual patient data from randomised trials. Lancet 377, 31–41, 2011.
11. Tosco P and Lazzarato L: Mechanistic insights into cyclooxygenase irre-
versible inactivation by aspirin. ChemMedChem 4, 939–945, 2009.
12. Chan AT, Ogino S, and Fuchs CS: Aspirin and the risk of colorectal can-
cer in relation to the expression of COX-2. N Engl J Med 356,
2131–2142, 2007.
13. Chan AT, Ogino S, and Fuchs CS: Aspirin use and survival after diagno-
sis of colorectal cancer. JAMA 302, 649–658, 2009.
14. Cook NR, Lee IM, Gaziano JM, Gordon D, Ridker PM, et al.: Low-dose
aspirin in the primary prevention of cancer: the Women’s Health Study: a
randomized controlled trial. JAMA 294, 47–55, 2005.
15. Sturmer T, Glynn RJ, Lee IM, Manson JE, Buring JE, et al.: Aspirin use
and colorectal cancer: post-trial follow-up data from the Physicians’
Health Study. Ann Intern Med 128, 713–720, 1998.
16. Chun KS, Akunda JK, and Langenbach R: Cyclooxygenase-2 inhibits
UVB-induced apoptosis in mouse skin by activating the prostaglandin E2
receptors, EP2 and EP4. Cancer Res 67, 2015–2021, 2007.
17. Chu AJ, Chou TH, and Chen BD: Prevention of colorectal cancer using
COX-2 inhibitors: basic science and clinical applications. Front Biosci 9,
2697–2713, 2004.
18. Wu T, Leng J, Han C, and Demetris AJ: The cyclooxygenase-2 inhibitor
celecoxib blocks phosphorylation of Akt and induces apoptosis in human
cholangiocarcinoma cells. Mol Cancer Ther 3, 299–307, 2004.
19. Mutoh M, Takahashi M, and Wakabayashi K: Roles of prostanoids in
colon carcinogenesis and their potential targeting for cancer chemopre-
vention. Curr Pharm Des 12, 2375–2382, 2006.
20. Wang D and DuBois RN. Cyclooxygenase-2: a potential target in breast
cancer. Semin Oncol 31, 64–73, 2004.
21. Wendum D, Masliah J, Trugnan G, and Flejou JF: Cyclooxygenase-2 and
its role in colorectal cancer development. Virchows Arch 445, 327–333,
2004.
22. Dempke W, Rie C, Grothey A, and Schmoll HJ: Cyclooxygenase-2: a
novel target for cancer chemotherapy? J Cancer Res Clin Oncol 127,
411–417, 2001.
23. Greenhough A, Wallam CA, Hicks DJ, Moorghen M, Williams AC, et al.:
The proapoptotic BH3-only protein Bim is downregulated in a subset of
colorectal cancers and is repressed by antiapoptotic COX-2/PGE(2) sig-
nalling in colorectal adenoma cells. Oncogene 29, 3398–3410, 2010.
24. Basu GD, Pathangey LB, Tinder TL, Lagioia M, Gendler SJ, et al.:
Cyclooxygenase-2 inhibitor induces apoptosis in breast cancer cells in an
in vivo model of spontaneous metastatic breast cancer. Mol Cancer Res 2,
632–642, 2004.
25. Lin DW and Nelson PS. The role of cyclooxygenase-2 inhibition for the
prevention and treatment of prostate carcinoma. Clin Prostate Cancer 2,
119–126, 2003.
26. Sun Y, Tang XM, Half E, Kuo MT, and Sinicrope FA: Cyclooxygenase-2
overexpression reduces apoptotic susceptibility by inhibiting the cyto-
chrome c-dependent apoptotic pathway in human colon cancer cells. Can-
cer Res 62, 6323–6328, 2002.
27. Schulte-Hermann R, Bursch W, Kraupp-Grasl B, Oberhammer F, and
Wagner A. Programmed cell death and its protective role with particular
reference to apoptosis. Toxicol Lett 64–65, 569–574, 1992.
28. Brueggemeier RW, Quinn AL, Parrett ML, Joarder FS, Harris RE, et al.:
Correlation of aromatase and cyclooxygenase gene expression in human
breast cancer specimens. Cancer Lett 140, 27–35, 1999.
29. Diaz-Cruz ES, Shapiro CL, and Brueggemeier RW: Cyclooxygenase
inhibitors suppress aromatase expression and activity in breast cancer
cells. J Clin Endocrinol Metab 90, 2563–2570, 2005.
30. Subbaramaiah K, Hudis C, Chang SH, Hla T, and Dannenberg AJ: EP2
and EP4 receptors regulate aromatase expression in human adipocytes
and breast cancer cells. Evidence of a BRCA1 and p300 exchange. J Biol
Chem 283, 3433–3444, 2008.
31. Subbaramaiah K, Morris PG, Zhou XK, Morrow M, Du B, Get al.:
Increased levels of COX-2 and prostaglandin E2 contribute to elevated
aromatase expression in inflamed breast tissue of obese women. Cancer
Discov 2, 356–365, 2012.
32. Subbaramaiah K, Howe LR, Bhardwaj P, Du B, Gravaghi C, et al.: Obe-
sity is associated with inflammation and elevated aromatase expression in
the mouse mammary gland. Cancer Prev Res (Phila) 4, 329–346, 2011.
33. Rose DP and Vona-Davis L: Biochemical and molecular mechanisms for
the association between obesity, chronic inflammation, and breast cancer.
Biofactors 40, 1–12, 2013.
34. Martinez-Gonzalez J and Badimon L: Mechanisms underlying the cardio-
vascular effects of COX-inhibition: benefits and risks. Curr Pharm Des
13, 2215–2227, 2007.
35. McCarty MF: Minimizing the cancer-promotional activity of cox-2 as a
central strategy in cancer prevention. Med Hypotheses 78, 45–57, 2012.
36. Fragiskos B, Chan AC, and Choy PC: Competition of n-3 and n-6 polyun-
saturated fatty acids in the isolated perfused rat heart. Ann Nutr Metab 30,
331–334, 1986.
37. Garg ML, Sebokova E, Thomson AB, and Clandinin MT: Delta 6-desa-
turase activity in liver microsomes of rats fed diets enriched with choles-
terol and/or omega 3 fatty acids. Biochem J 249, 351–356, 1988.
38. Gronn M, Christensen E, Hagve TA, and Christophersen BO: Effects of
dietary purified eicosapentaenoic acid (20:5 (n-3)) and docosahexaenoic
acid (22:6(n-3)) on fatty acid desaturation and oxidation in isolated rat
liver cells. Biochim Biophys Acta 1125, 35–43, 1992.
OMEGA-3/OMEGA-6 RATIO, COX-2, AND ADENOCARCINOMAS 5
Downloaded by [74.39.145.132] at 08:53 04 November 2014
39. Lands WE, Libelt B, Morris A, Kramer NC, Prewitt TE, et al.: Mainte-
nance of lower proportions of (n-6) eicosanoid precursors in phospholi-
pids of human plasma in response to added dietary (n-3) fatty acids.
Biochim Biophys Acta 1180, 147–162, 1992.
40. Vecchio AJ, Simmons DM, and Malkowski MG: Structural basis of fatty
acid substrate binding to cyclooxygenase-2. J Biol Chem 285,
22152–22163, 2010.
41. Funahashi H, Satake M, Hasan S, Sawai H, Newman RA, et al.: Opposing
effects of n-6 and n-3 polyunsaturated fatty acids on pancreatic cancer
growth. Pancreas 36, 353–362, 2008.
42. Calder PC: n-3 fatty acids, inflammation and immunity: new mechanisms
to explain old actions. Proc Nutr Soc 72, 326–336, 2013.
43. West NJ, Clark SK, Phillips RK, Hutchinson JM, Leicester RJ, et al.:
Eicosapentaenoic acid reduces rectal polyp number and size in familial
adenomatous polyposis. Gut 59, 918–925, 2010.
44. Bartram HP, Gostner A, Scheppach W, Reddy BS, Rao CV, Dusel G,
Richter F, Richter A, Kasper H. Effects of fish oil on rectal cell prolifera-
tion, mucosal fatty acids, and prostaglandin E2 release in healthy subjects.
Gastroenterology 105:1317–1322, 1993.
45. Bartram HP, Gostner A, Reddy BS, Rao CV, Scheppach W, et al.: Miss-
ing anti-proliferative effect of fish oil on rectal epithelium in healthy vol-
unteers consuming a high-fat diet: potential role of the n-3:n-6 fatty acid
ratio. Eur J Cancer Prev 4, 231–237, 1995.
46. Fabian CJ and Kimler BF. Marine-derived omega-3 Fatty acids. Am Soc
Clin Oncol Educ Book 97–101, 2013.
47. Fernandez E, Chatenoud L, La VC, Negri E, and Franceschi S: Fish con-
sumption and cancer risk. Am J Clin Nutr 70, 85–90, 1999.
48. Terry P, Wolk A, Vainio H, and Weiderpass E: Fatty fish consumption
lowers the risk of endometrial cancer: a nationwide case-control study in
Sweden. Cancer Epidemiol Biomarkers Prev 11, 143–145, 2002.
49. Jedrychowski W, Maugeri U, Pac A, Sochacka-Tatara E, and Galas A:
Protective effect of fish consumption on colorectal cancer risk. Hospital-
based case-control study in Eastern Europe. Ann Nutr Metab 53,
295–302, 2008.
50. Fong LY, Ho JH, and Huang DP: Preserved foods as possible cancer haz-
ards: WA rats fed salted fish have mutagenic urine. Int J Cancer 23,
542–546, 1979.
51. Stich HF, Chan PK, and Rosin MP: Inhibitory effects of phenolics, teas
and saliva on the formation of mutagenic nitrosation products of salted
fish. Int J Cancer 30, 719–724, 1982.
52. Gonzalez CA, Sanz JM, Marcos G, Pita S, Brullet E, et al.: Dietary fac-
tors and stomach cancer in Spain: a multi-centre case-control study. Int J
Cancer 49, 513–519, 1991.
53. Jakszyn P and Gonzalez CA. Nitrosamine and related food intake
and gastric and oesophageal cancer risk: a systematic review of
the epidemiological evidence. World J Gastroenterol 12, 4296–4303,
2006.
54. Ren ZF, Liu WS, Qin HD, Xu YF, Yu DD, et al.: Effect of family history
of cancers and environmental factors on risk of nasopharyngeal carci-
noma in Guangdong, China. Cancer Epidemiol 34, 419–424, 2010.
55. Lin Y, Ueda J, Kikuchi S, Totsuka Y, Wei WQ, et al.: Comparative epi-
demiology of gastric cancer between Japan and China. World J Gastroen-
terol 17, 4421–4428, 2011.
56. Ye WM, Yi YN, Luo RX, Zhou TS, Lin RT, et al.: Diet and gastric can-
cer: a casecontrol study in Fujian Province, China. World J Gastroenterol
4, 516–518, 1998.
57. Takezaki T, Inoue M, Kataoka H, Ikeda S, Yoshida M, et al.: Diet and
lung cancer risk from a 14-year population-based prospective study in
Japan: with special reference to fish consumption. Nutr Cancer 45,
160–167, 2003.
58. Stott-Miller M, Neuhouser ML, and Stanford JL: Consumption of deep-
fried foods and risk of prostate cancer. Prostate 73, 960–969, 2013.
59. Joshi AD, John EM, Koo J, Ingles SA, and Stern MC: Fish intake, cook-
ing practices, and risk of prostate cancer: results from a multi-ethnic case-
control study. Cancer Causes Control 23, 405–420, 2012.
60. He K, Xun P, Brasky TM, Gammon MD, Stevens J, et al.: Types of
fish consumed and fish preparation methods in relation to pancreatic
cancer incidence: the VITAL Cohort Study. Am J Epidemiol 177,
152–160, 2013.
61. Ansorena D, Guembe A, Mendizabal T, and Astiasaran I: Effect of fish
and oil nature on frying process and nutritional product quality. J Food
Sci 75, H62–H67, 2010.
62. Strobel C, Jahreis G, and Kuhnt K: Survey of n-3 and n-6 polyunsat-
urated fatty acids in fish and fish products. Lipids Health Dis 11,
144, 2012.
63. Zhang XM, Wakabayashi K, Liu ZC, Sugimura T, and Nagao M: Muta-
genic and carcinogenic heterocyclic amines in Chinese cooked foods.
Mutat Res 201, 181–188, 1988.
64. Liu XL: [Genotoxicity of fried fish extract, MeIQ and inhibition by
green tea antioxidant]. Zhonghua Zhong Liu Za Zhi 12, 170–173,
1990.
65. Khan MR, Busquets R, Saurina J, Hernandez S, and Puignou L: Identifi-
cation of seafood as an important dietary source of heterocyclic amines
by chemometry and chromatography-mass spectrometry. Chem Res Toxi-
col 26, 1014–1022, 2013.
66. Skog KI, Johansson MA, and Jagerstad MI: Carcinogenic heterocyclic
amines in model systems and cooked foods: a review on formation, occur-
rence and intake. Food Chem Toxicol 36, 879–896, 1998.
67. Hamilton MC, Hites RA, Schwager SJ, Foran JA, Knuth BA, et al.: Lipid
composition and contaminants in farmed and wild salmon. Environ Sci
Technol 39, 8622–8629, 2005.
68. Karapanagiotidis IT, Bell MV, Little DC, Yakupitiyage A, and Rakshit
SK: Polyunsaturated fatty acid content of wild and farmed tilapias in
Thailand: effect of aquaculture practices and implications for human
nutrition. J Agric Food Chem 54, 4304–4310, 2006.
69. Young K: Omega-6 (n-6) and omega-3 (n-3) fatty acids in tilapia and
human health: a review. Int J Food Sci Nutr 60(Suppl 5), 203–211,
2009.
70. Kantor ED, Lampe JW, Peters U, Vaughan TL, and White E. Long-chain
omega-3 polyunsaturated fatty acid intake and risk of colorectal cancer.
Nutr Cancer 66, 716–727, 2013.
71. Brasky TM, Lampe JW, Potter JD, Patterson RE, and White E: Specialty
supplements and breast cancer risk in the VITamins And Lifestyle (VITAL)
Cohort. Cancer Epidemiol Biomarkers Prev 19, 1696–1708, 2010.
72. Brasky TM, Kristal AR, Navarro SL, Lampe JW, Peters U, et al.: Spe-
cialty supplements and prostate cancer risk in the VITamins and Lifestyle
(VITAL) cohort. Nutr Cancer 63, 573–582, 2011.
73. Torfadottir JE, Valdimarsdottir UA, Mucci LA, Kasperzyk JL, Fall K, Tet
al.: Consumption of fish products across the lifespan and prostate cancer
risk. PLoS ONE 8, e59799, 2013.
74. Szymanski KM, Wheeler DC, and Mucci LA: Fish consumption and pros-
tate cancer risk: a review and meta-analysis. Am J Clin Nutr 92,
1223–1233, 2010.
75. Arem H, Neuhouser ML, Irwin ML, Cartmel B, Lu L, et al.: Omega-3 and
omega-6 fatty acid intakes and endometrial cancer risk in a population-
based case-control study. Eur J Nutr 52, 1251–1260, 2013.
76. Bell GA, Kantor ED, Lampe JW, Kristal AR, Heckbert SR, et al.: Intake
of long-chain omega-3 fatty acids from diet and supplements in relation
to mortality. Am J Epidemiol 179, 710–720, 2014.
77. Manson JE, Bassuk SS, Lee IM, Cook NR, Albert MA, et al.: The VITa-
min D and OmegA-3 TriaL (VITAL): rationale and design of a large ran-
domized controlled trial of vitamin D and marine omega-3 fatty acid
supplements for the primary prevention of cancer and cardiovascular dis-
ease. Contemp Clin Trials 33, 159–171, 2012.
6J. J. DINICOLANTONIO ET AL.
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... Omega-3 FAs, including eicosapentaenoic and docosahexaenoic acids (EPA and DHA, respectively), are widely accepted to have antiinflammatory properties by competing with AA for COX2 binding, and subsequently producing PGE3 instead of PGE2. 224 In contrast, omega-6 FAs, such as LA and AA, are the precursors for proinflammatory eicosanoids. 225 The recommended dietary ratio of omega-6:3 FAs is 1:1; however, the Western diet, which is significantly enriched in omega-6s, has a ratio of 15:1, 225 and this has significant implications for the progression of several cancers including breast and colorectal. ...
... 225 The recommended dietary ratio of omega-6:3 FAs is 1:1; however, the Western diet, which is significantly enriched in omega-6s, has a ratio of 15:1, 225 and this has significant implications for the progression of several cancers including breast and colorectal. 226 Conversely, a diet rich in omega-3 FAs has been associated with the pathological improvement of several inflammatory diseases, such as arthritis and asthma 224,227,228 (Table 1), as well as reduced risks of developing breast, colorectal and prostate cancers. 224,229 It is important to note, however, that excessive omega-3 consumption can also have undesirable side effects including immunosuppression. ...
... 226 Conversely, a diet rich in omega-3 FAs has been associated with the pathological improvement of several inflammatory diseases, such as arthritis and asthma 224,227,228 (Table 1), as well as reduced risks of developing breast, colorectal and prostate cancers. 224,229 It is important to note, however, that excessive omega-3 consumption can also have undesirable side effects including immunosuppression. 230 Therefore, it is essential that careful optimisation of omega-3:omega-6 ratios is undertaken for each patient. ...
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... The most common dietary sources of n-3 PUFAs are fish oil, vegetable oil, nuts and flaxseeds, while dietary intake of sources rich in n-6 PUFAs includes meat, poultry, eggs, sunflower oil and soybean oil. Epidemiological evidence indicates that the anti-inflammatory effects of the n-3 PUFAs eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA) decrease the risk of developing cancer [57,[141][142][143] (Figure 2). A high intake of n-6 PUFA-rich diets is generally considered unhealthy, predominantly due to the pro-inflammatory effects of arachidonic acid (ARA) [70,71]. ...
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... Accordingly, Japanese men, who consume approximately 8 times more fish than their American counterparts, have a rate of prostate cancer mortality many-fold lower [10]. Ultimately, a more thorough review of the literature would suggest that increased Ω-3 consumption does not increase prostate cancer risk, but decreases prostate cancer mortality in addition to reducing sudden cardiac death and CV events [11,12]. ...
... Ω-3 levels are naturally high in wild fish, whereas farm-raised fish tend to be grain fed and have resultant lower Ω-3 levels. Ω-3 are not synthesized de novo, rather they stem from unicellular organisms such as algae, at the base of the marine food chain [12]. Fish consume algae in the wild and as a result compose their own Ω-3, whereas most farm-raised fish (including tilapia and catfish) are not fed this natural diet and thus have low Ω-3 levels. ...
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... 3, 7 n-3 PUFA are not synthesized in fish de novo but stem from unicellular organisms at the base of their natural food chain. 3,13 Although farm fed fish are typically grain fed, in the last month or months before harvest, the fish diet is changed to a higher content of n-3 PUFA to meet the values seen in typical wild fish of a given species. 14 Recognizing the benefits of n-3 PUFA consumption, an expert panel for the US military from the Nutritional Armor for the Warfighter Conference unanimously agreed that a daily recommended n-3 PUFA intake should be established to receive CV, immunological, and surgical benefits. ...
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AIM: To explore the relationship between consumption of fish sauce, other dietary factors, living habits and the risk of gastric cancer. METHODS: From May 1994 to July 1995, a population-based 1:2 case-control study was in Carried out in high-risk areas of gastric cancer, Changle and Fuqing cities, Fujian Province. Totally 272 cases and 544 age, gender-matched controls were included. Risk state analyses were made by ASRS package. RESULTS: Risk state single-factor analysis indicated that gastric cancer risk rose with high intake of fish sauce (OR = 2.57), salted vegetables (OR = 1.41), salted/fried fish and small shrimps (OR = 1.57), low consumption of fresh vegetables (OR = 1.95), fresh citrus fruits (OR = 1.41), other fresh fruits (OR = 1.31), green tea (OR = 1.72), exposure to moldy foods (OR = 2.32), irregular dinners (OR = 5.47) and familial history of malignancy (OR = 3.27). No significant relationship was observed between smoking, drinking, salt intake, use of refrigerator and gastric cancer risk. The results of risk state conditional Logistic regression showed that fish sauce, salted dried fish and small shrimps, irregular dinners, familial history of malignancy were included in the best risk set. The summary ARS for the four factors was 75.49%. CONCLUSION: High intake of fish sauce, salted foods, moldy foods, irregular dinners and familial history of malignancy were possible risk factors for gastric cancer, whereas fresh vegetables and fruits. And green tea might have protective effects for gastric cancer. Keywords: stomach neoplasms/etiology, living habits, food habits, risk facto Citation: Ye WM, Yi YN, Luo RX, Zhou TS, Lin RT, Chen GD. Diet and gastric cancer: a case-control study in Fujian Province, China. World J Gastroenterol 1998; 4(6): 516-518
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Background: In contrast to most observational studies, the randomized Physicians' Health Study found no association between aspirin use and colorectal cancer after 5 years. Objective: To determine the effect of randomly assigned aspirin treatment and self-selected aspirin use on the incidence of colorectal cancer after 12 years and to identify factors influencing the self-selection of regular aspirin use. Design: Randomized clinical trial and prospective cohort study. Setting: Male physicians throughout the United States. Patients: 22 071 healthy male physicians who were 40 to 84 years of age in 1982. Intervention: 325 mg of aspirin every other day. In 1988, the aspirin arm of the randomized trial was stopped early. Participants then chose to receive either aspirin or placebo for the rest of the study. Measurements: Annual questionnaires asking about aspirin use and other variables, including occurrence of cancer. Results: Colorectal cancer was diagnosed in 341 patients during the study period. Over 12 years of follow-up, random assignment to aspirin was associated with a relative risk for colorectal cancer of 1.03 (95% Cl, 0.83 to 1.28). Various gastrointestinal symptoms and diagnoses were strong predictors of less frequent aspirin use in 1988. The relative risk for colorectal cancer in persons who used aspirin frequently after 1988 was 1.07 (Cl, 0.75 to 1.53). Conclusions: In the Physicians' Health Study, both randomized and observational analyses indicate that there is no association between the use of aspirin and the incidence of colorectal cancer. The low dose of aspirin used and the short treatment period may account for the null findings. However, other characteristics associated with the use of aspirin in observational studies remain a plausible alternative explanation.
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Evidence from experimental studies suggests that the long-chain ω-3 fatty acids eicosapentaenoic acid and docosahexaenoic acid have beneficial effects that may lead to reduced mortality from chronic diseases, but epidemiologic evidence is mixed. Our objective was to evaluate whether intake of long-chain ω-3 fatty acids from diet and supplements is associated with cause-specific and total mortality. Study participants (n = 70,495) were members of a cohort study (the Vitamins and Lifestyle Study) who were residents of Washington State aged 50-76 years at the start of the study (2000-2002). Participants were followed for mortality through 2006 (n = 3,051 deaths). Higher combined intake of eicosapentaenoic acid and docosahexaenoic acid from diet and supplements was associated with a decreased risk of total mortality (hazard ratio (HR) = 0.82, 95% confidence interval (CI): 0.73, 0.93) and mortality from cancer (HR = 0.77, 95% CI: 0.64, 0.92) but only a small reduction in risk of death from cardiovascular disease (HR = 0.87, 95% CI: 0.68, 1.10). These results suggest that intake of long-chain ω-3 fatty acids may reduce risk of total and cancer-specific mortality.
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Research suggests that long-chain omega-3 polyunsaturated fatty acids (LC-PUFAs) eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA) have antineoplastic properties, yet evidence for association between LC-PUFAs and colorectal cancer (CRC) remains inconsistent. Using the VITamins And Lifestyle (VITAL) cohort, we evaluated how EPA/DHA intake, and its primary sources, fish oil supplement use and dark fish consumption, relate to CRC risk. A total of 68,109 Washington residents aged 50-76 completed a questionnaire between 2000-2002 and were followed for CRC through 2008 (n = 488). Persons using fish oil supplements on 4+ days/wk for 3+ yr experienced 49% lower CRC risk than nonusers (hazard ratio = 0.51, 95% CI = 0.26-1.00; P trend = 0.06). The association between fish oil use and decreased CRC risk was primarily observed for men (P interaction = 0.02; P trend men = 0.02; P trend women = 0.88) and for colon cancer (P difference = 0.05; P trend colon = 0.03; P trend rectum = 0.87). Although dark fish and total EPA + DHA intake were not associated with CRC risk overall, these associations varied by genetic risk (P interaction = 0.009 and 0.02, respectively), with inverse associations observed among low-moderate genetic risk groups and positive associations observed among high risk groups. Results suggest that associations between LC-PUFA intake and CRC may vary by gender, subsite, and genetic risk, providing additional insight into the potential role of LC-PUFAs in cancer prevention.
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Data from laboratory studies, observational research, and/or secondary prevention trials suggest that vitamin D and marine omega-3 fatty acids may reduce risk for cancer or cardiovascular disease (CVD), but primary prevention trials with adequate dosing in general populations (i.e., unselected for disease risk) are lacking. The ongoing VITamin D and OmegA-3 TriaL (VITAL) is a large randomized, double-blind, placebo-controlled, 2x2 factorial trial of vitamin D (in the form of vitamin D3 [cholecalciferol], 2000IU/day) and marine omega-3 fatty acid (Omacor® fish oil, eicosapentaenoic acid [EPA]+docosahexaenoic acid [DHA], 1g/day) supplements in the primary prevention of cancer and CVD among a multi-ethnic population of 20,000 U.S. men aged ≥50 and women aged ≥55. The mean treatment period will be 5years. Baseline blood samples will be collected in at least 16,000 participants, with follow-up blood collection in about 6000 participants. Yearly follow-up questionnaires will assess treatment compliance (plasma biomarker measures will also assess compliance in a random sample of participants), use of non-study drugs or supplements, occurrence of endpoints, and cancer and vascular risk factors. Self-reported endpoints will be confirmed by medical record review by physicians blinded to treatment assignment, and deaths will be ascertained through national registries and other sources. Ancillary studies will investigate whether these agents affect risk for diabetes and glucose intolerance; hypertension; cognitive decline; depression; osteoporosis and fracture; physical disability and falls; asthma and other respiratory diseases; infections; and rheumatoid arthritis, systemic lupus erythematosus, thyroid diseases, and other autoimmune disorders.
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Upper body obesity is a risk factor for postmenopausal breast cancer and is related to an aggressive tumor phenotype and a poor prognosis regardless of menopausal status. After the menopause, the major mechanism for the association with disease risk is elevated estrogen production by adipose tissue, due to a high level of aromatase activity: these hormone-dependent tumors express both estrogen and progesterone receptors. Other important biological factors of risk include leptin and adiponectin, adipokines with opposing endocrine and paracrine activities, and obesity-related hyperinsulinemia. Chronic inflammation of the breast adipose tissue, which occurs in some obese women and is indicated by the accumulation of macrophages around dead adipocytes ("crown-like structures"), rather than adiposity per se, may prove to be the pathological lesion responsible for both local aromatase induction, and enhanced invasiveness and metastatic capacity through biological mechanisms that involve leptin, tumor necrosis factor-α, and insulin. A causal association between obesity in premenopausal women and breast cell epithelial-mesenchymal transition, perhaps with the participation of the Wnt signaling pathway, and aggressive hormone-independent breast cancer is suggested by a number of experimental and clinical studies. © 2013 BioFactors, 2013.
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Several studies have indicated dietary fish oil (FO) as a protective agent in colon carcinogenesis. Rectal cell proliferation as an intermediate biomarker of cancer risk was shown to be reduced by dietary FO in patients with adenomatous polyps and healthy subjects consuming a low-fat diet. Because the synthesis of prostaglandins (PG) which seem to be involved in this process is dependent on the ratio of n-3:n-6 fatty acids in the diet, the present study was designed to investigate whether this FO effect is also detectable in volunteers eating a high-fat diet (50% of energy) with a low n-3:n-6 ratio of 0.25. Twelve healthy volunteers received in addition to a controlled basal diet either FO (4.4 g n-3 fatty acids/day) or corn oil supplements (double-blind, crossover) for two 4-week periods. No significant differences between the two study periods were found for rectal cell proliferation as assessed by bromodeoxyuridine immunohistochemistry and ornithine decarboxylase activity, as well as for mucosal PGE(2) release and mucosal membrane fatty acid composition. The results emphasize the importance of dietary n-3:n-6 ratio in determining the effects of FO on rectal cell proliferation.