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Department of Nutrition, College of Human Ecology, and * Department of Pathology, College of Veterinary Medicine, University of Tennessee, Knoxville, TN 37996-1900
2To whom correspondence should be addressed.
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ABSTRACT |
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 TOP ABSTRACT INTRODUCTIONMATERIALS AND METHODSRESULTSDISCUSSIONREFERENCES |
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KEY WORDS: • Apc • arachidonic acid • cancer • eicosapentaenoic acid • mice
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INTRODUCTION |
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TOPABSTRACTINTRODUCTIONMATERIALS AND METHODSRESULTSDISCUSSIONREFERENCES |
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). Epidemiologic studies indicate
that consumption of fish oil correlates with a reduced risk of
colorectal cancer (Caygill et al. 1996
, Kato et al. 1997
). Fish oil is rich in (n-3) polyunsaturated fatty
acids
(PUFA),3
viz., eicosapentaenoic acid [EPA, 20:5 (n-3)] and docosahexaenoic
acid [DHA, 22:6 (n-3)]. Studies in humans and in chemically induced
colonic tumor animal models overwhelmingly indicate a protective effect
of (n-3) PUFA; the mechanism is largely thought to be related to a
reduction in prostaglandin biosynthesis (Anti et al. 1992
, Bartram et al. 1993
, Chang et al. 1998
, Hendrickse et al. 1995
, Kim et al. 1998
, Latham et al. 1999
, Lindner 1991
, Minoura et al. 1988
, Nelson et al. 1988
, Reddy and Maruyama 1986
, Reddy et al. 1991
).
Studies of the antitumorigenicity of (n-3) PUFA in the multiple
intestinal neoplasia (ApcMin/+) mouse model
have been more equivocal. This is the first study to report that
purified EPA reduces intestinal tumors in this mouse model and that the
antitumorigenicity is related to arachidonic acid [AA, 20:4 (n-6)]
metabolism. Over the last several years, the
ApcMin/+ mouse model has been used to
evaluate the effects of nutrition intervention on intestinal
tumorigenesis because of its germline mutation in the murine
adenomatous polypsis coli (Apc) gene (Oshima et al. 1995
, Paulsen et al. 1997
, Wasan et al. 1997
). Development of colorectal cancer in humans from
dysplastic crypts to metastatic carcinoma involves a series of genetic
mutations, the earliest often involving the adenomatous polypsis coli
(APC) gene (Kinzler and Vogelstein 1996
,
Powell et al. 1992
). Individuals with familial
adenomatous polyposis (FAP) carry a germline mutation in
APC, and mutational damage or loss of the wild-type
allele initiates intestinal tumor formation (Levy et al. 1994
, Miyoshi et al. 1992
). Somatic mutations
resulting in loss of full-length APC protein also occur
early in spontaneous forms of the disease (Powell et al. 1992
), indicating that an APC defect is associated
with a majority of human colorectal cancers (Jen et al. 1994
, Smith et al. 1993
).
ApcMin/+ mice spontaneously develop
adenomas throughout the intestinal tract with preferred localization in
the small intestines (Chiu et al. 1997
). These adenomas
have been shown to be sensitive to modulators of the AA pathway. A
number of nonsteroidal anti-inflammatory drugs (NSAIDs) can
significantly reduce tumor load in this model (Boolbool et al. 1996
, Chiu et al. 1997
, Jacoby et al. 1996
, Ritland and Gendler 1999
), and these
effects have been attributed to inhibition of prostaglandin
biosynthesis (Boolbool et al. 1996
, Minoura et al. 1988
, Reddy and Maruyama 1986
, Reddy et al. 1991
). Similarly, dietary (n-3) PUFA can reduce tumor
load in mice with an Apc gene defect. Paulsen et al. (1997)
found that a fish oil concentrate enriched with EPA
(54%) and DHA (30%) reduced tumor number and size in
ApcMin/+ mice with more consistent effects
in female mice compared with their male counterparts. In comparison,
Oshima et al. (1995)
, using Apc
knockout mice with Apc truncation at codon 716
(Apc
716), showed that dietary DHA decreased
tumor number in female, but not male mice. However, antagonism of AA or
its metabolism has not yet been established as the driving force behind
the antitumorigenicity of (n-3) PUFA.
We showed previously that dietary EPA potently antagonized
incorporation of AA into phospholipids while increasing tissue EPA and
inhibiting prostaglandin formation (Li et al. 1994
).
Conversely, feeding AA systemically increased tissue AA content and
eicosanoid formation in vivo; supplementing AA to a diet containing EPA
completely eliminated the effects of dietary EPA (Li et al. 1994
). Therefore, in this study, we hypothesized that feeding
EPA would reduce tumor load in male
ApcMin/+ mice by antagonizing AA
metabolism, and that providing AA and EPA in the diet concomitantly
would eliminate this effect (i.e., rescue the tumors), suggesting that
the beneficial effects of (n-3) PUFA are mediated through AA.
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MATERIALS AND METHODS |
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TOPABSTRACTINTRODUCTIONMATERIALS AND METHODSRESULTSDISCUSSIONREFERENCES |
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Twenty male C57BL/6J ApcMin/+ mice (Jackson
Laboratories, Bar Harbor, ME), 38–43 d of age, were randomly assigned
to four diet groups (n = 5 mice/group) on arrival.
They were housed in a temperature-controlled room with 12-h periods
of light and dark and given free access to food and water. The health
of the mice was checked daily. Food was withheld overnight before the
mice were killed. All animal procedures were approved by the University
of Tennessee Animal Care and Use Committee and were in accordance with
the NIH guidelines (NRC 1985
).
Diets.
All diets were based on the composition of the AIN-93G diet (American Institute of Nutrition 1993
) and composed of fat-free powder diet
(900 g/kg; Dyets, Bethlehem, PA) plus soybean oil (70 g/kg). In
addition, the diet was supplemented with 30 g/kg purified fatty acid
ethyl esters in the form of oleic acid [(OA), 18:1 (n-9)] (30 g/kg),
AA (15 g/kg) + OA (15 g/kg), EPA (15 g/kg) + OA (15 g/kg), or AA (15
g/kg) + EPA (15 g/kg) (Table 1). Overall fatty acid composition of the diet is shown in Table 2
. The ethyl esters of OA and AA were purchased from Nu-Chek-Prep
(Elysian, MN) and the EPA ethyl ester (>97% purity) was kindly
supplied by the National Oceanographic and Atmospheric Administration
(Charleston, SC). The ethyl ester of OA was used as a control because
we demonstrated previously that supplementing OA in the diet at the
levels used in this study has no effect on tissue contents of AA and
EPA and eicosanoid biosynthesis (unpublished results). All diets were
supplemented with the antioxidant tertiary butylhydroquinone (Eastman
Chemical Company, Kingsport, TN) at 20mg/kg diet to limit oxidation of
the PUFA added to the diets. All diets were prepared in the absence of
UV light, immediately divided into daily aliquots and stored under an
atmosphere of nitrogen at -80°C to prevent oxidation. Mice were
provided with fresh food daily, and weights were recorded weekly.
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Upon arrival, all mice were initially provided a nonpurified diet
(Harlan Teklad, Madison, WI) before the start of the experimental diets
at 42–45 d of age. Mice were fed the assigned diets for ~8 wk. At
98–100 d of age, mice were killed by cervical dislocation; tumor
number, size and location were determined as previously described
(Chiu et al. 1997
). Portions of normal-appearing
intestine and several of the largest tumors were harvested for
histologic examination. Basal levels and ex vivo production of
prostaglandin E2 (PGE2) and
6-keto-prostaglandin F1
(6-keto-PGF1)
were determined for each mouse from samples of normal-appearing
small intestine.
Fatty acid analysis.
The fatty acid methyl esters (FAME) of the tissue phospholipids were
prepared and analyzed as described previously (Whelan et al. 1993
). Briefly, tissues were homogenized in ice-cold saline
and lipids were extracted with chloroform/methanol (1:2, v/v), followed
by extraction (x2) with chloroform. The pooled chloroform extracts
were evaporated and resuspended in a small volume of chloroform, and
the phospholipids were separated by TLC on silica gel 60 HP-TLC
plates (Merck, Darmstadt, Germany) with chloroform/methanol (8:1, v/v)
as the solvent system. Bands corresponding to the phospholipids were
scraped, dissolved in toluene and saponified with 0.5 mol/L KOH in
methanol for 8 min at 86°C. After acidification with 0.7 mol/L HCl in
methanol, the fatty acids were extracted with hexane (x2), evaporated
and methylated with ethereal diazomethane. The FAME were resuspended in
hexane and analyzed using a Hewlett-Packard model 5890 series II
gas chromatograph equipped with flame ionization detector and a DB23
fused silica capillary column (0.25 mm i.d. x 30 m x 0.25
µm film; J&W Scientific, Folsom, CA). Separation was
achieved by temperature programming from 160 to 250°C at 3.5°C/min
with hydrogen as the carrier gas. The internal standard, pentadecaenoic
acid (15:0) methyl ester (Avanti Polar Lipids, Alabaster, AL) was added
to each sample before the saponification step. The FAME were identified
by comparison of retention times with those of known standards
(Nu-Chek-Prep).
Measurement of prostaglandins.
After the mice were killed, normal-appearing intestinal sections
were quickly perfused with ice-cold saline (NaCl, 154 mmol/L),
immediately snap-frozen in liquid nitrogen and stored at -80°C.
For analysis, the tissues were homogenized using a Tenbroeck tissue
grinder (Pyrex, U.K.) in ice-cold Tris-HCI buffer (0.1 mol/L, pH
7.4). Prostaglandin production was determined by incubating the
homogenate for 0 min (basal) or 15 min (ex vivo) at 37°C.
Indomethacin (final concentration, 1 mmol/L) was added followed by
formic acid in methanol (pH 3.0) to arrest prostaglandin synthesis.
Prostaglandins were isolated by solid-phase extraction using an
octadecyl (C18) cartridge (Burdick & Jackson, Muskegon, MI) and eluted
with 100% methanol. The recovery of prostaglandins was determined by
adding 0.37 nBq [3H]-prostaglandin D2
(PGD2) to the sample as an internal standard before
processing. The methanol was evaporated under a stream of nitrogen gas
and the extracts were resuspended in PBS (pH 7.4) containing gelatin
(1.0 g/L). PGE2 and 6-keto-PGF1 were
measured by RIA as described previously using antiserum obtained from
PerSeptive Diagnostics (Cambridge, MA) (Whelan et al. 1993
). Cross-reactivities at half-maximal binding of
various prostanoids with PGE2 antiserum are as follows:
PGE2 (100%), PGE3 (26%),
6-keto-PGF1 (<1%), PGF1 (1%),
thromboxane (TX)B2 (<1%), PGD2 (<1%) and
PGF2 (1%). Cross-reactivities with various
prostanoids with 6-keto-PGF1 antiserum are as follows:
6-keto-PGF1 (100%), -17, 6-keto-PGF1
(14%), PGE2 (<1%), PGF2 (2%),
PGF1 (8%), PGD2 (<1%) and
TXB2 (<1%). All standards were purchased from Cayman
Chemical (Ann Arbor, MI); [3H]-PGE2,
[3H]-PGD2 and
[3H]-6-keto-PGF1 were obtained from New
England Nuclear (Boston, MA). An aliquot of the homogenate from each
sample was used to determine protein concentration by the modified
Lowry protocol (Markwell et al. 1981
).
Statistical analyses.
Values are expressed as means ± SEM. Differences in final body weights, tumor number, tumor size and biochemical variables were analyzed statistically by one-way ANOVA followed by Fisher’s least significant difference multiple comparison method to determine differences among groups. The Statistical Analysis System (SAS Version 6.12, SAS Institute, Cary, NC) was used to evaluate the data. Square root transformations of raw data were performed in cases of unequal variances. Differences were considered significant at P < 0.05.
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RESULTS |
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TOPABSTRACTINTRODUCTIONMATERIALS AND METHODSRESULTSDISCUSSIONREFERENCES |
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At the end of the study, the mean weight of the mice in the OA group
was significantly lower than those of the EPA and AA + EPA groups, most
likely a reflection of the average tumor load in the respective groups
(Fig. 1
). The only mice still gaining weight at the end of the study were those
in the EPA group. It has been our experience that increasing tumor load
has a marked negative effect on growth patterns in these mice after
75 d of age (Chiu et al. 1997
).
|
Including AA, EPA, or AA + EPA in the diets resulted in characteristic
changes in phospholipid fatty acid composition (Li et al. 1994
, Whelan et al. 1993
) (Table 3). Tissue AA [20:4 (n-6)] levels from the AA group were significantly
higher compared with the OA group (control), whereas the levels of
linoleic acid [18:2 (n-6)] were significantly lower. Including EPA
[20:5 (n-3)] in the diet enriched phospholipids with EPA, with a
concomitant decline in tissue AA levels. When AA and EPA were included
simultaneously in the diet (AA + EPA), tissue AA levels were fourfold
higher and tissue EPA levels were 85% lower than in the EPA group.
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Tumor number was not significantly different in the AA-supplemented
group compared with the OA (control) group; however, mice in the EPA
group had 68 and 54% fewer tumors than those in the OA and AA groups,
respectively (P < 0.05) (Table 4). When AA was supplemented to the EPA-containing diet (AA + EPA),
the average number of tumors was more than twice that observed in the
EPA group, paralleling the results of the AA group. The tumors, on
average, were significantly smaller in the EPA group compared with the
other dietary groups, and supplementation of AA to the EPA-fed mice
resulted in significantly larger tumors (P < 0.05).
Overall, >98% of tumors were located in the small intestines.
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Ex vivo prostaglandin production was significantly correlated with
tissue AA content (Table 5
). Basal levels of PGE2 and
6-keto-PGF1 were consistently lower in the
EPA-fed group compared with the OA and AA groups (Table 6); including AA in the diet that contained EPA (AA + EPA) resulted in
PGE2 and 6-keto-PGF1
levels that were significantly higher than in mice supplemented with
EPA alone. Ex vivo prostaglandin production was also significantly
higher in mice fed the diet containing AA compared with the OA and EPA
groups, whereas the EPA group had the lowest production. The addition
of AA to the diet containing EPA (AA + EPA) eliminated any reductions
in prostaglandin production due to EPA supplementation, with the
exception of basal 6-keto-PGF1 compared with
the OA control group.
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DISCUSSION |
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TOPABSTRACTINTRODUCTIONMATERIALS AND METHODSRESULTSDISCUSSIONREFERENCES |
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) with potential antagonism among the
(n-3) and (n-6) families of fatty acids (Li et al. 1994
). We controlled dietary fat composition by substituting
the ethyl esters of EPA and/or AA for OA; thus any modification in
tumor load would be the direct result of dietary changes of these
select fatty acids. Oshima et al. (1995)
observed that
supplementation of DHA ethyl ester to diets of
Apc716 knockout mice reduced tumor number in
females, but not males. Small sample sizes could have accounted for the
differences, but the type of (n-3) PUFA used could have been an
important factor. If EPA is the most biologically potent of the (n-3)
PUFA, the efficacy of DHA may depend in part upon the extent of its
retroconversion to EPA. However, tissue fatty acid and eicosanoid data
were not presented in that study. In a study investigating dietary
supplementation of EPA plus DHA, tumor load in
ApcMin/+ mice was reduced in both males and
females, with a more consistent effect in females (Paulsen et al. 1997
). The major dietary difference in these two earlier
studies using (n-3) PUFA was the inclusion of EPA in the latter.
The link between efficacy of EPA and AA metabolism is buoyed by
the overwhelming evidence that NSAIDs can reduce tumor load in this
animal model by 50–98% (Boolbool et al. 1996
,
Chiu et al. 1997
, Jacoby et al. 1996
,
Ritland and Gendler 1999
). NSAIDs are believed to act
through the inhibition of cyclooxygenase-1 (COX-1) and cyclooxygenase-2
(COX-2), the committed steps in prostaglandin biosynthesis
(Boolbool et al. 1996
, Kawamori et al. 1998
, Sheng et al. 1997
). Of the two identified
COX isoforms, inhibition of COX-2, the inducible form, is believed to
be most relevant in this model, which overexpresses COX-2 in tumors
(Kargman et al. 1995
, Mei et al. 1999
,
Oshima et al. 1996
, Sano et al. 1995
,
Williams et al. 1996
). Selective inhibition of COX-2
suppresses intestinal tumor formation by 50% (Nakatsugi et al. 1997
, Oshima et al. 1996
). Crossing COX-2
knockout mice with Apc knockout mice reduces tumors by 85%
(Oshima et al. 1996
), and dose-dependent
overexpression of COX-2 is associated with increased tumor number
(Oshima et al. 1996
). COX-2 expression has also been
inversely associated with apoptosis (Boolbool et al. 1996
, Tsujii and DuBois 1995
). Like NSAIDs,
dietary (n-3) PUFA are effective competitive inhibitors of COX
activity; they have been shown to reduce COX-2 expression (Singh et al. 1997
) and increase apoptosis and differentiation in a
chemically induced colonic tumor rat model (Chang et al. 1998
, Latham et al. 1999
), whereas diets high in
(n-6) PUFA (viz., linoleic acid) increase COX-2 expression
(Singh et al. 1997
). AA, in particular, has been found
to increase COX-2 gene expression in intestinal crypt epithelial cells
in vitro (Peri et al. 1997
). We showed previously that
dietary AA and EPA have an antithetic relationship on prostaglandin
production in vivo (Li et al. 1994
), and this inverse
relationship might explain the demonstrated antitumorigenic effect of
(n-3) PUFA. Consequently, in this study, we observed characteristic
reductions in prostaglandin biosynthesis after EPA supplementation, and
this was reversed by the addition of AA to the EPA diet. These results
paralleled tumor load.
A number of studies also suggest that a possible
prostaglandin-independent mechanism may exist (Chan et al. 1998
, Charalambous et al. 1998
, Chiu et al. 1997
, Piazza et al. 1997a
and 1997b
,
Simmons et al. 1999
). For example, Chan et al. (1998)
recently reported that elevating cellular AA levels in
vitro exerts tumor suppressor effects in HCT116 and SW480 colon cancer
cell lines by enhancing ceramide-induced apoptosis, possibly
explaining the antitumorigenicity of NSAIDs. Although we and others
have shown that dietary AA has a dramatic and potent effect on altering
tissue content of AA systemically (Li et al. 1994
,
Mann et al. 1994
, Whelan et al. 1992
and 1993
), we have consistently failed to demonstrate significant
reductions in tumor number following a doubling of AA content in
intestinal phospholipids of ApcMin/+ mice
(Chiu et al. 1997
). The mode of delivery of AA
influences cellular distribution and utilization of this fatty acid
(Chulada et al. 1996
, Hamilton et al. 1999
); therefore, differing environments (i.e., in vivo vs. in
vitro) could explain these seemingly discordant results.
Alternatively, others have suggested that an increase in lipid
peroxidation may be responsible for the antitumorigenic effects of
(n-3) PUFA. It has been reported that dietary (n-3) PUFA increase
oxidation potential of tissues, resulting in increased products of
lipid peroxidation leading to tumor death (Gonzalez et al. 1991
). However, AA has an unsaturation index similar to that of
EPA. Adding AA to the diet did not reduce tumor load (Chiu et al. 1997
), and doubling the dietary unsaturation index by
adding AA to the EPA diet (AA + EPA) more than doubled the tumor number
(compared with the EPA group) as opposed to reducing further the tumor
number as might be predicted by the above hypothesis. Therefore,
although indices of lipid peroxidation were not measured, it is
reasonable to conclude that lipid peroxidation may not have been
responsible for the reduction of intestinal tumors in the EPA-fed
group.
In summary, the tightly controlled dietary design of this study strongly reinforces previous data in other models on the antitumorigenicity of EPA. EPA reduced the number and size of tumors in male ApcMin/+ mice, and these effects were associated with reductions in tissue AA content and prostaglandin levels. AA, on the other hand, had no effect on tumor load despite increasing tissue AA concentration and ex vivo prostaglandin production. Dietary AA largely reversed changes observed with EPA alone when AA and EPA were fed concomitantly, suggesting that EPA reduces tumor load, at least in part, by acting as an antagonist to AA. Although these effects appear to be related to prostaglandin inhibition, we cannot exclude potential involvement of prostaglandin-independent pathways.
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ACKNOWLEDGMENTS |
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FOOTNOTES |
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3 Abbreviations used: AA, arachidonic acid;
Apc, murine adenomatous polyposis coli;
APC, human adenomatous polyposis coli;
Apc716, Apc
knockout mouse with Apc truncation at codon 716;
ApcMin/+, multiple intestinal neoplasia
mouse; COX, cyclooxygenase; DHA, docosahexaenoic acid; EPA,
eicosapentaenoic acid; FAME, fatty acid methyl esters; FAP, familial
adenomatous polyposis; NSAIDs, nonsteroidal anti-inflammatory
drugs; OA, oleic acid; PGD2, prostaglandin D2;
PGE2, prostaglandin E2; PUFA, polyunsaturated
fatty acids; 6-keto-PGF1, 6-keto-prostaglandin
F1; TX, thromboxane.
Manuscript received December 1, 1999. Initial review completed January 14, 2000. Revision accepted January 31, 2000.
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