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Environmental factors,
including those related to diet, are believed to contribute
significantly to the cause of many forms of cancer. Dietary
fat intake is among the most widely studied dietary risk factors
for breast and prostate cancers.
In recent years,
increasing attention has been paid to the intake of specific
fats rather than total fat intake, and notable among these
have been fish oils. Long-chain EPA and DHA, which are polyunsaturated
omega-3 fats contained primarily in fatty fish, have been
shown consistently to inhibit the proliferation of breast
and prostate cancer cell lines in the test tube and to reduce
the risk and progression of these tumors in animal experiments.
Regarding fish
consumption, the concentrations of EPA and DHA in fish oil
vary between fish species, with relatively high concentrations
found in fatty species native to cold waters, such as salmon,
mackerel, sardines, and herring, and relatively low concentrations
in lean fish, such as sole, halibut, and cod. The interpretation
of "total fish consumption" in epidemiologic studies
can therefore be problematic, because the absolute and relative
amounts of fatty acids reflected in this measure vary greatly
among populations.
Many studies examined
fish consumption in relation to breast and prostate cancer
risk, although only a few accounted for the type of fish consumed
or examined the intake of specific marine fatty acids. The
studies also varied greatly with respect to important methodologic
factors, such as sample size, adjustment for potentially confounding
variables, the detail and quality of the dietary assessment,
and the duration of follow-up.
In addition, epidemiologic
studies to date have not examined intakes of specific fat
in relation to endometrial and ovarian cancers. Clinical and
experimental studies of these cancers also have been scarce.
How
Fish Oil Prevents Cancer
Several mechanisms
have been proposed by which the intake of marine fats may
lower the risk of cancer. Among the most important of these
is the inhibition of eicosanoid biosynthesis from arachidonic
acid (AA; 20:4n-6), an omega-6 fat metabolized in the body
from linoleic acid. Eicosanoids are a class of compounds derived
from polyunsaturated acids and include prostaglandins, hydroxyeicosatetraenoic
acids, and leukotrienes.
Prostaglandins
are oxygenated, unsaturated cyclic fats that perform a variety
of hormone-like actions. Those converted from AA by the cyclooxygenase-2
enzyme, notably prostaglandin E2 (PGE2), have been linked
to carcinogenesis in several types of studies:
- Animal experiments
of mammary tumor development,
- Studies of the
proliferation of breast and prostate cancer cell lines in
vitro, and
- Human studies
of fish oil intake, epithelial cell proliferation rates,
and PGE2 biosynthesis.
Tumor cells typically
produce large amounts of AA-derived PGE2, which may impede
immune system function, possibly through its role in the generation
of suppressor T cells. Fish oils inhibit cyclooxygenase-2
and the oxidative metabolism of AA to PGE2.
EPA and DHA also
have been shown to inhibit lipoxygenase which metabolizes
AA to hydroxyeicosatetraenoic acids and leukotrienes. Hydroxyeicosatetraenoic
acid has been linked to the suppression of apoptosis, the
stimulation of angiogenesis, stimulation of tumor cell adhesion,
and expression of the invasive phenotype.
Lipoxygenase inhibitors
have also been discussed recently as a potentially important
class of chemopreventive agents.
Eiocosanoids derived
from AA also may be involved in other processes related to
cancer progression, as well as cancer initiation. These include:
- Alteration of
tumor cell membranes
- Modulation of
oncogene expression
- Formation of
cytotoxic peroxidation products
- Inhibition of
mitosis
- Promotion of
insulin resistance
- Modification
of estrogen metabolism
Estrogen can be
metabolized along 2 major pathways, to 16-{alpha}-hydroxyestrone
or to 2-hydroxyestrone. 16-{alpha}-Hydroxyestrone is considered
to be the more biologically active of the 2 estrogen metabolites
and has been observed to increase mammary epithelial cell
proliferation rates in experimental studies.
In contrast, 2-hydroxyestrone
may decrease proliferation and has been associated in some,
but not all, studies with reduced breast cancer risk. Thus,
"Western" diets that are rich in linoleic acid may
decrease the production ratio of 2-hydroxyestrone to 16-{alpha}-hydroxyestrone
and thereby increase cancer risk.
Several studies
focused specifically on DHA and its role in the development
of breast and prostate cancers. For example, DHA may activate
peroxisome-proliferator activated receptor-{gamma}, ligands
of which have shown antiproliferative effects in vitro on
prostate cancer cell lines. DHA also has been shown to improve
the response of breast tumors to cytotoxic agents.
Differences
in Fish Oil Consumption
Studies of fish
oil consumption trends have shown inverse associations between
per capita consumption of fish oil and the incidence of and
mortality rates from prostate and breast cancer. Moreover,
the shift toward a Western diet usually involves a concurrent
decrease in omega-3 fat intake and increase in omega-6 fat
intake, such as that observed in Japan over the past several
decades (with a concurrent rise in breast cancer incidence).
Whereas the intakes
of these two classes of fats were, for most of human history,
similar in quantity (i.e., an intake ratio near unity), modern
diets now heavily favor the intake of omega-6 fats. Indeed,
the results of several human and animal studies suggest that
reductions in breast cancer and PGE2 biosynthesis can best
be achieved with a relatively high intake ratio of omega-3
to omega-6 fats.
Hence, the processes
that ultimately modulate the concentration of tumor growth -- enhancing
eicosanoids may depend more on the relative concentrations
of specific fatty acids in the diet than on their absolute
concentrations.
The concentrations
of EPA and DHA relative to those of other fats contained in
fish vary between species, and relatively high concentrations
are found in fatty fish, such as salmon, mackerel, sardines,
and herring, species that are generally native to cold waters.
Lean fish, which typically are native to warmer waters, tend
to have lower concentrations of EPA and DHA and may sometimes
have higher concentrations of AA.
For example, a
100-g serving of Pacific herring contains 1.0 g EPA and 0.7
g DHA (19). In contrast, a 100-g serving of haddock contains
0.1 g each of EPA and DHA. Thus, different types of fish may
have different effects on processes related to cancer development.
Factors
Complicating Proper Interpretation of Fish Oil Clinical Studies
For studies that
examined only total fish consumption in relation to cancer
risk, assumptions regarding the type of fish consumed (and,
therefore, EPA and DHA intake) can be made from the per capita
intake of fish oil. For example, total fish consumption in
a Scandinavian population might reflect a greater intake of
fatty fish than would the same total fish consumption in a
population in the United States, because the per capita intake
of omega-3 fats and the per capita intake ratio of omega-3
to omega-6 fats in Scandinavia are up to 5- and 10-fold, respectively,
those in the United States.
Data from a few
experimental studies suggest that the strength of the association
with fish oils may be reduced in the presence of high antioxidant
intake, because both the former and the latter inhibit the
formation of AA-derived peroxidation products. This has been
put forth as a potential reason for the largely negative results
of studies in the United States, where supplementation with
antioxidants is widespread.
However, this explanation
is not entirely convincing because the formation of cytotoxic
peroxidation products is only one of several mechanisms that
may underlie the association between fish oils and cancer
risk. Nevertheless, adjustment for dietary antioxidants in
ecologic and analytic studies of omega-3 fatty acids to date
has been infrequent.
Intake of fish
oils also has been observed to inhibit the metastasis of human
breast cancer cell lines growing as solid tumors in animal
models. Hence, the association between fatty acids and cancer
risk may be clarified further through the analysis of epidemiologic
data that take into account various follow-up (or induction)
periods, that are from studies with repeated assessment of
diet during the follow-up period, and that provide information
on cancer at various stages of growth and progression.
In conclusion,
the development and progression of breast and prostate cancers
appear to be affected by processes in which EPA and DHA play
important roles.
Given the lack
of studies that examined the intake or tissue concentrations
of specific fish oils and the fact that most studies of fish
consumption did not account for the type of fish consumed,
there are still too few data from epidemiologic studies to
evaluate the strength, consistency and dose response of the
relation between fish oil intake and human cancer.
Although there
is ample evidence from test tube and animal studies that these
essential fats can inhibit the progression of tumors in various
organs, particularly the breast and prostate, the evidence
from epidemiologic studies is less clear. Although most of
the studies did not shown an association between fish consumption
or fish oil intake and the risk of hormone-related cancers,
the results of the few studies from populations with a generally
high intake of fish oils are encouraging.
American
Journal of Clinical Nutrition, Vol. 77, No. 3, 532-543,
March 2003
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