[CANCER RESEARCH 41 , 3783-3785. September 1981]
0008-@472/81/0041-0000502.00
Dietary Fat, Immunological Response, and Cancer in Rats'
Paul M. Newberne
DepartmentofNutrition and Food Science, Massachusettslnstitute of Technology, Cambridge, Massachusetts 02139
Abstract
lmmunocompetence can be modified by dietary means.
Quality and quantity of fat have been associatedwith differ
ences in tumor induction and immunological response in ani
mals, and epidemiobogical observations have indicated that
certain dietary lipids are associated in some obscure way with
changes in tumor incidence in human populations. Data pre
sented at this Workshop indicate that dietary fats are associ
ated with an enhancement of cancer of the breast, prostate,
and colon in human populations and with cancer of the breast
and possibly the liver in animal models. Polyunsaturated fats
are more enhancing, but cholesterol, other dietary sterols, and
their degradation products appear to influence cancer induc
tion either directly or indirectly. Fats appear to be involved in
promotion rather than initiationof the carcinogenesis process.
That this is not established, however, indicates that an immu
nobogical mechanism may be involved in these phenomena.
Quality and quantity of dietary fat influence lipid metabolism
and sterol synthesis. Obesity depresses immune functions, and
further, Is involved in some obscure manner with endometrial
cancer in women. Lipemia is associated with aberrations of
immune function in people; polyunsaturated fats (a) decreased
rejection crisis in renal transplant patients and (b) suppressed
delayed hypersensitivity to skin tests in cancer patients and
control subjects with evidence for a regulatory role by unsatu
rated fats on lymphocyte reactivity, possibly through effects on
prostaglandinsand hormone synthesis. The oxidation products
of cholesterol exhibit profound effects over some aspects of
immune response, and plasma lipoproteins and their subjects
are involved in some manner with immunoregulatory aspects
of lymphocytes, inhibiting in vivo and in vitro functions. Clearly,
dietary and endogenous lipids influence immunocompetence
and, in this manner, probably susceptibility to cancer.
human populations and in experimentally induced tumors. This
brief presentation addresses certain aspects of fat and cancer,
in particular, the quality and quantity of fat and how it may
relate to tumors of selected organ sites and how a high-fat diet
affects immunocompetence.
A more extensive
review of fat
and cancer is included in other sections of these proceedings.
Reference to a few epidemiobogical studies and some specific
animal experimentations are described here.
Materialsand Methods
Male Sprague-Dawley rats (Charles River Breeding Labora
tories, Inc., Wilmington, Mass.), about 4 weeks old, 45 to 50 g
body weight, were fed diets ad!ibitum from weaning for various
periods of time. Thirty to 50 animals were used in each trial.
Rats were housed individually in screen-bottomed stainless
steel cages in climate-controlled animal facilities and were
weighed when placed on the experimental diets and weekly
thereafter. For further experimental details, consult the various
references cited. The data given here relate primarily to effects
of fats on tumor induction and, where appropriate, effects on
the immunological response.
Results
Rats fed a diet high in beef fat (28%), with enough corn oil
(2%) to prevent essential fatty acid deficiency, were signifi
cantly more susceptible to induction of colon tumors by di
methylhydrazine than those fed a lower concentration of fat
(Ref. 22; Table 1). Not only did the incidence of colon tumors
increase with high dietary fat, but the number of tumors per
tumor-bearing rat increased at both carcinogen dose levels.
Additional studies (9), using the same dietary regimen and
the same carcinogen dosages, revealed an increased total
number of colon tumors and an increased percentage
Introduction
An animal's nutritional state may appreciably influence its
response to various stresses and the way it metabolizes ex
ogenous or endogenous chemicals in the liver (20, 22). In
addition, the immunocompetence can be modified by dietary
means (19). In a number of studies, we have observed a
marked dietary effect on tumor induction by various chemical
carcinogens. Quality and quantity of fat have been associated
with differences in tumor induction and immunological re
sponse (1). Epidemiological observations and experimental
animal studies have indicated that certain dietary factors are
associatedin some obscure way with changesin tumor mci
dence in human populations and in experimental animals. The
major focus of this Workshop is on fat's influence on cancer in
I Presented
at
the
Workshop
on
Fat
and
Cancer,
December
1 0
to
1 2,
1979,
Bethesda, Md. These studies were supported by Grant ROl CA2691 7 from the
National Cancer InstItute and Grant ES 00597 from the National Institute of
Environmental Health Sciences.
SEPTEMBER
of the
colon occupied by lymphoid follicles in the high-fat, high-car
cinogen group (Table 2).
In further studies (20) designed to compare effects of satu
rated and unsaturated fats on aflatoxin B1-induced liver tumors,
tumor incidence increased and lymphocyte response to mito
gen stimulation decreased in rats fed corn oil (Table 3); lym
phocyte response was diminished regardless of whether or not
the carcinogen was administered. These 3 examples clearly
illustrate that fat has a profound effect on chemically induced
Table 1
Dietary fat and rat colon tumors
DimethylhydrazineDietdose
ratControl300862.0High-fat3001
(mg/kg)%
of rats with colon
carcinomaNo.
of tumors/tu
mor-bearing
003.7Control1
50561.1High-fat1
50852.6
a Taken
from Ref. 22, with permission.
Tumors
were Induced
by dirnethylhy
drazine.
1981
Downloaded from cancerres.aacrjournals.org on June 18, 2017. © 1981 American Association for Cancer Research.
3783
P. M. Newberne
Table 2
Dietary fat and lymphoid tissue associated with rat colon tumors8
tumorsMucinous
of
adonocarcinomas
of colon occu
of colon
zine dose
masControl3008.4432377High-fat3009.483694Control1
pied by folliclesbNo.
tumors%
DietDimethylhydra
(mg/kg)%
2892High-fat1
a Taken
509.61
507.633694
from
Ref.
b Areas occupied
9,
with
permission.
by lymphoid
Tumors
follicles
were
indexb28
Beef
fat Corn oilAflatoxin
with liver
tumors
BRat
No.s
%Phytohemagglutinin
stimulation
2+325374.5±420
1228
30+6010018.4
2—30081.6±530
30—30021.4±16
±
index = ratio between
mean cpm stimulatod
cultures
divided
by
dimethylhydrazine.
by ocular
microscopic
measurements.
of time, response to mitogens was decreased, and renal trans
plants survived for longer time periods; there were also other
indications that polyunsaturated fatty acids depressed the im
mune system.
Prostaglandmnsand hormonal mediation have been impli
cated in some studies with polyunsaturated fatty acid effects
and the response of the immunological system (12). Hypercho
lesterolemia also decreases resistance to infection and trans
a Taken from Ref. 20, with permission.
b Stimulation
induced
were determined
Table 3
Dietary fat, liver tumors, and lymphocyte stimulation after exposure to aflatoxin
% of dietary fat
content
Adenocarcino
by
mean cpm unstimulated.
cancer and that, in some cases, this modified carcinogenesis
is associated with changes in the lymphatic tissue in the colon
and in lymphocyte response to mitogen stimulation in vitro.
Discussion
It has been shown conclusively that quality and quantity of
dietary fat influences tumor incidence in animals, particularly
in the mammary glands, colon, and prostate, and to a lesser
extent in the liver. Colon, mammary, and prostate cancer in
human populations have also been associated positively with
dietary fat content (1). Also, in mice and rats, dietary fat
plantable tumors, diminishes lymphocyte response to sheep
and RBC and other antigens, and ‘
‘turns
off' ‘
the incorporation
of labeled acetate into cholesterol (2, 12, 13). Cholesterol
synthesis is an important event leading to cell proliferation and
response to antigen; impairment of this activity is associated
with elevated dietary cholesterol, which profoundly affects
immune functions.
Finally, as opposed to the direct dietary effects of various
fats on the immune responses, plasma lipoproteins exert im
portant influences on immunocompetence and are tools for
studying the effects of endogenous processes on tumor im
munobiobogy (3—5,7). Effects of lipoprotein subsets on im
munoregulatory properties, specific receptors, and other as
pects of fats and cancer mediated through the immune system
clearly help us to understand the modulation of carcinogenic
processes by fats.
enhances mammary and liver tumors and other selected tumors
of various target organs (1 1, 23—26).
Although numerous attempts have been made to associate
saturated fats with breast and colon cancer in human popula
tions, none have been definitive. An increased incidence of
cancer in arteriosclerotic patients treated with polyunsaturated
fatty acid-enriched diets over an 8-year period revealed diffi
culties in attempting to assess human data (21).
Many investigators have raised the question of how dietary
lipid may influence the immune system in relation to both
infectious disease and cancer. Some studies have shown that
saturated fats increase resistance to tuberculosis, indicating
that fat affects the immune system (10).
Genetically obese mice have impaired immunity as demon
strated by diminished ability to react to a contact sensitizing
agent, reduced capacity to reject skin grafts, and diminished
ability to generate cells that are active in cytotoxic systems
(15). In other studies, hyperlipidemic rabbits exhibited de
creased resistance to infection as did obese dogs (27). These
observations are associated in some way with the immune
system (8, 19).
More recent studies have demonstrated that polyunsaturated
fatty acids regulate lymphocyte reactivity(6, 14, 16—1
8). When
animals were fed polyunsaturated fatty acids (compared to
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SEPTEMBER
1981
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3785
Dietary Fat, Immunological Response, and Cancer in Rats
Paul M. Newberne
Cancer Res 1981;41:3783-3785.
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