Effects
of voluntary running wheel exercise on
the growth and metastasis of transplanted prostate cancer in rates
R. BRYNER, D. RIGGS, D. DONLEY, J. WHITE,
I. ULLRICH, D. LAMM, R. YEATER
West Virginia University,
Morgantown, WV, Departments of Exercise Physiology, Medicine and Urology,
School of Medicine, West Virginia University, Morgantown, WV
Bryner, R., Riggs, D.,
Donley, D., White, J., Ullrich, I., Lamm, D., Yeater, R. Effects of voluntary
running wheel exercise on the growth and metastasis of transplanted prostate
cancer in rates. JEPonline.
Vol.
1 No. 2, July, 1998. Regular physical activity
has been associated with a decreased incidence of certain cancers. Some,
animal studies have found that exercise training enhances resistance to
experimentally induced tumor growth, but prostate cancer has received little
attention. This study examined the effects of voluntary wheel running on
the growth and metastasis of transplanted prostate cancer in rats. Animals
were randomly assigned to running wheel (RW: n = 19) or control (C: n =
18) groups. The RW animals had free access to the running wheels throughout
the study except for week 12. Animals were given a maximal treadmill test
before training and during week 12 (baseline). Forty-eight hours after
the treadmill test, all animals were inoculated with 1 x 106 transplantable
rat prostate cancer subcutaneously (day = 0). Tumor incidence and volume
were determined biweekly until sacrifice at day 52. Weight and peak VO2
did not differ between groups before training. Weight tended to be greater
(p =. 029) for C vs RW (C: 417.1 ± 51.5 vs. RW: 377.2 ± 36.1
grams) and peak VO2 greater (p < 0.01) for RW vs C (RW: 67.0 ±
4.8 vs. C: 56.4 ± 3.3 ml/kg/min) at week 12. Mean tumor volume across
all measurements was lower (p <0.01) in RW vs C (6668.2 ± 5678.0
vs 7942.0 ± 7020.7 mm3).
Number of lung metastatic lesions did not differ between groups (RW: 214.5
± 120.6 vs C: 181.6 ± 137.7). Tumor volume correlated negatively
(p = .05) with the 12-week max treadmill time. In conclusion, voluntary
wheel running produced a significant improvement in the cardiorespiratory
fitness of rats and was associated with a significant reduction in prostate
tumor volume. However, exercise had no effect on lung metastases.
Introduction
There is a limited
amount of epidemiological data that would suggest an inverse relationship
between physical activity and the risk of colon cancer, (1)
breast cancer, (2) and lung cancer (3).
A number of studies (4,5) have shown
that higher levels of physical activity were associated with a decreased
risk of prostate cancer while others evidence has suggested no association,6
or even an increased risk of prostate cancer (7). Oliveria
and others (8) reported that higher cardiorespiratory
fitness levels were inversely associated with the probability of development
of incident prostate cancer. However, the majority of epidemiological evidence
is far from conclusive regarding the effect of exercise training on prostate
cancer development.
Some studies utilizing laboratory rodents
have reported that exercise can have a protective effect on the induction
of chemically induced cancers (9,10),
especially mammary tumors (11). However, other investigators
(12) using treadmill exercise have found no beneficial effect of exercise
on tumor incidence or progression. Hoffman-Goetz et al. (13),
found no significant difference in lung metastases of CIRAS 3 tumor in
C3H mice who underwent moderate exercise training for four weeks prior
to and four weeks after tumor inoculation. The conflicting data that exists
has drawn some investigators to criticize the use of forced exercise because
of the potential stress that it places on the animals. Enhanced stress
may alter the animals' immune system and subsequent immune mediated response
to cancer. On the other hand, running which is voluntary may not have such
an adverse effect. For this reason, protocols which allow rodents free
access to running wheels may be more appropriate to study the effects of
exercise training on cancer incidence and progression.
Treadmill protocols used in most experimental
designs may be insufficient to produce desired cardiovascular or immunological
changes. Investigators cite observations that rodents naturally run in
multiple short intervals as opposed to the typical 15 to 60 minutes used
in most treadmill exercise studies. It has been reported from videotape
analysis that mice, given free access to running wheels, will typically
run for 20-30 seconds, exit from the wheel, and then return a minute or
two later (14). Analyses of 24-hr running wheel distances
have reported ranges from approximately 1.5 to 13 km daily with the mean
usually between 5 to 10 km (14,15,16).
This represents a much greater exercise load than is typically used in
most treadmill training studies. Recent data collected in our laboratory
showed that running 20 m/min either 15 min/day three days/ week for six
weeks (17) or 30 min/day five days/week for eight weeks
(unpublished data) did not result in a significant increase in maximum
VO2 in rats. On the other hand, studies
which have allowed rodents free access to running wheels have reported
significant increases in lymphokine activated killer (LAK) cells (14),
significantly increased fraction of OX52+/CD5- natural killer cell activity
(15),
and even a significantly reduced growth of human breast carcinomas
(16) when compared to sedentary animals. Therefore, the purpose of
this study was to examine the effects of voluntary exercise on the development,
growth and metastasis of a transplanted prostate cancer.
Methods
Animals
Thirty-eight male Lobund-Wistar rats were
randomized into two groups; Running Wheel exercise (RW: 19 rats) and Control
(C: 18 rats). Animals were housed two per cage for a short acclimatization
period on a 12 hour reversed light/dark cycle, with an ambient temperature
of approximately 210C. Running Wheel rats were then separated into individual
cages and had free access to a running wheel. All animals were given free
access to both food and water throughout the study. Mean weight for both
groups at the start of the study can be found in table 1. The maximum VO2
of all animals was determined prior to running wheel access (baseline)
and during week 12 of the study.
Exercise Training
The RW rats were given continuous access
to the running wheel for 11 weeks. At the end of week 11, doors to the
wheels were closed for one week (week 12). It was during this time that
the second maximum VO2 test and tumor inoculation
took place. During weeks 13-19, doors to the running wheels were again
opened for the RW group. Each wheel was fitted with a counter which was
checked daily that continuously recorded revolutions.
Maximum Exercise Test
Rats in both RW and C were given an incremental
maximal treadmill exercise test at baseline and at week 12 to determine
peak oxygen consumption. Exercise tests were conducted on a motor driven
treadmill entirely enclosed in an environmental chamber. Animals began
walking at 10 m/min, zero percent elevation for three minutes at which
time the treadmill speed was increased to 15 m/min for three minutes followed
by 20 m/min for the remainder of the test. The treadmill elevation was
raised two percent every three minutes until the rats refused to walk even
with electrical stimulation. Oxygen consumption (VO2),
carbon dioxide production and RER were monitored continuously with the
aid of an Oxymax metabolic treadmill system (Columbus Instruments International
Corporation, Columbus Ohio). The average of the final minute was calculated
and recorded to represent maximal values. Total time to fatigue was also
recorded. All exercise test values can be found table 1.
Tumor Model
Model: The prostate adenocarcinoma (PA
III) tumor arose spontaneously from aged Lobund-Wistar rats (18).
This tumor model is morphologically and biologically similar to aggressive
hormone-independent human adenocarcinoma of the prostate. This tumor model
has both a high incidence of tumor occurrence (100%) and metastasis (98%)
with a latency period of approximately one month. The PAIII prostate cancer
model has been shown to metastasize from the primary tumor site to lung
tissue. In the present experiment, the tumor was enzymatically dissociated
and then transplanted as a single cell suspension (106
cells/recipient)
under the skin of the right flank at least forty-eight hours after maximum
exercise tests during week 12.
Tumor Measurements
Primary subcutaneous tumor incidence was
evaluated by inspection and palpation. Tumor dimensions (length and width)
were measured twice a week with a Vernier caliper until the time of sacrifice
at day 52. Tumor volume was calculated using the formula V = 0.4(L.W2).
The same individual with several years of experience with this type of
procedure performed all measurements.
Determination Of Tumor Metastasis
At day 52, all animals were sacrificed
and the lung tissue was collected and fixed in Bouin's fluid which stained
metastasis a bright yellow. The lungs were then rinsed with 70% alcohol
and tumor metastasis counted by visual inspection.
Determination of Adrenal Gland Weights
One adrenal gland was removed from a subset
of animals in each group and served as a measure of induced stress as indicated
by adrenal hypertrophy. The adrenal glands were removed, trimmed of excess
fat and connective tissue, blotted dry and wet weighed.
Statistical Analysis
Differences between groups in baseline
and week 12 test values were determined using a two-way ANOVA. An independent
t-test was used to isolate any significant difference. Within group differences
in exercise test values were determined using a paired t-test. The standard
alpha level of 0.05 was divided by two (p<0.025) and selected as the
criteria for statistical significance for all analyses using a t-tests.
Fisher exact analysis was used to determine differences in tumor incidence.
All correlation analyses were performed using the Pearson's Product Moment
Correlation. A probability level of 0.05 was selected as the criterion
for statistical significance for all other analyses.
Results
Body weight of the RW and C rats can be
found in table 1. There was no significant difference in the initial body
weights between groups. During the initial 12 weeks, body weight increased
significantly ((p<0.01) in both RW and C but weight was greater for
C than for RW (p = 0.029) at week 12. Peak VO2
and time to exhaustion during the maximum treadmill test which were determined
immediately before (pre) and after the initial 12 week training period
(post) can also be found in table 1. Peak VO2
was not different between groups before training but was significantly
greater (p<0.01) in RW versus C at week 12. There was an increase which
approached significance (p = 0.03) in the maximum VO2
pre to post in RW (63.0 ± 4.8 to 67.0 ± 4.8 ml/kg/min) while
C experienced a significant (p<0.01) decrease (63.4 ± 5.4 to
56.4 ± 3.3 ml/kg/min). The average daily meters run correlated significantly
(p<0.01) with the 12-week peak VO2.
Treadmill test time to fatigue increased significantly (p<0.01) in RW
(18.5 ± 4.0 min to 24.6 ± 1.3 min.), but did not change in
C (14.0 ± 4.5 min. to 16.6 ± 4.0 min.). Post test time was
significantly (p<0.01) greater in RW when compared to C. Treadmill time
to fatigue correlated positively (p<0.01) with peak VO2.
Table 1. Physiological variables
determined
prior to (PRE) and immediately after (POST)
the
initial 11-weeks of running wheel exercise
(mean±SD).
|
RW |
Control |
Body Weight (g)
PRE
POST |
342.4 ± 32.0
377.2 ± 36.1* |
327.6 ± 31.7
417.1 ± 51.5* |
Peak VO2 (ml/kg/min)
PRE
POST |
63.0 ± 4.8
67.0 ± 4.8*^ |
63.4 ± 5.4
56.4 ± 3.3* |
Treadmill Time To Fatigue (min)
PRE
POST |
18.5 ± 4.0
24.6 ± 1.3*^ |
14.0 ± 4.5
16.6 ± 4.0 |
RW,
running wheel exercise group; Control, sedentary control group *(P<0.01),
significantly different pre to post, ^(P<0.01), significant difference
between groups
The number of rats displaying a palpable tumor
is listed in table 2. The first day that tumors could be palpated with
confidence in either group was day 16 post inoculation. There was no difference
between groups in the number of rats displaying tumors at this day or any
day that measurements were taken. Mean tumor volume across all time measurements
was lower
( p<0.01) in RW compared with C (6668.2
± 5678.0 vs 7942.0 ± 7020.7 mm3).
Table 2. Number of animals
displaying palpable tumors
|
|
|
DAY |
|
|
|
|
| GROUP |
16 |
18 |
25 |
29 |
38 |
45 |
52 |
RW
(n=19) |
7 |
11 |
12 |
18 |
18 |
18 |
18 |
Control
(n=18) |
11 |
14 |
16 |
17 |
18 |
18 |
18 |
RW, running wheel
exercise group; Control, sedentary control group
Analysis of individual tumor measurements
revealed a smaller although not significant (p = 0.06) tumor volume at
day 38 in RW vs C (5919.0 ± 2543.4 vs 8036.4 ± 3968.4 mm3)
(Figure 1). No other significant differences were observed between
groups at any of the other time measurements.
Figure 1: The mean (± SD)
tumor volume measurements taken from time of inoculation until sacrifice.
RW = voluntary running wheel animals; C = sedentary control animals. 
The number of pulmonary metastases at the
time of sacrifice was not different between groups (RW: 214 ± 120.6
vs C: 181.6 ± 137.7) . Adrenal gland weights, also collected at
the time of sacrifice, were not different between groups (RW: 23.1 ±
2.8 vs C: 22.0 ± 5.0 mg).
The average meters run daily each week
over the course of the 19 weeks is shown in Figure 2. Arrow indicates
week of tumor inoculation. Meters run per week showed a gradual increase,
peaking at week nine of training. There was an approximate 50 percent decrease
during week 13 which was the first full week of training post tumor inoculation.
Meters run per day increased again during week 14 and appeared to remain
constant until week 18. The average meters run per day for all animals
before tumor inoculation (BT) and after tumor inoculation (AT) was not
different (BT: 2802.2 ± 2586.4 vs AT: 2453.6 ± 2482.6).
Tumor volume at day 38 was negatively correlated
(R = -0.375; p = 0.05) with the 12-week maximal treadmill time. Tumor volume
at this time did not correlate positively with the 12-week peak VO2. The
average daily meters run correlated significantly (R = 0.621; p<0.01)
with the 12-week peak VO2. The number of lung metastatic lesions correlated
significantly (R = 0.438; p<0.05) with the 12-week peak VO2 and tended
to correlate (R = 0.464; p = 0.06) with the average daily meters run. The
adrenal weight also correlated significantly (R = 0.521; p<0.05) with
the number of lung metastases.
Discussion
Voluntary wheel running produced a significant
improvement in the cardiorespiratory fitness of rats and was associated
with a significant reduction in prostate tumor volume relative to sedentary
C. However, exercise had no effect on lung metastases. When the tumor volumes
were analyzed for each measurement period, the RW group displayed a smaller,
although not significant, primary tumor mass on day 38 post inoculation
compared to controls.
Epidemiological studies have indicated
a potential relationship between physical activity and the incident rate
of a number of site-specific cancers. To the authors' knowledge, this is
the first study which examined the effects of voluntary running wheel exercise
in rodents on the growth of an experimentally transplanted prostate adenocarcinoma
and its metastases. Animal studies have used numerous tumor models to determine
the effectiveness of exercise training on cancer induction, development
and growth and have found varying results. Jadeski and Hoffman-Goetz (10),
reported that mice which exercised 20 m/min, 30 min/day, five times/ week
for nine weeks had a significantly lower retention of radiolabelled H-ras-transformed
fibroblasts (CIRAS 1) as compared to sedentary control. Chronic exercise
retarded retention of intravenously injected CIRAS 3 tumor cells in the
lungs of treadmill trained mice below that of the sedentary groups (9).
Thompson et al. (11) reported that high intensity treadmill
running five days per week was associated with a protective effect for
rats who developed chemically induced mammary tumors. Only the high intensity
training (70% maximal treadmill intensity) whether 20 or 40 min/day and
not the low intensity (35%) afforded the animals protection. Time of tumor
appearance was significantly sooner in mice which ran three days prior
to and 14 days post inoculation of 2.5 x 105 mammary
adenocarcinoma cells compared with a group of sedentary controls
(19). The contradictory results found in the literature may be explained,
in part, by the use of different experimental designs as well as an inhomogeneous
response to a given exercise workload. In a previous study conducted in
our laboratory the metabolic cost (i.e., oxygen consumption) of running
20 m/min was approximately 73.41 ml/kg/min with a range of 54.67 to 98.80
(SD: 13.13) (17). Clearly this indicates that some animals
were exercising at a much higher intensity than others and that they were
different with respect to exercise efficiency. This might elicit a greater
stress response in some animals compared to others with a subsequent detrimental
effect on the immune system and interferance with anticancer activity.
Animals allowed free access to running
wheels for 11 weeks experienced a significant improvement in their peak
VO2 and running time to fatigue. These results are similar to those reported
by Lamber and Noakes (20), who reported that rats which
spontaneously ran greater than 11.6 km/wk in wheels for eight weeks improved
both their maximum VO2 and submaximal VO2
measures, while those running less then 11.6 km/wk still improved their
running efficiency. In the present study, the average daily meters run
ranged from a low of 614.4 during week one to a high of 4441.9 during week
nine with an over all average of 2376.3 meters/day. Oliveria and others
reported that higher cardiorespiratory fitness levels in men were inversely
associated with the probability of development of incident prostate cancer
after controlling for age, body mass index, and smoking habits (8).
Welsch et al. (16) reported that the growth of human
breast carcinomas in mice was significantly inversely correlated with the
mean number of miles that each mouse ran per day. Although running wheel
exercise was associated with a reduced prostate tumor volume in the present
study, tumor volume did not correlate with the 12-week peak VO2
values. Tumor volume at day 38 did have a direct correlation with the 12-week
maximal treadmill time to fatigue. The treadmill time to fatigue correlated
directly with the peak VO2. An increase
in treadmill time not only reflects an improved aerobic capacity but also
an enhanced efficiency of running. This measure may better reflect the
animals overall fitness.
A number of mechanisms have been postulated
to explain the apparent association between exercise and the resistance
to tumor growth in animals. Some of these factors include the ability of
exercise to modulate dietary factors, body composition and even immune
function. Eight weeks of spontaneous running wheel activity was associated
with a significant increase in the cytotoxic activity of lymphokine activated
killer cells in rats (14). Five weeks of voluntary running
in wheels significantly increased the fraction of splenic OX52+/CD5- natural
killer cells compared with sedentary controls
(15).
These authors reported that voluntary exercise augmented natural cytotoxicity
mechanisms in vivo as measured by an increased clearance of injected 51Cr-labeled
YAC-1 lymphoma cells from the lungs relative to sedentary controls. We
did not assess whether immune changes occurred in the present study.
The number of pulmonary metastases was
not different between RW and sedentary control animals. Lung metastases,
however, were correlated positively with the 12-week peak VO2
and approached a significant correlation with the average daily meters
run. An association between increased training volume and the incidence
of infectious illness has been reported (21). A sustained
suppression of NK cell numbers has been observed following exercise of
a highly intense or prolonged (22) nature. In addition,
natural killer cell activity has been reported to be suppressed following
exercise of high intensity (75% of maximum VO2)
but not following exercise of moderate (50%) or low (25%) intensity (23).
It is believed that the reduced number of NK cells and NK cell activity
following exercise may be a result of elevated plasma levels of cortisol.
Administration of corticosteroids to human subjects results in a transient
lymphopenia (24). Exercise of long duration is known
to increase plasma cortisol levels and these levels remain elevated for
some time after exercise. The rise in cortisol immediately following exercise
is directly related to the magnitude of the subsequent lymphopenia (25).
Animals which ran the most in this study may have experienced an elevated
plasma cortisol response during and after exercise. This could have led
to enhanced lung metastases in those animals which developed a tumor with
metastatic properties. Adrenal weights correlated significantly with the
number of lung metastatic lesions although adrenal weights did not differ
between groups. Adrenal hypertrophy has been associated with extreme stress
in rodents (26). It is important to point out however,
that this correlation was across all animals, not just those from RW. This
would indicate that the running wheel exercise was not the only potential
cause of adrenal hypertrophy but that it may have simply been a general
stress response to the overall tumor burden. Additionally, because we did
not measure plasma cortisol, this theory is only speculation.
The type of tumor model used in an experiment
can contribute to the potential outcome. The prostate adenocarcinoma tumor
used in the present study arose spontaneously and was originally discovered
in aged germ free Lobund Wistar rats (18). Transplanted
tumor cells from this model are normally fast acting and aggressive with
a latency period of approximately one month in control animals. Jadeski
and Hoffman-Goetz (10), demonstrated in mice that moderate exercise conditioning
can reduce tumor retention but only for tumor cells considered mildly aggressive
(CIRAS 1). The same study showed no effect of exercise training for a tumor
model that was aggressive (CIRAS 3). The tumor model used in the present
study may have been too aggressive to accurately test the long term benefits
of exercise training on prostate cancer prevention. However, voluntary
running wheel exercise was associated with a reduced overall tumor volume
in the present study despite the use of such an aggressive prostate adenocarcinoma,
pointing to the potential importance of this association.
In conclusion, running wheel exercise for
11 weeks produced a significant increase in the peak VO2
and the treadmill time to fatigue in rats. Voluntary running for 19 weeks
was associated with a significant reduction in overall tumor volume. Spontaneous
wheel running did not limit the number of lung metastatic lesions. The
mechanisms causing this effect as well as their clinical relevance remain
to be determined.
Address correspondence
and reprint requests to: Randall
W. Bryner, Ed.D., Department of Exercise Physiology, P.O. Box 6116,
274 Coliseum, Morgantown, WV 26506-6116. Phone: 304-293-7767; FAX: 304-293-4641.
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