(CANCER RESEARCH 50. 142-146. January I. 1990]
Experimental Induction of Neoplasia in the Accessory Sex Organs of Male
Lobund-Wistar Rats
Dennis M. Hoover, Kevin L. Best, Brian K. McKenney, Roy N. I amura, and Blake L. Neubauer
IJlly Research laboratories, Division of fili Lilly and Company, (Greenfield, Indiana 46140
ABSTRACT
of neoplasia in the dorsolateral prostate (8). F344 rats given a
combination of 3,2'-dimethyl-4-aminobiphenyl
and ethinyl es-
Experimental induction of neoplasia in the urogenital tract was studied
in male Lobund-Wistar rats. Animals were given single 30.0-mg/kg i.v.
injections of /V-nitroso-/V-methylurea (NMU) followed 7 days later by
s.c. implantation of a 2.0-cm Silastic capsule containing testosterone
propionate (TP). Additional rats were given the NMU or TP treatments
individually. Control animals were given a single i.v. injection of saline
followed by implantation of an empty Silastic capsule. The Silastic
implants for each group were replaced every 2 months. This hormone
treatment regimen produced significantly (/' < 0.05) elevated serum
testosterone concentrations relative to control for 42 days following
implantation. Animals were killed at 92, 177, 259,361, or 427 days postNMl injection. A high treatment-related incidence of adenocarcinoma
occurred in the dorsal and lateral prostatic lobes of animals given the
combined NMU-TP treatment. In addition, a few animals had adenocarcinomas of the coagulating gland or the seminal vesicle. The estimated
probability of neoplasia in the accessory sex organs by 427 days after
initiation of the NMU-TP treatment was 68%, with no occurrence before
9 months. The NMU-TP treatment was also associated with an incidence
of focal dysplasia in the accessory sex organs, particularly in the coagu
lating gland. These findings indicate that NMU-TP treatment of LobundWistar rats can provide a useful experimental system to study the
biochemical and molecular events involved in the induction of accessory
sex organ neoplasia.
tradiol had an 85.7% incidence of microscopic adenocarcino
mas of the ventral lobe of the prostate but no further progres
sion of these tumors was evident (9). The present study was
done to further evaluate NMU-TP-induced neoplasia in LW
rats in order to develop a reliable animal model of induced
prostatic neoplasia. The effects of treatment were evaluated in
a sequential order to study early stages in neoplastic develop
ment.
INTRODUCTION
Prostatic cancer is the most prevalent form of cancer and the
third leading cause of cancer deaths in men (1). Its incidence
increases almost logarithmically with age, faster than any other
cancer. The impact of this disease on the population is antici
pated to increase in the future with an aging population.
Appropriate model systems are essential for a better under
standing of prostatic carcinogenesis. Most experimental inves
tigation of prostatic cancer has been done using implanted
tumor systems in rodents (2). These tumor systems have the
advantages of consistent reproducibility and comparatively
short duration. However, the rodent transplantable tumor
models allow evaluation only of progression and metastasis but
not of the early stages of initiation and transformation.
Establishment of an inducible model system is required to
gain an understanding of the initial events in prostatic carci
nogenesis (3). Spontaneous neoplasia of the prostate in rats is
generally rare. An exception appears to be the spontaneous
occurrence of prostate carcinoma in 10% of aged LW rats (4,
5). Treatment of LW rats with TP caused an increased incidence
and decreased age of onset of the tumor (6). When NMU and
TP implants were combined, large prostatic adenocarcinomas
occurred in 77.5% of LW rats (7). Attempts to chemically
induce prostatic neoplasia in rat strains other than LW were
not as successful. Wistar rats pretreated with cyproterone ace
tate and subsequently given NMU and TP had a 35% incidence
MATERIALS
AND METHODS
LW rat breeding stock was a gift from Dr. Morris Pollard (University
of Notre Dame) and was maintained as a closed colony at HarÃ-an
Industries (Cumberland. IN). Male rats were received at the Lilly
Research Laboratories at 30 days of age and maintained until the start
of the experiment 60 days later. The animals were housed two or three
per wire grid bottom cage, in a light-controlled environment (lights on,
6 a.m.; lights off, 8 p.m.). Water and food (Purina Certified Rodent
Chow 5001; Ralston-Purina, St. Louis, MO) were provided ad libitum.
The rats were randomly distributed into four groups. Rats of two
groups received single i.v. femoral vein injections of NMU (Sigma
Chemical Company, St. Louis, MO; 30.0 mg/kg body weight) dissolved
in isotonic sterile saline. All rats were anesthetized with methoxyflurane
(Metofane; Pittman-Moore, Washington Crossing, NJ) for treatment.
Rats of the other two groups received i.v. injections of sterile saline.
One week later, one group given the NMU and one group given the
saline injection were implanted s.c. in the scapular region with 2.0-cm
Silastic (Dow-Corning, Midland, MI) implants of TP (Sigma), while
under methoxyflurane anesthesia. Approximately 50.0 mg TP were
packed as an acetone (OmniSolv, glass-distilled; EM Science, Cherry
Hill, NJ) slurry into 0.062-inch (inside diameter) x 0.125-inch (outside
diameter) Silastic tubing sealed at one end with about 1.0 mm Silastic
medical grade adhesive (Dow-Corning). The TP-containing Silastic
implants were placed in a vacuum oven at room temperature for 24 h
to dry. The implants were then packed with additional TP using a
round wooden stick and sealed with about 1.0 mm Silastic adhesive.
The implants were again dried in a vacuum oven at room temperature
for 24 h, washed once with 60% ethanol:water followed by sterile water
rinse to remove TP remaining on the capsular surface, and stored at
—¿20°C.
The TP-containing Silastic implants were replaced at 60-day
intervals according to a previously published protocol (10).
At 92, 177, 259, 361, and 427 days following NMU treatment, rats
from each group were anesthetized with methoxyflurane and blood was
collected via cardiac puncture. Serum samples were analyzed for glu
cose, urea nitrogen, creatinine, total bilirubin, alkaline phosphatase,
and alanine transaminase using an autoanalyzer (Monarch; Instrumen
tation Laboratories, Lexington, MA). The animals were sacrificed by
CO? asphyxiation and necropsy was performed. The following tissues
were collected in 10% neutral buffered formalin and processed for
histológica! evaluation: prostate (dorsal, lateral, and ventral lobes);
seminal vesicle; coagulating gland; urinary' bladder; urethra; testis;
epididymis; lung; liver; heart; kidney; thymus; iliac lymph node; thyroid;
adrenal; brain; and pituitary. Animals found moribund were killed and
necropsied. Several animals that died following anesthesia early in the
Received 6/27/89: revised 9/21/89; accepted 10/3/89.
The costs of publication of this article were defrayed in part by the payment
study were not evaluated.
of page charges. This article must therefore be hereby marked advertisement in
All tumors of the seminal vesicle, prostate gland, and coagulating
accordance with 18 U.S.C. Section 1734 solely to indicate this fact.
1The abbreviations used are: LW rat, Lobund-Wistar rat: TP, testosterone
gland were pooled for statistical purposes. The use of interim sacrifices
propionate: NMU, ,Y-methyl-iV-nitrosourea.
and termination of moribund animals prior to the end of study dictated
142
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ACCESSORY SEX ORGAN NEOPLASIA
the use of survival function statistical methodology. A cause of death
was determined for all animals which died or were killed moribund. All
neoplasms which were a cause of death were classified as fatal. Neo
plasms found incidental to another cause of death or neoplasms found
at scheduled kills were classified as incidental for the purpose of the
analysis. Nonparametric estimates of the tumor onset function were
calculated for each treatment group by the method of Kodell et al. (11).
Tumor onset was defined as the probability of occurrence of a tumor
by a specific time. The curves were then tested for equivalence across
all groups by the methodology described by Peto et al. (12).
To evaluate the time course of androgen release from the TP-treated
animals, a separate group of age-matched LW rats was implanted with
either TP-containing or empty Silastic capsules as described above.
Blood was collected from these animals by orbital sinus puncture at
weekly intervals for 3 months beginning on day 7. The blood was
allowed to clot and testosterone was measured in the serum using
radioimmunoassay (Radioassay Systems Laboratories, Carson, CA)
following extraction of steroids from blood by solid phase chromatography. Validation of the radioimmunoassay for this application fol
lowed previously published criteria (13). In this assay, blood samples,
charcoal-treated rat serum, H3O blanks, and pooled control serum
internal standards were measured following extraction using BakerBond octadecyl (C,K) reversed-phase solid matrix extraction columns
(J. T. Baker Chemical Company, Phillipsburg, NJ). Charcoal-treated
serum blanks representing less than 100-pg standards read between 90
and 95% of the predicted values, and intra- and interassay variations
averaged approximately 6 and 15%, respectively. All samples were run
in duplicate. Data from the testosterone radioimmunoassay were ana
lyzed using a modification of a program developed by Rodbard et al.
(14). Significant differences between TP and control values were deter
mined by Dunnett's multiple comparison procedure (15).
RESULTS
No treatment-related abnormalities were found in clinical
chemistry parameters. In the sequential pathological evalua
tions, animals given TP or NMU-TP had enlargement of the
dorsal, lateral, and ventral prostate; the seminal vesicles; and
the coagulating glands, evident grossly. Increased luminal se
cretion was evident histologically. Large prostatic abscesses
with complete obliteration of normal architecture occurred after
6 months of treatment in animals in each treatment group
(NMU, 1 of 45; TP, 2 of 42; NMU-TP, 2 of 42) but not in the
controls.
A treatment-related increase in the incidence of focal epithe
lial dysplasia occurred in the ventral, dorsal, and lateral prostate
and the coagulating glands of animals given NMU-TP (Table
1). These dysplasias were small singular or multiple lesions
characterized by pleomorphism of the epithelium (Fig. 1). The
epithelial cells varied in size and shape and were often crowded
along the basement membrane. Nuclei were variable in size
(often enlarged), irregular in shape, and hyperchromatic. The
altered foci in the coagulating gland had prominent cytoplasmic
basophilia. Similar changes occurred in the groups given NMU
or TP alone but were less frequent. Control animals had a low
incidence of focal epithelial dysplasia restricted to the coagu
lating gland. Small foci of inflammation and inflammatory
associated hyperplasia (Table 1) occurred occasionally in both
treated and control animals, particularly in the dorsal and
lateral prostatic lobes, but had no apparent treatment relation
ship.
Neoplasia of the accessory sex organs occurred in each treat
ment group but was much higher in the combined NMU-TP
group than in groups given either NMU or TP alone (Table 2).
The plot of the tumor onset functions (Fig. 2) demonstrated an
abrupt increase in tumor probability after 361 days for the
NMU-TP group, which reached 0.68 (68%) by 427 days on
test. The increased probability of tumors in the NMU-TP group
was highly significant (P < 0.01) as measured by Peto's test of
homogeneity of tumor onset across the groups.
Most of the primary malignant neoplastic masses in the
dorsal and lateral prostate and the seminal vesicle ranged in
diameter from 1 to 3 cm, were pale and firm, and had irregular
surfaces. These neoplasias were adenocarcinomas characterized
by pleomorphic epithelial cells in abundant fibrous connective
tissue stroma (Fig. 3). The epithelial cells formed irregular and
poorly defined acinar structures and had a high mitotic index.
A polymorphonuclear leukocytic infiltrate generally accom
panied the neoplastic proliferation. The neoplasms obliterated
the normal parenchyma of the organ and infiltrated adjacent
tissues. Metastasis of these tumors to the musculature of the
abdominal wall adjacent to accessory sex organs was common
(Fig. 4). Metastasis also occurred to lymph nodes, lung, liver,
and adrenal. Urethral obstruction and hydronephrosis com
monly occurred secondary to obstruction caused by the adeno
carcinomas.
Small areas of localized adenocarcinoma in the coagulating
gland and in the seminal vesicle were found only microscopi
cally. Malignancy of these lesions was demonstrated by epithe
lial cell invasion into adjacent smooth muscle. Occasional neo
plastic (Table 3) and nonneoplastic lesions in organs other than
the accessory sex organs occurred in each group but had no
apparent treatment relationship.
Implantation of the 2.0-cm TP-containing Silastic capsules
s.c. produced significantly (P < 0.05) elevated serum testoster
one concentrations over control values from days 7 through 42
(Fig. 5). Peak testosterone concentrations were observed at day
21 postimplantation and declined thereafter. No significant
difference in serum testosterone concentrations of the two
groups were observed at days 49, 56, or 60.
Table 1 Nonneoplastic proliferative lesions in the accessory sex organs
ControlInflammatory
77yvis2(11)°0000000178-427276(22)1(4)000004(15)NMU0-177181(5)0000002(11)178-427266(23)0I
0-1
hyperplasiaDorsal
associated
prostateVentral
and lateral
prostateSeminal
vesicleCoagulating
glandFocal
(38)1(6)M6)03(19)3(19)010
(5)001(5)008(40)178-427166
(4)01
dysplasiaDorsal
epithelial
prostateVentral
and lateral
prostateSeminal
vesicleCoagulating
glandDay
1Percent of animals affected
(4)1(4)1
(4)0013(50)TP0-177182(11)0000002(11)178-4272410(42)01
(4)1
(4)010(42)NMU-TP0-1772001
(63)
143
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ACCESSORY SEX ORGAN NEOPLASIA
«*.
'%'^TätF*
|df
WZLÌ
A^i-ijfifer
&
Fig. 1. Histological section showing an area of focal dysplasia in the coagu
lating gland of a rat 427 days after initiation of NMU-TP treatment. The epithelial
cells are crowded along the basement membrane and have enlarged nuclei. Note
normal adjacent epithelium (arrow). H & E, x 380.
Fig. 3. Histological section of an adenocarcinoma of the seminal vesicle of a
rat 375 days after initiation of NMU-TP treatment. The epithelial cells form
poorly defined aciner structures within an abundant fibrous connective tissue
stroma. H & E. x 160. Inset, & HE, x 640.
Table 2 Summary of incidental and fatal tumors of the accessory sex organs
No. of observed tumors/no, at risk
DayInterim
sacrifice259-361362-427Interim
deaths2622762X1375379TotalControl0/80/190/190/190/190/100/100/45NMU0/111-/150/190/190/190/100/101/45TPl/8b2/16*0/180/180/180/100/103/42NMU-TP0/93/8»-"'1/18'2/17'1/15'1/
" Seminal vesicle adenocarcinoma, localized.
* Coagulating gland adenocarcinoma. locali/ed.
' Prostate adcnocarcinoma.
" Seminal vesicle adenocarcinoma with metastasis.
' Prostate adcnocarcinoma with metastasis.
SALINE* VEHICLE
ce
O
SALINE.
TP
NMU+VEHICLE
*
r
M
: '
Fig. 4. Histological section of a prostatic adenocarcinoma metastatic to the
musculature of the adjacent abdominal wall. The neoplastic epithelial cells form
ductal structures (O). infiltrating between skeletal muscle (A/). H & E, x 750.
NMU*TP
Table 3 Neoplasms of organs other than the accessory sex organs
NMU-TP
Control
NMU
TP
N 45
45
42
42
Benign
Granular cell tumor
Bronchoalveolar adenoma
Intratubular seminoma
Adrenocortical adenoma
Pheochromocytoma
C-cell adenoma
Schwannoma
m
oOC
O.
DAY ot STUDY
Malignant
Fibrous histiocytoma
Fig. 2. Estimated probability of adenocarcinoma onset plotted against days
on test. All probabilities are equal to zero prior to 259 days.
DISCUSSION
The present study demonstrated a high incidence of adeno
carcinoma in the accessory sex organs of male LW rats given a
single dose of NMU followed by repeated TP treatments; the
estimated probability of occurrence reached 68% by 427 days
after initiation. This was comparable to the incidence (77.5%)
previously reported in LW rats given NMU-TP (7). Unlike
previous studies utilizing NMU-TP treatment, however, malig
nant neoplasia was not limited to prostate but also occurred in
the seminal vesicles and coagulating glands. This occurrence is
not entirely surprising because androgens induce growth and
proliferation in the adult seminal vesicle similar to those in the
prostate (16), and NMU is known to have effects on many
tissues (17). Spontaneous malignancy of the seminal vesicles of
both rats and humans is rare (18-20) and has been observed in
only a small number of experimental studies (20, 21). Sponta
neous malignancy of the coagulating gland in the rat has not
144
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ACCESSORY SEX ORGAN NEOPLASIA
8000 -i
cates direct alkylation of DNA in the rat prostate as the mech
anism by which neoplasia is induced. The involvement of the
ras oncogene family in the development of the NMU-induced
carcinomas of the accessory sex glands in male LW rats is the
subject of ongoing investigation.
During the course of the present study, the TP-implanted
animals were exposed to bimonthly oscillations in circulatory'
testosterone levels. Previous studies have found that androgen
depletion/repletion protocols have the capacity to elicit a sig
nificant wave of cell proliferation in androgen-sensitive cell
lines (25, 26). The direct implication is that the androgensensitive cells of the accessory sex glands went through succes
sive waves of proliferation followed by loss of cells. It may be
speculated that such cycles select for subpopulations of trans
formed cells.
The fact that NMU-TP treatment in LW rats induces a high
incidence of prostatic adenocarcinoma makes it a valuable
model for the study of this disease process. Identification of
specific molecular and heterotypic cellular interactive mecha
nisms involved in the inductive process may allow further
comparison to the disease process in humans and assist in
development of effective therapeutic approaches.
7000 -
6000 •¿
U
O
oc
ill
Iin
5000 -
LU (3
t- o.
4000
3000 E
U
C/)
2000 CONTROL
1000
—¿I—
10
20
30
40
—¿i—
60
SO
70
80
ACKNOWLEDGMENTS
DAY Of STUDY
The authors gratefully acknowledge the assistance of K. S. Howell
in preparation of the manuscript and J. P. Slaughter and C. E. Sullivan
for technical assistance.
Fig. 5. Circulating testosterone in male rats implanted with TP in Silastic
capsules. Values represent the mean ±SE (bars) of eight observations per group.
*. Significantly different from control (P < 0.05).
been reported and experimental induction has previously been
reported only once (20).
Sequential evaluation in this study suggested rapid neoplastic
growth following a preliminary latency period. Neoplasia was
not found during the first 6 months after NMU-TP treatment
and potential preneoplastic changes were limited to a low
incidence of dysplasia. During the interim evaluations, only a
relatively low incidence of the neoplasia was found in early
stages after 9 months. The lack of tumors in early evaluations
and the extensive necrosis which occurred at the center of the
large primary neoplasms later suggested rapid growth of tumor
mass.
Experimental induction of nonneoplastic proliferative lesions
has been observed previously in the dorsolateral and ventral
prostates (8, 9) and also occurred in our study. However,
dysplasia has not been reported previously in the coagulating
gland. In this study, a 40 and 60% incidence of focal dysplasia
before and after 6 months of treatment, respectively, was found
in rats given NMU-TP. The coagulating gland of control rats
had no dysplasia within the first 6 months and only a 15%
incidence after 6 months. Unlike the dorsal and lateral lobes of
the prostate, the coagulating gland was comparatively free of
spontaneous inflammatory changes. Inflammation may be as
sociated with a degree of reactive proliferation sufficient to
interfere with the study of other morphological changes. The
low incidence of inflammatory lesions and occurrence of dys
plasia would make the coagulating gland a suitable target organ
for the study of preneoplastic lesions. Such studies would have
relevance to prostatic cancer in men because the coagulating
gland has homology with regions of the human prostate (22,
23).
NMU is a broad spectrum carcinogen (17), potentially caus
ing neoplasia in multiple organs. NMU is known to cause direct
mutagenesis and activation of Ha-ras-1 oncogenes during the
initiation of mammary carcinogenesis in rats (24). This impli-
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Experimental Induction of Neoplasia in the Accessory Sex
Organs of Male Lobund-Wistar Rats
Dennis M. Hoover, Kevin L. Best, Brian K. McKenney, et al.
Cancer Res 1990;50:142-146.
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