[CANCER RESEARCH 49, 6396-6400. November 15, 1989]
Alteration of Pancreatic Endocrine Cell Patterns and Their Secretion during
Pancreatic Carcinogenesis in the Hamster Model1
Parviz M. Pour2 and Richard H. Bell
The Eppley Institute for Research in Cancer and Department of Pathology and Microbiology, University of Nebraska Medical Center, Omaha, Nebraska [P. M. P.], and
Veterans Administration Medical Center, University ofCincinatti, Cincinniti, Ohio [R. H. B.¡
ABSTRACT
MATERIALS
Proliferation of endocrine cells was found to occur during early, i.e.,
first 12 weeks, exocrine pancreatic carcinogenesis after 6 weekly treat
ments of Syrian hamsters with the pancreatic carcinogen A'-nitrosobis(2oxopropyl)amine (BOP). Cells containing insulin (Ins), glucagon (Glu),
and somatostatin (Som) were noted in all stages of tumor development
and were present in adenocarcinomas and in métastasesto the liver.
Some of the cancer cells were of ¡impiumilo(hybrid) type, i.e., produced
both murili and endocrine substances. Measurement of these hormones
revealed a significant decrease in plasma Ins during early stages of
carcinogenesis with concomitant increase of Ins level in pancreatic juice
at 12 weeks after 6 weekly BOP treatments. Plasma Glu and Som were
not changed. The changes noted, particularly in relation to Ins, suggest
that proliferation of endocrine cells in pancreatic carcinogenesis may be
associated with alterations in hormone secretion.
Animals
INTRODUCTION
Pancreatic cancer, which has become a common international
health problem, is characterized by an extremely poor prognosis
and lack of response to therapeutic approaches (1, 2). There
are as yet no methodologies for early detection of the disease
for possible screening of populations at high risk (3-9). The
presently existing tumor-associated antigens, such as CA 19-9,
DU-PAN-2, carcinoembryonic antigen, etc., are useful for mon
itoring the disease, but their efficacy in early cancer detection
has remained disappointing. Therefore, more specific and sen
sitive methods are required. Our recent studies in the hamster
pancreatic cancer model, which in clinical, biological, and mor
phological aspects closely resembles the human disease (1014), have provided data which seem promising for developing
early diagnostic modalities.
We have identified Ins3 and growth hormone-like substances
in the pancreatic juice of untreated hamsters (15). This finding
was not surprising, as pancreatic hormones, including Ins, Glu,
Som, and EGF-like substances, have been found in the pan
creatic juice of several species, including humans (16-21). In a
later study, we noted the proliferation of Ins, Glu, and Som
cells simultaneous with that of ductal/ductular cells in early
pancreatic carcinogenesis (12). This phenomenon (which imi
tates the embryonic development of the pancreas) persisted
throughout the carcinogenesis process, and endocrine cells were
found in almost all induced cancers (10-14).
The current study was designed to quantitate the proliferation
of endocrine cells during pancreatic carcinogenesis and to de
termine if changes in the endocrine cell population were asso
ciated with alteration of hormone levels in plasma and pan
creatic juice.
Received 11/29/88; revised 3/21/89. 8/14/89; accepted 8/18/89.
The costs of publication of this article were defrayed in part by the payment
of page charges. This article must therefore be hereby marked advertisement in
accordance with 18 U.S.C. Section 1734 solely to indicate this fact.
' Supported by United States Public Health Service National Cancer Institute
Grant CA38922, by Laboratory Core Grant CA36727, and by American Cancer
Society Grant SIC-16.
2 To whom requests for reprints should be addressed, at 42nd & Dewey Ave.,
Omaha, NE 68105.
'The abbreviations used are: BOP, A'-nitrosobis(2-oxopropyl)amine; Ins. in
sulin; Glu, glucagon; Som, somatostatin.
AND METHODS
Male Syrian hamsters from the Eppley Colony were housed in groups
of five in plastic cages on granular cellulose bedding (Bed-O-Cobs, The
Anderson Cob Division, Maumee, OH), kept under standard laboratory
conditions, and given Wayne Lab Blox (Allied Mills, Chicago, IL) and
water ad libitum.
Carcinogenesis Experiments
Experiment 1: Pattern of Endocrine Cells during Pancreatic Carcino
genesis. Male Syrian hamsters were treated weekly for 6 weeks with
BOP (10 mg/kg s.c.) and sacrificed in groups of three to four hamsters
12 and 33 weeks after the last BOP injection. Similar numbers of
hamsters were used as controls. The pancreases of these animals were
processed for immunohistochemistry for demonstration of Ins, Glu,
and Som as described below.
Experiment 2: Hormone Levels in Plasma and Pancreatic Juice. This
experiment was designed after the results of Experiment 1 were evalu
ated. Male hamsters were treated weekly for 6 weeks with BOP (10
mg/kg s.c.). Four, 8, and 12 weeks after the last BOP injection,
pancreatic juice (stimulated by secretin/CCK-OP) and plasma were
examined in groups of 20 animals per interval for the presence of Ins,
Glu, and Som and compared to age-matured controls. The levels of all
three hormones were determined in plasma, but the amount of juice
obtained was too small to allow for measurement of Som.
Carcinogen. BOP was synthesized in our Institute as described (22),
dissolved in physiological saline shortly before use, and given s.c.
Collection of Pancreatic Juice and Plasma. A perfusate solution
containing secretin and CCK-OP was made up as follows: (a) vials of
Secretin-Kabi were reconstituted in 7.5 ml of saline yielding a stock
solution of 819 nm, (b) CCK-octapeptide (Kinevac, Squibb) was recon
stituted as 1 Mg/ml solution in saline, (<•)
the perfusate solution con
tained 0.1-ml CCK-OP stock solution, 0.6-ml secretin stock solution,
and 19.3-ml BSA/saline per 20 ml. Hamsters were anesthetized with
nembutal (80 mg/kg body weight i.p.). A femoral venous catheter was
inserted for the perfusion solutions. The common bile duct was ligated
at the ampulla and at the liver hilum and cannulated between these
ligatures with PE 10 tubing to collect pancreatic juice. A bolus of 0.5cc perfusate solution was initially give i.v., followed by a continuous
infusion of 0.8 cc/h. Pancreatic juice was collected into iced, covered
tubes containing 20 n\ of trasylol (100,000 KIU/ml). Following juice
collection, blood was drawn from the inferior vena cava, and the plasma
separated by centrifugation in tubes containing 0.1 ml trasylol. Speci
mens were frozen at —¿70°C
prior to radioimmunoassay.
Radioimmunoassay. Ins, Glu, and Som were all performed by doubleantibody radioimmunoassay in the Core Ligand Laboratory, National
Diabetes Research and Training Center, University of Michigan, Ann
Arbor, MI, with the following antibodies:
Insulin. The anti-pork Ins serum (Ann Arbor) reacts with Ins and
proinsulin. Pork Ins labeled with '"I is employed as the trace and
human Ins as the standard. Second antibody is used to separate the
bound and free fractions. The sensitivity limit is 0.08 ^unit/tube,
interassay variability 8.4%, and intraassay variability 6.4% (23). lodination was performed by the modified method of Freychet et al. (24).
Glucagon. The anti-beef/pork-Glu serum (G9-M, Ann Arbor) reacts
with the carboxyl terminal of the Glu molecule and has negligible crossreactivity with Glu-like materials present in the intestinal mucosa (25).
Beef-pork Glu is used as '"I-labeled trace (New England Nuclear) and
standard. Separation of the bound and free fractions is accomplished
using second antibody (Ann Arbor). The limit of sensitivity is 2.0 pg/
6396
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ENDOCRINE CELLS DURING PANCREATIC CARCINOGENESIS
Table I Number of pancreatic endocrine cells derived from a point system
auantitation
tube, the interassay variability 10.2% with the intraassay variability at
7.5%. lodination was performed by the method of Brower et al. (26).
Somatostatin. A dextran-coated charcoal separation radioimmunoassay using Ann Arbor antibody "Big Wig" OSI 184 was produced in
Experimental intervals
Typea
Cell
rabbit. The methodology is modified from Gerich et al. (27). The limit
of sensitivity is 1.6 pg/tube with the intra- and interassay variability at
5.3 and 9.8%, respectively. Samples are not extracted prior to analysis.
Immunohistochemistry. Pancreases were fixed in Bouin's solution for
2 weeksControl
weeks
33
weeksTreated
weeks
33
hamsters86+17
hamsters173
±47° 310 ±168°
233 + 67
196 ±31° 415 + 86°
70+11
187 ±88
65 ±34°
474 ±101°
26 ±8
63+18
S
0.9
0.7
1.2
1.2
Ratio fi:a
3.3
3.7
Ratio ß:&
2.7
0.6
3.0
0.91
2.7
2.9
Ratio a:512
a Most of these endocrine cells were of extrainsular origin; data represent
nean ±SD.
6 h, processed for histology by conventional methods, and embedded
in paraffin. Tissues were cut in serial secretions and examined by
antibodies against Ins, Glu, and Som (Immunon, Lipshaw, Detroit,
MI) by ABC techniques using commercially available kits (Immulok
Inc., CarpinterÃ-a, CA). We have previously shown that the antibodies
provided by the kits react very well with hamsters' pancreatic endocrine
cells (12). Control slides were prepared similarly but either without
treatment with primary antibody or after absorption of antibodies with
the relevant hormones.
Histological Examination. Tissues were examined microscopically at
40 x magnification. In each section 10 islets at different, but assigned
areas (duodenal lobe, body, and tail of gastric lobe, body and tail of
splenic lobe) were evaluated for determination of the ratio of a:ß:o
cells
by counting the cells stained with the given antibody and cells which
were unstained. The average value of 10 islets was then considered as
the representative value for those specimens.
For determination of the number of each endocrine cell type (Ins,
Glu, and Som) in each specimen, the following rule was used: an islet
containing a particular endocrine cell was considered as 1 point, re
gardless of the number of the given endocrine cell in that islet. In
extrainsular tissue, however, each type of endocrine cell (scattered
between the exocrine cells) was counted as a point. For example, if in
one microscopic field an islet contained 12 Glu cells (considered as 1
point only), one duct had 1 Glu cell (I point) and two ductules 2 Glu
cells (2 points), a total of 4 points was given. Endocrine cells occurring
within carcinomas were not counted, since their numbers were usually
very high. This type of evaluation was used because in carcinogentreated hamster the number of endocrine cells was increased in the
extrainsular tissue with no changes in the islets. A collection of five
cells or less were regarded as extrainsular islet cells. For that reason
other methods, such as linear scan could not be used. The ratio of a, 0,
and ócells was calculated from counting each cell population in the
appropriate sections of each pancreas by the above method; it does not
refer to the cell ratios within the islet. For evaluation of each cell type,
sections from the entire pancreas were used and evaluated twice and
the mean of two values was regarded as representative.
Statistical Analysis. A Kruskal-Wallis nonparametric rank test was
used to determine significant differences between the groups.
-
~
.7
RESULTS
Experiment 1: Pattern of Endocrine Cells during Pancreatic
Carcinogenesis. Focal or multifocal hyperplasia and hypertro
phy of ductal and ductular epithelium were seen as early as 12
weeks posttreatment in all BOP-treated hamsters, and one of
the three hamsters had a microscopic noninvasive cancer. At
33 weeks, in one out of three hamsters, there was an invasive
adenocarcinoma which had metastasized into the liver. In ad
dition, there were numerous hyperplastic and dysplastic ducts/
ductules in all BOP-treated hamsters, an intraductal carcinoma
and a ductular carcinoma /// situ in one, and an invasive ade
nocarcinoma with métastasesinto the liver in another hamster.
Partial ductal occlusion due to hyperplastic changes with small
areas of atrophy were found in a few hamsters, and there was
no correlation between the atrophie changes and the number of
endocrine cells.
The number (points) of individual endocrine cells at 12 and
33 weeks are listed in Table 1. There were no changes in the
distribution and number of endocrine cells in islets between
treated and untreated hamsters. However, the number of extrainsular cells were increased in BOP-treated hamsters. The
ratio of ß:acells remained stable (0.7-0.9) at each interval,
Fig. 1. Hyperplastic ducts and ductules in the early stages of pancreatic
carcinogenesis in the Syrian hamster. The black-stained cells populating the
ducts/ductules are Glu cells, some of which seem to reach the ductal lumen by a
narrow neck. Note that in some ducts. Glu cells comprise about 50% of the cell
population. Peroxidase-antiperoxidase (PAP) with anti-Glu serum (200 x).
whereas the ratio of ß:osharply decreased at 33 weeks. The
same was true for the a:<5ratio. An increased number of all
three cell types were found in extrainsular tissue of treated
hamsters at both intervals. At 12 weeks the number of Ins and
Glu cells was greater than that of Som cells, whereas at 33
weeks, a dramatic increase of Som cells was found. The increase
in the number of endocrine cells was mainly due to the appear
ance of single or a small group of immunoreactive cells within
the hyperplastic ductal/ductular epithelium. At 33 weeks most
hyperplastic lesions contained a large number of endocrine cells,
particularly Ãćells, which in some areas constituted about 50%
of ductular cell population (Figs. 1-3). The great individual
differences in the number of endocrine cells, particularly at 33
weeks, was due to differences in the number of induced lesions
in each animal. In fact, the appearance of endocrine cells seemed
to be directly proportional to the number of changes found.
6397
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ENDOCRINE CELLS DURING PANCREATIC CARCINOGENESIS
-.
*»f
v
'»
»-»>
.v
Fig. 2. Numerous cells imrnunoreactive with anti-Som populating hyperplastic
common duct and the adjacent pancreatic ducts (black areas). Note the slender
shape of many of the stained cells, many or which reach the lumen by a narrow
cytoplasm (PAP. 200 K).
Fig. 3. Métastasesof a pancreatic adenocarcinoma into the liver. Note pres
ence of material imrnunoreactive with anti-Som in goblet-like cells (black areas)
(PAP, 200 x). Inseî,
high powered view of amphicrine cells which seem to contain
both mucin and material ¡mmunoreactivewith anti-Som (PAP, 400 x).
The increase in the number of Ins and Glu cells seems to be a
marker for the early event, whereas appearance of Som cells
reflected a more advanced stage of tumor development.
Although most endocrine cells were found at the base of
ductal/ductular epithelium, many of them reached the lumen
by tiny cytoplasmic portions (Figs. 1 and 2). In one of the three
cases examined at 33 weeks, over 30% of the cells populating
ductules and numerous cells along the entire length of hyperplastic common duct epithelium were comprised of Som cells
(Fig. 2).
In one hamster with a large invasive adenocarcinoma a re
markably large number of Som cells were identified intermin
gled with goblet cells. These cells were also found in the
metastatic foci of this cancer into the liver (Fig. 3). In this case
many 5 cells seemed to have both mucin and endocrine granules
(Fig. 3). There were also numerous endocrine-like cells which
were either faintly stained or unstained and seemed to present
immature endocrine cells.
Unlike Som cells, Ins or Glu cells were not found in either
the common duct epithelium or the intestine. Som cells were
detected in various numbers scattered throughout the duodenal
mucosa. However, their numbers did not differ between the
treated and control hamsters.
Experiment 2: Hormones in the Serum and Pancreatic Juice.
In this experiment, plasma and pancreatic juice levels of Ins,
Glu, and Som were examined every 4 weeks after the conclusion
of BOP treatment. Because BOP-treated hamsters develop pan
creatic atrophy and duct occlusion, it was only possible to
collect pancreatic juice during the early stages of carcinogenesis
4, 8, and 12 weeks after BOP treatment. Subsequently, the
volume of pancreatic juice fell to unusable levels. Even in the
early stages of carcinogenesis, a sufficient volume of pancreatic
juice could be obtained only to measure Ins and Glu.
Histologically, as in Experiment 1, proliferation of ductal/
ductular cells was found as early as 4 weeks in a few hamsters,
but was more frequent at 8 weeks and was pronounced at 12
weeks. At 8 weeks hyperplastic ducts and ductules occurred in
most hamsters and at 12 weeks all hamsters had hyperplastic
lesions and three had ductular carcinoma in situ. We did not
evaluate the number of each endocrine cell type because surgery
and treatment with secretin-CCK are known to stimulate their
secretion and hence could have masked their real numbers and
patterns.
Table 2 summarizes the levels of hormones found in the
plasma and pancreatic juice of BOP-treated and untreated
hamsters.
Plasma levels of Ins, Glu, and Som did not change signifi
cantly with age in control animals. In BOP-treated animals,
there was a significant decrease in plasma insulin levels at 12
weeks when compared to its levels at 4 weeks (P < 0.01) while
at the same time the pancreatic juice levels of Ins increased
twofold. The difference in the levels of Ins in the pancreatic
juice was, however, not significant. Plasma Glu and Som levels
did not differ significantly between control and BOP-treated
animals. In pancreatic juice in both BOP-treated and control
groups, there were high levels of reactivity to anti-Glu, and this
reactivity was significantly greater in BOP-treated animals.
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ENDOCRINE CELLS DURING PANCREATIC CARCINOGENESIS
Table 2 Pancreatic
nil)Weeks"BOP-treated
hormone concentration
in pancreatic
juice and/or
serum during pancreatic
Insulin l»I
carcinogenesis
(ng/ml)Plasma0.525
(pg/ml)Plasma47
size*17-188-1112-1811-12116-7Plasma5.95
hamsters4812Control
\.<)f}d2.68
±
1.404.98
±
2.058.07
±
1.675.89
±
±2.512.51
1.96''6.60
±
0.0740.363
±
0.0940.462
±
0.0740.407
±
6.035.3
±
8.839.0
±
6.912.0
±
±534
Ie49±
560±
hamsters4812Sample
2.404.49
±
1.672.47
±
0.0900.391
±
±7.518.3
±653
±6'52
7.514.9
+
2.513.96
±
1.744.44
±
0.0940.234
±
±3.15Juicec4.55
±2.19Glucagon
±0.127Juicec24.7
±9.4Somatostatin ±9
" After BOP treatment.
* Number of animals from which both pancreatic juice and serum could be collected.
c Values were corrected for protein concentration; data are give in mean ±SD.
"P<0.01.
' P < 0.04. Comparison was made between the values with the same superscript letters (i.e., a with a. b with b).
DISCUSSION
Confirming our previous study (11-14), proliferation of en
docrine cells was found during pancreatic carcinogenesis in
hamsters treated with BOP. The presence of the endocrine
cells, even within the metastatic foci of pancreatic ductal type
carcinomas seen in this study, as well as in human cases (28),
clearly indicates that the endocrine cells are an integral part of
exocrine pancreatic tumors. An association between prolifera
tion of exocrine and endocrine cells during pancreatic cancer
development, imitating embryonic development of pancreatic
tissue, is not surprising as both cells have a common precursor
(11-14, 29-41). The occasional occurrence of hybrid (amphicrine) cells (endocrine-mucin producing cells), observed also in
some human tumors (42, 43), clearly confirms this issue and
also explains the presence of endocrine hormones in the pan
creatic juice.
We and others (15-21) have identified pancreatic endocrine
hormones in pancreatic juice and have assumed that the exo
crine secretion of the hormones is due to a direct access of the
hormones to ductal lumen (21). The present study confirms
this view. The increase in Ins in pancreatic juice of BOP-treated
hamsters could well be the result of proliferation of Ins cells in
the ductal epithelium. On the other hand, the decrease in
plasma Ins, which has been noted previously (44), may relate
to a relative shift in a fixed rate of Ins secretion from blood to
juice. Based on control data, the decrease in the plasma Ins
level in BOP-treated hamsters could have been an aging phe
nomenon and unrelated to carcinogenesis. However, the drop
in the control group was gradual and insignificant. We did not
measure the blood glucose levels in these hamsters to see
whether a correlation exists between the blood Ins and glucose
concentrations. A study by Rogers et al. (44) did not show any
alteration of blood glucose levels despite a significant decrease
of Ins levels during pancreatic carcinogenesis in this model.
Possibly, development of hyperglycemia requires a greater de
crease in Ins levels. Further studies are required for classifica
tion.
The assay of Glu in pancreatic juice revealed large amounts
of reactivity to anti-Glu, which is probably an artifact from
nonspecific interference in the radioimmunoassay (16). Never
theless, the data in Table 2 clearly show that whatever sub
stances in the juice cross-react with anti-Glu used, their concen
trations are considerably higher in BOP-treated hamsters than
in controls. Identification of these substances requires further
studies.
Som levels could not be examined in the pancreatic juice due
to the limited amount of the material obtained. Clearly, addi
tional experiments with improved methodology to detect hor
mone concentrations are needed. Examination of Som in pan
creatic juice would be more useful than its level in plasma,
because the latter is of extrapancreatic origin and may not
reflect its pancreatic origin and because juice levels of Som have
been noted to rise in conditions associated with hyperplasia of
Som cells (17).
Proliferation of endocrine cells with that of exocrine cells is
not unique to hamsters and has been observed by us4 and by
others (29-42) in over 80% of human pancreatic cancer speci
mens. We do not yet know whether endocrine cell proliferation
in humans is associated with hormonal hypersécrétion
because
of the lack of relevant clinical data. However, since over 80%
of pancreatic cancer patients generally develop diabetes or
hyperglycemia (45-52), it is possible that the situation in hu
mans is similar to our experimental results, i.e., an altered
serum hormone level during pancreatic carcinogenesis.
It must be pointed out that in the hamster model, endocrine
cell proliferation appears to be prevalent during the early stages
of cancer development and less prominent at advanced stages,
possibly due to increasing dedifferentiation in growing tumors.
The same appears to apply to the human situation. In one study
(35) a higher incidence of endocrine cells was found in welldifferentiated adenocarcinomas of the pancreas (82%) than in
moderately differentiated (39%) and in undifferentiated types
(18%). Therefore, the biological activity of endocrine cell pro
liferation may be clinically detectable at early stages of carci
nogenesis and the correlation between the degree of tumor
differentiation and presence of endocrine cells as tumor cell
components may have prognostic value.
Further studies are necessary to further delineate the present
findings, especially in view of the existing confusion relative to
the relationship between diabetes and pancreas cancer.
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Downloaded from cancerres.aacrjournals.org on June 17, 2017. © 1989 American Association for Cancer Research.
Alteration of Pancreatic Endocrine Cell Patterns and Their
Secretion during Pancreatic Carcinogenesis in the Hamster
Model
Parviz M. Pour and Richard H. Bell
Cancer Res 1989;49:6396-6400.
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