Atypical Acinar Cell Foci Research Articles

Possible inhibition effects of resveratrol on pancreatic tumorigenesis in the azaserine-rat model.

Resveratrol, which is thought to have a preventive effect on the formation of different types of cancer, is abundant in grapes and other foods. Resveratrol has been shown to have anti-cancer effects by in vitro andin vivo studies, however this is the first time its effect on atypical acinar cell foci (AACF), known as precursor forms of pancreatic carcinoma, has been experimentally investigated. Male Sprague Dawley rats, each consisting of 5 experimental groups (Cont, AzCont, AzRes10, AzRes15, and AzRes20), 10 of which were 14 days old, were used in the study. In the azaserine groups (AzCont, AzRes10, AzRes15, and AzRes20), it was investigated how the development of Atypical Cell Foci (AACF) resulting from intraperitoneal injection (i.p.) of azaserine (30 mg/kg bw) in 14-day-old rats was affected by dietary restoration. Male rats in the resveratrol group (AzRes10, AzRes15, and AzRes20) were fed diets containing 10%, 15%, or 20% mmol resveratrol for an 8-month experimental period 1 week after the last azaserine injection. Pancreas preparations prepared from histological sections were examined for AACF burden and analyzed via a video image analyzer. One-way analysis of variance (ANOVA) non-parametric statistical analyses were performed to test whether there was a difference between the averages of the experimental and control groups. The AACF load in the azaserine group (AzCont) compared to the control group (Cont) was found to be statistically significant in all categories (p < 0.05). The calculated estimated mean AACF volume (mm3) values and the AACF ratio as a percentage of the calculated organ volume were statistically significantly lower in all resveratrol groups (AzRes10, AzRes15, and AzRes20) compared to the azaserine control group (AzCont). The calculated estimated mean AACF volume (mm3) values and the AACF ratio as a percentage of the calculated organ volume were statistically significantly lower in all resveratrol groups (AzRes10, AzRes15, and AzRes20) compared to the azaserine control group (AzCont) (p < 0.05). In addition, the calculated estimated mean AACF diameter (mm) in the AzRes10 and AzRes15 groups, in the AzRes15 group the calculated estimated mean AACF number in the whole organ and the calculated average AACF number per unit area were found to be statistically significant compared to the azaserine control group (AzCont) (p < 0.05). According to the results of our study, it has been shown that atypical acinar cell foci (AACF) formed in the exocrine pancreas of rats with azaserine can be reduced by a diet containing resveratrol. It was determined that the tumor burden decreased statistically significantly (p ≤ 0.05) in resveratrol-treated rats. Accordingly, it is thought that the inhibitory effects of resveratrol may contribute to studies that reduce the occurrence of pancreatic cancer.

Inhibition Effects of Acetylsalicylic Acid with Nitric Oxide (NO-ASA) on Neoplastic Changes in the Exocrine Pancreas Acinar Cells of the Azaserine Injected Rats.

Atypical acinar cell foci (AACF) seen in pancreatic cancer are fatal and have been studied with some causative agents. However, for the first time, the effect of acetylsalicylic acid with nitric oxide (NO-ASA) on AACF was examined in this study. Although NO-ASA has very successful inhibitory effects against some types of cancer, it has not been investigated whether they can exert their inhibition effects on AACFs. For experimental purposes, 21 14-day-old male Wistar albino rats were used. Azaserine (30 mg/kg) was dissolved in 0.9% NaCl solution and injected intraperitoneally (i.p.) into 14 rats, except for the Control group (Cont) rats, for three weeks. Rats that were injected with azaserine once a week for three weeks and those that did not receive treatment were divided into experimental groups. 15 days after the end of the azaserine injection protocol, NO-ASA was applied to azaserine with NO-ASA (Az+NO-ASA) group rats three consecutive times with an interval of 15 days by gavage. At the end of the 5-month period, pancreatic tissue was dissected and weighed. Pancreas preparations prepared from histological sections were examined for AACF burden and analyzed via a video image analyzer. One-way analysis of variance (ANOVA) non-parametric statistical analyses were performed to test whether there was a difference between the averages of the experimental and Control groups. AACF burden in both groups injected with azaserine was found to be statistically significant in all categories compared to that of the Control group (p < 0.05). The average Calculated Estimated average AACF volume (mm3) values, the Calculated estimated average AACF diameter (μm), the Estimated average number of AACF per unit volume, AACF rate as a % of Calculated Organ Volume were higher in the AzCont group rats than in the Az+NO-ASA group, when compared, and there was an important level statistical difference between the groups (p < 0.05). It was determined that for all parameters AACFs load in Az+NO-ASA group rats were significantly reduced compared to that of AzCont group rats (p < 0.05). We observed that, as a result of the NO-ASA application, the experimental AACF focus ratio created by azaserine injection was significantly inhibited. The inhibitory effect of AACFs in Az+NO-ASA group rats may have resulted from the significant and independent chemopreventive and/or chemotherapeutic activity of NO-ASA against exocrine pancreatic AACF foci.

Can Echinococcus Granulosus Infestation Prevent Pancreatic Cancer? An invivo Experimental Study.

Hydatid cyst is a zoonotic infestation caused by Echinococcus granulosus, and it is known that some parasites found in humans cause cancer in humans or some may have a protective effect against cancer. Cancer is one of the most serious health problems of today and it has been shown in some studies that parasites such as Echinococcus granulosus can have an inhibitory effect. The aim of this study was determined as whether Echinococcus granulosus has an inhibitory effect on exocrine pancreatic cancer with the help of the azaserine-rat model used in different cancer studies. Material and Methods: During experimental process a total of 45 male Wistar rats used, 14-day-old male Wistar rats were divided into groups according to the experimental protocol, administered azaserine injection protocol or kept as a control group without azaserine injection. Animals are grouped as Group 1, Control Group (group not treated with Azaserine and not injected with protoscolex.) (E-A-) (n=7); Group 2, Group injected with (IP) Azaserine only (30mg/kg) (E-A+) (n=8);Group 3, Group injected (IP) with protoscolex suspension of 1 cc only (E+A-) (n=15);Group 4, Group injected both Azaserine (IP) and protoscolex suspension (IP) (E+A+) (n=15). Atypical Acinar Cell Foci (AACF) load in the exocrine pancreas of each rat was measured quantitatively with the help of a video image analyzer and the AACF load was calculated with the help of a mathematical model. Results: Findings showed that the Atypical Acinar Cell Foci (AACF) burden was statistically significantly lower in the Azaserine+ protoscolex (Azaserine-injected-protoscolex-implanted) rat group compared to the other groups, suggesting that Echinococcosis in the azaserine-rat model could inhibit the development of precursor foci of neoplastic changes in the exocrine pancreas. Conclusion: The most significant aspect of our study is that it contributes new insights into the controversy that Echinococcosis suppresses pancreatic cancer.

Inhibitory effects of acetylsalicylic acid on exocrine pancreatic carcinogenesis

We investigated short (6 months) and long (12 months) term inhibitory effects of low (200 ppm) and high (400 ppm) dosages of acetylsalicylic acid (aspirin) on exocrine pancreatic carcinogenesis. It is known that exocrine pancreatic carcinogenesis can be detected by the presence of atypical acinar cell foci (AACF) in pancreas. We investigated possible inhibitory effects of acetylsalicylic acid in an azaserine-treated rat model. AACF were produced in rats by injection with azaserine according to previous studies. Our findings showed that the number, volume and diameter of pancreatic AACF were reduced after acetylsalicylic acid application. These observations suggest that acetylsalicylic acid may exert a protective effect against neoplastic development of pancreatic acinar cells in azaserine injected rats. Our findings corroborate reports in the literature concerning the effects of aspirin in reducing neoplastic development.

Possible neoplastic effects of acrylamide on rat exocrine pancreas

We investigated whether the acrylamide formed during cooking carbohydrate-rich foods at high temperatures causes neoplastic changes in rat pancreas. Azaserine, which is an amino acid derivative that has the ability to initiate neoplastic changes in rat pancreas, was injected into 14-day-old male rats once a week for three weeks. Acrylamide was given to both azaserine-injected and non-injected rats at doses of 5 and 10 mg/kg/day in drinking water for 16 weeks after which tissue slides were prepared from the pancreata. Pancreas weights and body weights of rats treated with azaserine and acrylamide together increased significantly compared to the other groups. Moreover, the size, average diameter and volume of atypical acinar cell foci that developed in the pancreata of rats treated with azaserine and acrylamide together increased significantly compared to rats treated with either azaserine or acrylamide alone and control groups. Atypical acinar cell adenoma or adenocarcinoma was not observed in the pancreata of rats in any group.

Duodenogastric reflux enhances growth and carcinogenesis in the rat pancreas.

Surgery for peptic ulcer disease may increase the risk of pancreatic cancer. The effect of duodenogastric reflux on pancreatic carcinogenesis was tested, and changes in the circulating levels of cholecystokinin (CCK) and gastrin were measured. Male Wistar rats (n = 40) weighing 250-300 g were randomized to undergo gastrotomy (control) or split gastrojejunostomy (to produce complete duodenogastric reflux) and then to receive azaserine (30 mg/kg/week intraperitoneally) or saline injections for 3 weeks. At 6 months, blood CCK was assayed and the pancreas was excised for quantitative estimation of atypical acinar cell foci (AACF), the precursor lesions of carcinoma. Rats that had undergone split gastrojejunostomy weighed 15-19 per cent less than controls (P < 0.05), but their relative pancreatic weight (mg pancreas per 100 g body-weight) was 52-60 per cent greater (P < 0.001). Acidophilic AACF occurred only in azaserine-treated rats with duodenogastric reflux. Although plasma CCK concentrations were unchanged, split gastrojejunostomy increased basal and postprandial gastrin levels by 98-175 per cent (P < 0.05). Duodenogastric reflux produces sustained hypergastrinaemia and promotes experimental pancreatic carcinogenesis.

Effects of a Diet High in Fish Oil (MaxEPA) on the Formation of Micronucleated Erythrocytes in Blood and on the Numberof Atypical Acinar Cell Foci Induced in Rat Pancreas by Azaserine

The present study was performed to investigate the influence of fish oil on the genotoxic effects of azaserine, using the formation of micronucleated erythrocytes as a measure for the degree of initiating potency and the number and size of putative preneoplastic pancreatic atypical acinar cell foci (AACF) as a measure for the actual number of initiated cells. Male Wistar rats were treated twice i.p. with 30 mg azaserine per kg body weight to induce AACF. During the initiation/early promotion phase the rats were maintained on diets containing 5 wt% vegetable oil (safflower and high-oleic sunflower oil), 25 wt% vegetable oil, 25 wt% fat (15% vegetable oil + 10 wt% fish oil), or 25 wt% fat (5% vegetable oil + 20 wt% fish oil), respectively. One day after carcinogen treatment, the numbers of micronucleated polychromatic erythrocytes were determined in blood smears obtained from 10 animals per group. Each high-fat diet resulted in higher percentages of micronucleated polychromatic erythrocytes than the low-fat diet. Dietary fish oil did not significantly influence the number of micronucleated cells. Two weeks after carcinogen treatment, the diets containing fish oil were replaced by the diet containing 25% vegetable oil, and the animals were further maintained for about 14 wk. Pancreatic tissue slides were microscopically evaluated for the number and size of AACF. Dietary fish oil caused an increase in the number and size of AACF, although a clear dose-effect relationship was absent. It was concluded that a high level of dietary fish oil, when given during the induction/early promotion phase, enhances azaserine-induced pancreatic carcinogenesis in rats.

Effect of hypergastrinemia on pancreatic carcinogenesis

Background: Previous studies in our laboratory demonstrated that pancreatic carcinomas in rodents express receptors for the peptide hormone gastrin that are not present in normal adult pancreas. In view of an abundant literature suggesting that gastrin may promote growth of various gastrointestinal tissues and tumors, the effect of hypergastrinemia on the process of pancreatic carcinogenesis was evaluated. Methods: Rats received subcutaneous injections of the pancreatic carcinogen azaserine at 19 and 26 days of age. Starting at 12 months of age, animals were randomized to treatment with the proton pump inhibitor lansoprazole or vehicle by gavage for 6 months. At autopsy, pancreatic wet weight normalized to body weight was recorded, as well as the number of benign and malignant pancreatic lesions. Results: Serum gastrin levels were determined by radioimmunoassay and showed a greater than two-fold increase in lansoprazole-treated animals. Pancreatic wet weight in hypergastrinemic rats was increased compared to controls (p <0.05). Premalignant lesions such as acidophilic atypical acinar cell foci, adenomas, heterogeneous phenotypic populations of nodules within nodules, and carcinoma-in-situ were not increased in the hypergastrinemic group. Likewise, there was no difference in the incidence of invasive carcinoma in hypergastrinemic animals (10%) compared to controls (5.7%). Conclusion: Hypergastrinemia stimulated an increase in pancreatic weight, but did not stimulate development of premalignant lesions or progression to cancer in the azaserine model of rat pancreatic acinar cell carcinoma.

Atypical acinar cell foci in human pancreas. Morphological and morphometric analysis.

The morphological and quantitative findings of the present study suggest that atypical acinar cell foci are not neoplastic in nature. Atypical acinar cell foci (AACF) are rare and unusual lesions in the human pancreas. The biological nature of AACF is poorly understood, and is not clear whether they represent neoplastic or degenerative changes in the acinar cells. To further characterize and understand the significance of AACF in relation to acinar cell tumor development, we have examined these lesions by light and electron microscopy and evaluated the growth pattern by measuring cell proliferation and the size of the foci in the pancreas of a 16-yr-old male. The pancreas was grossly unremarkable. AACF were randomly distributed throughout the pancreas, well delineated, and showed minimal variation in sizes. The constituent cells contained uniform nuclei, pale vacuolated cytoplasm, and exhibited low nuclear-cytoplasmic ratio. Electron microscopic examination showed a few zymogen granules and markedly dilated rough endoplasmic reticulum. Proliferative index in AACF (13%) was less than in adjacent uninvolved acinar tissue (19%). Quantitative stereological analysis showed the pancreas to contain approximately 1800 AACF/cm3 with a mean focal diameter of 360 microns.

Cell proliferation and apoptosis in the exocrine pancreas of azaserine-treated rats and N-nitrosobis(2-oxopropyl)amine-treated hamsters

Altered cell proliferation is an important characteristic of neoplastic development, hence the quantitation of cell growth in normal and (pre)neoplastic pancreatic tissue will provide useful information on the process (and modulation) of pancreatic tumour promotion in experimental animals. Cell proliferation was estimated by means of BrdU-incorporation in normal pancreatic tissue and in putative preneoplastic pancreatic tissue of azaserine-treated rats and of N-nitrosobis(2-oxopropyl)amine (BOP)-treated hamsters at 2, 6, 12, 26 and 52 weeks post-treatment. Furthermore, the effects of diets high in vegetable oil or fish oil on the BrdU labeling index, the Ki-67 labeling index as well as the apoptotic labeling index were determined in azaserine-induced atypical acinar cell foci (AACF) in the pancreas of rats. In saline- and azaserine-treated rats, the BrdU labeling index (LI) in normal pancreatic acinar cells showed a similar time-related decrease. In azaserine-treated rats, the BrdU-LI in AACF was significantly higher than in normal acinar tissue. The BrdU, Ki-67 and apoptotic labeling indices in pancreatic AACF of rats fed diets high in vegetable oil versus fish oil were 24.8+/-1.7 vs 15.5+/-1.2 (BrdU; P<0.05), 9.9+/-0.8 vs 6.5+/-0.5 (Ki-67; P<0.001) and 1.31+/-0.12 vs 0.97+/-0.11 (apoptosis; P<0.05), respectively. In hamsters, up to 26 weeks after BOP-treatment the BrdU-LI in acinar cells was significantly higher than in saline-treated animals. In BOP-treated hamsters, ductal cells showed a significantly increased LI 2 weeks post-treatment, whereas the LI in centroacinar cells had significantly increased 2 and 26 weeks post-treatment. In hamster pancreas the LI was significantly higher in tubular ductal complexes than in cystic ductal complexes and was highest in borderline lesions. It is concluded that (i) determination of BrdU-LI provides a reliable parameter to discriminate between putative preneoplastic lesions with a high or low growth potential, hence with a high or low potential to develop into ultimate carcinomas, (ii) BOP causes increased DNA synthesis in normal acinar cells, leading to increased risk of additional DNA damage, implicating the acinar cell to be putatively involved in the development of ductular adenocarcinomas in the hamster pancreas and (iii) quantitation of cell proliferation and apoptosis may be useful to determine the enhancing or inhibitory effects of life-style factors on pancreatic carcinogenesis.

Characterization of a Transitional Type of Pancreatic Atypical Acinar Cell Foci (AACF) Induced by Azaserine in Rats

Multiple and single intraperationeal injection of azaserine in male Leeds rats induced atypical acinar cell foci. These foci were classified histologically into two population, basophilic and acidophilic. The earliest observed microscopic lesions display morpholic characteristics of acinar cells which they apparently arise. It has been reported that the existence of two phenotypically different populations of atypical acinar cell foci with differing proliferative capicities in pancreases of rats. 0nly a small fraction of these lesions appear to have the potential to into neoplasms. Several question concerning these two pupulation of foci are still unknown, what is the relation if any between acidopophilic and basophilic foci. In previous studies it has been speculated that basophilic foci may be capable of progression to acidophilic foci and these foci may be involved in the induction of pancreatic cancer. In this study one unusual atypical acinar cell focus was observed that could represent a transitional type of atypical acinar cell foci (AACF).

Effects of dietary beta-carotene and selenium on initiation and promotion of pancreatic carcinogenesis in azaserine-treated rats.

In the present study the effects of 0.1 or 1.0 g beta-carotene/kg diet (L beta C or H beta C) and 1.0 mg or 2.5 mg selenium/kg diet (LSel or HSel), as well as combinations of the respective low and high concentrations of beta-carotene and selenium (LMix or HMix) on the initiation/early promotion phase or on the late promotion phase of pancreatic carcinogenesis in azaserine-treated rats, were investigated using cell proliferation and volumetric data of atypical acinar cell foci (AACF) as parameters. The present results indicate chemopreventive effects of dietary selenium, dietary beta-carotene and of their combination on the development of acinar pancreatic lesions induced in rats by azaserine. The inhibitory effect was most pronounced when beta-carotene and/or selenium were added to the diets during the late promotion phase of the carcinogenic process, although inhibition was also observed with these compounds when they were added to the diets during the first 5 weeks of the study only (initiation/early promotion phase). Neither in the initiation/early promotion phase nor in the late promotion phase was a dose-related trend observed. The multiplicities of AACF with a diameter over 1.0 mm and of carcinomas in situ (CIS), as well as the incidence of CIS were not significantly different among the groups. However, in the late promotion experiment a dose-related decline in multiplicity could be observed in the selenium supplemented groups and in the groups receiving combinations of beta-carotene and selenium. Cell proliferation in azaserine-induced AACF, as estimated by the bromodeoxyuridine (BrdU) labeling index, was significantly higher in H beta C, HSel, LMix and HMix groups (initiation/early promotion phase) as well as in H beta C, LSel, HSel, LMix and HMix groups (late promotion phase) than in high fat controls. From the present results it can be concluded that: (i) beta-carotene and selenium have inhibitory effects on pancreatic carcinogenesis induced in rats by azaserine; (ii) the most clear effects were observed when selenium was given as such, or in combination with beta-carotene during the late promotion phase; and (iii) beta-carotene and selenium stimulate cell proliferation in AACF.

Pancreatic hypertrophy with acinar cell nodules after longterm fundectomy in the rat.

The effect of gastric fundectomy with hypergastrinaemia on the pancreas in rats was studied for 14 months. Rats with hypercholecystokininaemia that had had a pancreaticobiliary diversion (PBD) operation and sham operated rats served as controls. Fundectomised rats showed a significant increase in pancreatic weight and total DNA and protein content compared with sham operated rats. DNA flow cytometry showed a significantly higher ratio of tetraploid to diploid nuclei in pancreatic tissue after fundectomy than after sham operation. Mean values of all these variables were significantly lower after fundectomy than after PBD. Acidophilic atypical acinar cell foci of the pancreas were diagnosed in both fundectomised and PBD operated rats, but not in sham operated controls. The volume density and 3H-thymidine labelling index of the acidophilic atypical acinar cell foci were significantly lower after fundectomy than after PBD. Changes consistent with pancreatic adenoma were diagnosed in the PBD group only. In conclusion, fundectomy lasting about half of the life span in rats causes pancreatic hyperplasia and hypertrophy, as well as development of acidophilic atypical acinar cell foci. Although hypergastrinaemia is a prominent feature, it may not be the only factor responsible for this pancreaticotrophical effect of fundectomy.

Effects of pancreaticobiliary diversion and gastric fundectomy on azaserine-induced pancreatic carcinogenesis in the rat.

The effects of pancreaticobiliary diversion (PBD) and gastric fundectomy on the pancreas in azaserine-treated rats were studied over 14 months. Sham-operated azaserine-treated animals served as controls. A significant increase in pancreatic weight and total DNA and protein content was found in PBD-operated and fundectomized animals. DNA flow cytometry showed a significantly increased ratio of tetraploid to diploid cells in pancreatic tissue in both experimental groups. Mean values of all these variables were significantly higher after PBD than after fundectomy. Acidophilic atypical acinar cell foci of the pancreas were observed in all of the experimental and 75% of the control animals. The volume density of these foci was significantly higher in each experimental group than in the controls. The volume density, radioactive thymidine labeling index, and mitotic index of the foci were significantly higher after PBD than after fundectomy. Changes consistent with pancreatic adenoma were diagnosed in the PBD group only. It is concluded that not only PBD with endogenous hypercholecystokininemia, but also fundectomy with endogenous hypergastrinemia lasting about half of the life span in rats, induces pancreatic hypertrophy and enhances the development of precancerous pancreatic changes after azaserine treatment. In comparison with PBD, fundectomy caused less pronounced changes and no observable neoplasia.

Inhibitory effect of a cholecystokinin antagonist on pancreatic carcinogenesis after pancreatobiliary diversion

The role of cholecystokinin (CCK) has been explored in pancreatic carcinogenesis following pancreatobiliary diversion (PBD), using the specific CCK receptor antagonist CR-1409. Male Wistar rats (n = 80) weighing 70-100 g were given weekly i.p. injections of azaserine (30 mg kg-1 week-1) for 3 consecutive weeks. One week later animals were randomised to receive either PBD or sham PBD and thereafter to receive s.c. injections of either saline or CR-1409 (10 mg kg-1 day-1, 5 days a week). Six months after operation surviving rats were killed as follows: sham + saline 20, PBD + saline 19, sham + CR-1409 14, PBD + CR-1409 11. Cardiac blood was taken for CCK assay and the pancreas was excised for wet weight measurement and quantitative estimation of atypical acinar cell foci (AACF), the precursor of carcinoma. PBD reduced median body weight (3-20% less than shams) but trebled the absolute and relative pancreatic weights (P < 0.001). CR-1409 blunted this adaptive response to PBD, reducing absolute pancreatic weight by 35% (P < 0.005). PBD quadrupled circulating CCK concentrations, regardless of the antagonist treatment. Acidophilic AACF occurred only in rats with PBD. CR-1409 markedly reduced the number of observed acidophilic AACF by 90% (P < 0.001) and the number of foci per pancreas by 93% (P < 0.001). Moreover, CR-1409 reduced the mean focal diameter of each lesion by 18% (P < 0.005), the mean focal volume by 58% (P < 0.05) and the percentage of pancreas occupied by acidophilic foci by 95% (P < 0.001). PBD enhances pancreatic carcinogenesis by causing hypercholecystokininaemia, and CR-1409 largely inhibits this enhancement.

Azaserine-induced pancreatic foci: detection, growth, labelling index and response to raw soya flour.

Atypical acinar cell foci were induced in the pancreases of rats by injection of azaserine. An incubation period of 6 weeks was sufficient for the detection of all glutathione S-transferase mu positive foci. In chow-fed rats, the labelling index of foci was 12-fold higher than normal pancreatic tissue. Feeding rats raw soya flour (RSF) for up to 20 weeks did not increase the number of foci per pancreas but did produce significant increases in labelling index and growth rate. In normal pancreatic tissue, the trophic response was complete after 4 weeks of RSF feeding. In foci, however, the trophic response to RSF was prolonged. Involution of normal pancreatic tissue was seen in rats fed RSF for 19 weeks and then switched to chow 1 week prior to death. No evidence for involution was seen in the foci of these animals, although a 40-fold reduction was seen in labelling index. The labelling index of these foci was reduced to the level seen in normal tissue of chow-fed rats. These results are consistent with increased cholecystokinin (CCK) responsiveness and CCK dependence in azaserine-induced pancreatic foci.

Early indicators of exocrine pancreas carcinogenesis produced by non-genotoxic agents

In the past 40 years the incidence of pancreatic cancer in many Western countries has increased. Since no single factor responsible for the development of pancreatic cancer has been identified, it is believed that non-genotoxic factors may play an important role in the pathogenesis of this highly fatal form of cancer. Focal abnormalities of acinar cells, referred to as atypical acinar cell foci or nodules, occur spontaneously in rats and some of other species. Their incidence increases with age from zerom at birth to about 75% in 2-year-old rats. These spontaneous lesions have a phenotype that cannot be distinguished from the putative, atypical preneoplastic, acinar cell foci induced in rat pancreas by the carcinogen azaserine. Unsaturated fat (corn oil) has been foun to increase the incidence of atypical acinar cell nodules and adenomas in the pancreas of non-carcinogen-treated rats without influencing the weight of the pancreas. Furthermore, unsaturated fat has a specific promoting effect on the growth potential of atypical acinar cell foci and nodules induced in rat pancreas by azaserine, resulting in an increase in the number and size of these lesions. Rats fed raw soya flour or trypsin inhibitors developed an enlarged pancreas as a result of hypertrophy and hyperplasia. They also develop acidophilic atypical acinar cell foci and nodules, adenomas and adenocarcinomas after being fed full-fat raw soya flour for 2 years. It may be concluded from the observations in rat pancreas that non-genotoxic compounds or condions that enhance pancreatic growth may be classified as non-genotoxic pancreatic tumour promoters. The oservations with corn oil, however, indicate that there may be non-genotoxic compounds that specifically enhance growth of spontaneous initiated atypical cell foci without causing hyperplasia of the pancreas. The possible mechanisms whereby unsaturated fat and trypsin exert their effects on exocrine pancreatic carcinogenesis are discussed.

Pancreatobiliary diversion enhances experimental pancreatic carcinogenesis

Since compensatory hyperplasia promotes experimental carcinogenesis in the gut, we tested the ability of two surgical models of pancreatic growth to promote pancreatic carcinogenesis. Male Wistar rats (n = 60) weighing 250-300 g underwent pancreatobiliary diversion (PBD), 90% small bowel resection (PSBR) or triple transection and reanastomosis of the small intestine (controls). Postoperatively, each group received azaserine (20 mg kg-1 wk-1 i.p.) for 6 weeks. Surviving rats were killed at 6 months, pancreatic wet weight was measured and histological sections were examined for atypical acinar cell foci (AACF), the putative precursor of carcinoma. Median relative pancreatic weight (mg pancreas/g body weight) was 2.20 for controls (n = 18), 4.08 for PSBR (n = 11) (P less than 0.001) and 6.86 for PBD (n = 16) (P less than 0.001). PSBR did not affect the development of acidophilic AACF, but PBD produced an enormous increase in their number per cm3 (median 96 vs. 0; P less than 0.001) and a 7-fold increase in their volume (P less than 0.001). Both operations cause pancreatic growth, but only PBD promotes carcinogenesis, possibly because of its unique hormonal effect.

Effects of dietary soya bean trypsin inhibitor concentrate on initiation and growth of putative preneoplastic lesions in the pancreas of the rat

Two studies evaluated the effects of soya bean trypsin inhibitor concentrate (STIC) on early stages of pancreatic carcinogenesis in Wistar rats. In experiment 1, the effects of a 3-month administration of diets containing 3.7% STIC were compared with the effects of administration of diets containing 20% corn oil, in rats pretreated with a single azaserine injection sufficient to initiate putative preneoplastic atypical acinar cell foci. Experiment 2 investigated the capacity of STIC to initiate pancreatic carcinogenesis. Diets containing 3.7% STIC were fed for 4 wk, then diets containing either 5 or 20% corn oil were fed for 3 months. Pancreases were quantitatively evaluated for foci. All groups of azaserine-initiated rats had large numbers of atypical acinar cell foci per cm 3 of pancreas. Of these, the group fed 3.7% STIC had pancreatic foci that occupied a significantly greater ( P < 0.01) percentage volume of pancreas than did groups fed 20% corn oil or control diets, which contained 5% corn oil and no added trypsin inhibitor. Very few or no foci were observed in all other groups of either experiment 1 or 2. STIC had a much greater effect on the growth of azaserine-induced lesions than did corn oil. STIC alone did not appear to initiate pancreatic lesions.

Cyclosporine Inhibition of Azaserine-Induced Atypical Acinar Cell Foci in Rat Pancreas

The effects of cyclosporine (CsA), an immunosuppressive agent, on azaserine-induced pancreatic carcinogenesis in rats were investigated using the short-term assays of the quantitation of atypical acinar cell foci. Male Lewis rats at 14 days of age were given a single intraperitoneal injection of azaserine (30 mg/kg). At 25 days of age, the treated rats were weaned and divided into two groups fed either basal diet or the same diet containing 0.011% CsA. Saline-injected rats were also fed the CsA diet. Rats were killed 4 months after azaserine injection and acidophilic and basophilic foci in the pancreas were quantified. The pancreas of the rats given saline injection and maintained on the CsA diet showed no significant histological alterations. The dietary CsA after the injection of azaserine markedly reduced the number of both acidophilic and basophilic foci. It is concluded that addition of CsA to the diet inhibits the growth of initiated cells to form foci in the pancreas of azaserine-treated rats. The experimental model is useful in analyzing the modifying role of this immunosuppressant in the induction and growth of epithelial cell tumors.