Immunohistochemical characterization of endocrine cells in experimental exocrine pancreatic cancer in the Syrian golden hamster.

Fifty exocrine pancreatic adenocarcinomas and 57 benign tumors induced in Syrian hamsters by N-nitrosobis(2-oxopropyl)amine (BOP) were examined for the presence of argyrophil cells antiinsulin, -glucagon, -somatostatin, -pancreatic polypeptide (PP), -gastrin/CCK, -vasoactive intestinal polypeptide (VIP), and - neuron-specific enolase (NSE) reactive cells. Argyrophil - and antihormone-reactive cells were found in the normal pancreatic ducts and in the acini, as well as in hyperplastic and atypical ducts/ductules, tubular complexes, benign lesions, and in 80% of ductal adenocarcinomas. Insulin and antiNSE-reactive cells were the most common, followed in decreasing frequency by glucagon, somatostatin, and PP cells. Antigastrin-/CCK-and -VIP-reactive cells were found in two cases. Argyrophil cells were present in about 60% of the tumors with Grimelius staining and in 55% of those with Churukian-Schenk staining. Insulin cells were seen in ductal cancer that had grown into a lymph node and in the lymph node metastases of another cancer. A novel finding was the presence of argyrophil and insulin cells within the lumen of some malignant glandular structures. Coexistence of several peptide cells was found in 52% of the cancers. The presence of argyrophil and hormone-producing cells in induced pancreatic ductal/ductular lesions further strengthens the existence of a close developmental relationship between exocrine and endocrine cells of the pancreas.     

Regulatory effects on the pancreas of intraduodenal pancreatic juice and trypsin in the Syrian golden hamster

The effect of intraduodenal trypsin activity on pancreatic exocrine secretion was studied in conscious Syrian golden hamsters provided with bile-pancreatic fistulae. The secretion (secretory volume, amylase and protein output) was stable during a collection period of 14 h without any duodenal infusions. Infusion into the duodenum of bicarbonate or bile did not affect the secretion. When, however, bile-pancreatic juice or trypsin was administered intraduodenally, a marked depression of amylase and protein output was found. After addition of trypsin inhibitor--in a dose sufficient to eliminate all trypsin activity--to either of the two infusates the secretion was restored to the initial values. In a long-term experiment (10 days) repeated subcutaneous injections of cholecystokinin caused a significant increase of pancreatic protein and amylase content in the hamster. Oral trypsin inhibitor administration for 10 days had similar, although not so pronounced effects. Subcutaneous secretin administration was without effect in this respect. The results show that pancreatic enzyme secretion in the Syrian golden hamster is controlled by a negative feedback regulation exerted by intraluminal trypsin. The findings also suggest that both cholecystokinin and orally administered trypsin inhibitor exert trophic effects on the pancreas.     

The effect of cellophane wrapping of the pancreas in the Syrian golden hamster: autoradiographic observations

We examined the effects of cellophane wrapping of the pancreas on the age-related uptake of tritiated thymidine (3H-TdR) by the differentiated cell types of the pancreas of the Syrian golden hamster. Fifty-two hamsters were studied. At 7 weeks of age, hamsters underwent cellophane wrapping (n = 32) or were allocated to a control group (n = 20). Animals 8-22 weeks of age (four at each interval) received 3H-TdR (2 microCi/g) intraperitoneally and were killed 1 h later. Pancreatic tissues from each animal was processed for autoradiography. The percent of acinar cells labeled with 3H-TdR at 8 weeks, in control and wrapped animals, was 1.17 +/- 0.26 and 1.51 +/- 0.38 respectively (p = N.S.). In control animals, this steadily diminished to 0.02 +/- 0.00 at 22 weeks. In wrapped animals, there was less of a tendency for acinar cell labeling to decrease with age, and the percent of labeled acinar cells in wrapped animals at 22 weeks was 0.05 +/- 0.00. The percent of ductular cells labeled with 3H-TdR at 8 weeks in control and wrapped animals was 0.24 +/- 0.24 and 0.98 +/- 0.24, respectively (p = N.S.), and at 22 weeks was 0.13 +/- 0.90 and 0.60 +/- 0.03, respectively (p less than 0.01). The percent of islet cells labeled with 3H-TdR at 8 weeks in control and wrapped animals was 0.16 +/- 0.01 and 0.42 +/- 0.01, respectively (p less than 0.05), and at 22 weeks was 0.18 +/- 0.01 and 0.63 +/- 0.05 (p less than 0.05), respectively.(ABSTRACT TRUNCATED AT 250 WORDS)     

Synergistic effect of ferric oxide on dimethylnitrosamine carcinogenesis in the Syrian golden hamster

Summary The carcinogenic effect of dimethylnitrosamine (DMN) injected subcutaneously in Syrian golden hamsters as well as the synergistic effect of intratracheal instillations of ferric oxide were studied. DMN alone induced cavernous hemangiomas, hemangioendotheliomas, hemangioendotheliosarcomas, as well as one hepatoma of the liver and one papilloma of the forestomach, but no tumors of the respiratory system. When ferric oxide was given in addition to DMN, liver tumors of vascular and biliary origin were seen, in addition to tumors of the nasal cavity, neuroepithelial tumors and one adenoma. It was concluded that subcutaneously injected DMN is a powerful hepatic carcinogen for the Syrian golden hamster, producing liver tumors of vascular, bile duct as well as liver cell origin. The lack of tumorigenic effect in the respiratory system was considered to be due to the lack of metabolism of DMN in the lung.

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Die synergistische Wirkung von Eisenoxyd auf die Carcinogenese durch Dimethyl-Nitrosamin beim Syrischen Goldhamster

Zusammenfassung Die carcinogene Wirkung von subkutan injiziertem Dimethyl-Nitrosamin (DMN) beim syrischen Goldhamster sowie der synergistische Effekt von intratrachealer Instillation von Eisenoxyd wurde untersucht. DMN allein verursachte cavernöse Haemangiome, Haemangioendotheliome, Haemangioendotheliosarkome sowie ein Hepatom in der Leber und ein Papillom des Magens, aber keine Tumoren des Atmungstraktes. Wenn Eisenoxyd zusätzlich zu DMN gegeben wurde, konnten Lebertumoren vaskulären und biliären Ursprungs gefunden werden, aber auch noch Tumoren der Nasenhöhle, neuroepitheliale Tumoren und ein Adenom. Daraus wird geschlossen, daß subkutan injiziertes DMN ein sehr wirksames Carcinogen für den syrischen Goldhamster darstellt, das Lebertumoren vaskulären, biliären und hepatozellulären Baues erzeugt. Das Fehlen der cancerogenen Wirkung im Atmungstrakt wird auf das Fehlen eines Metabolismus des DMN in der Lunge zurückgeführt.

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Supported by N. I. H. Contract PH 43-68-959

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Parts of the work reported in this paper were undertaken during the tenure of a Research Training Fellowship awarded by the International Agency for Research on Cancer.     

Pineal melatonin concentrations in the Syrian hamster

Pineal melatonin concentrations exhibited a marked diurnal rhythmicity in gold hamsters maintained in a light-dark cycle of 15 h of light and 10 h of darkness. When tissue was collected at 3-h intervals throughout a 24-h period, daytime levels of 95--232 pg/pineal gland rose to concentrations of 760--1335 pg/pineal gland (P greater than 0.001 vs. all other values) at 0400 h, 8 h after the onset of darkness. When tissue was collected sequentially during the dark phase, pineal melatonin concentrations remained significantly elevated from 0200--0500 h (P less than 0.01 and P less than 0.001 vs. daytime values, respectively). Superior cervical ganglionectomy abolished the rhythm of pineal melatonin concentrations, and the concentrations were maintained at 60--105 pg/pineal gland throughout a 24-hr period.     

Effects of cerulein on the normal pancreas and on experimental pancreatic carcinoma in the Syrian golden hamster

The effects of cerulein on normal pancreas and on N-nitrobis (2-hydroxypropyl) amine (BHP)-induced experimental pancreatic carcinoma in Syrian golden hamsters were studied. Twenty hamsters received a subcutaneous injection of cerulein (20 micrograms/kg). The results showed that when cerulein was injected subcutaneously for 10 days, pancreatic weight and amylase increased. DNA and the pancreatic weight/DNA ratio were also increased significantly in treated hamsters compared with controls (p less than 0.02 versus p less than 0.01). These results indicated that chronic cerulein injection had hypertrophic and hyperplastic effects. DNA synthesis, as measured by histoautoradiography of tritiated thymidine-labeled tissue, increased in pancreatic acinar cells (p less than 0.01) and increased slightly in islet cells and in ductal cells. Tritiated thymidine uptake in the pancreas of the treated group indicated a rather selective exocrine gland incorporation by acinar rather than ductal cells. Sixty hamsters received a subcutaneous injection of BHP (500 mg/kg) once a week, while 63 hamsters received BHP (500 mg/kg) plus cerulein (20 micrograms/kg). Twenty-seven hamsters received cerulein (20 micrograms/kg) alone. All animals were killed from 8 to 27 weeks later, and no cancer-bearing hamsters were observed during the eighth and ninth week following administration. From the 10th to 14th weeks after administration of BHP and cerulein, 87.9% (13 of 15) had tumors compared with 18.7% (3 of 16) after BHP alone (p less than 0.01). One of three and two of 13 tumors were adenoma.(ABSTRACT TRUNCATED AT 250 WORDS)     

Risk of pancreatic cancer after cholecystectomy: a cohort study in Sweden

BACKGROUND: Although some experimental studies have indicated that cholecystectomy may increase the risk of pancreatic cancer, data from epidemiological studies are conflicting. AIMS: We conducted a register based retrospective cohort study to explore the relationship between cholecystectomy and pancreatic cancer. SUBJECTS: The cohort included 87 263 men and 181 049 women with a documented cholecystectomy for cholelithiasis between 1965 and 1997. METHODS: By record linkage to the nationwide and virtually complete registers of Cancer, Emigration, and Causes of Death, the cohort was followed up until the occurrence of any cancer, emigration, death, or the end of follow up, 31 December 1997, whichever came first. Relative risk was estimated by standardised incidence ratio (SIR) using the Swedish nationwide sex, age, and calendar year specific cancer incidence rates as reference. RESULTS: During the period of observation, 1053 cases of pancreatic cancer were found, among which 231 (22%) occurred within 12 months after operation. After excluding cases and person years accrued during the first two years of follow up, we observed a non-significant 6% excess risk for pancreatic cancer (95% confidence interval (CI) -2 to 14%). The relative risk did not increase with increasing follow up duration, with a SIR equal to 0.98 (95% CI 0.79-1.20) 20 years or more after operation. Patients with a comorbidity of diabetes or chronic pancreatitis had higher relative risks (SIR=1.79, 95% CI 1.39-2.28; SIR=3.17, 95% CI 1.37-6.24, respectively). After excluding patients with recorded diabetes or chronic pancreatitis, the relative risk was close to unity (SIR=1.01, 95% CI 0.94-1.09). CONCLUSIONS: Our findings do not support the hypothesis that cholecystectomy increases the subsequent risk of pancreatic cancer.     

Vasoactive intestinal peptide inhibits the growth of hamster pancreatic cancer but not human pancreatic cancer in vivo

We have previously shown that hamster H2T pancreatic ductal cancer has a receptor for vasoactive intestinal peptide (VIP) which is not present on a cell line of human pancreatic ductal cancer (MIA). The purpose of this study was to examine the effect of chronic administration of VIP on the growth of both H2T hamster pancreatic carcinoma and MIA human pancreatic carcinoma in vivo. The growth of H2T was studied in hamsters; a control group of six hamsters received 0.1% bovine serum albumin (BSA) in saline, and two treatment groups of six hamsters each received VIP (1 and 10 nmol/kg), all administered three times a day by i.p. injection for 35 days. Both doses of VIP inhibited the growth of H2T tumor (tumor area, weight, DNA, RNA, and protein content). The growth of MIA was studied in athymic Balb/c mice, one group of 10 received 0.1% BSA and the other 10 received VIP (1 nmol/kg), both three times a day by i.p. injection for 3 months. There was no difference in tumor growth rate between the two groups. Treatment with VIP did not have any effect on body weight or size of the normal pancreas in either the hamsters or the mice. We conclude that the differential response of hamster and human pancreatic cancer to VIP treatment may be due to the presence or absence of VIP receptors.     

Risk of pancreatic and periampullar cancer following cholecystectomy

An increased risk of pancreatic cancer following cholecystectomy has been reported in some studies but not in others. In order to settle this question, a population-based cohort consisting of 62,615 patients who had undergone cholecystectomy was followed up for the occurrence of pancreatic and periampullar cancer up to 23 years. After excluding the first year after operation, there were 261 pancreatic cancers vs 216.8 expected [standardized incidence ratio (SIR)=1.20; 95% confidence interval (CI)=1.06–1.37]; and 11 periampullar cancers vs 7.2 expected (SIR=1.52; 95% CI=0.76–2.72). The increased risk of pancreatic cancer was most prominent up to four years after operation, but was also significantly increased 15 years or more after operation (SIR=1.35; 95% CI=1.00–1.78). We conclude that there is a modest excess risk of pancreatic and periampullar cancer following cholecystectomy, most prominent up to four years after operation, but that also exists 15 years or more after operation.     

Choclo virus infection in the Syrian golden hamster

Andes virus and Choclo virus are agents of hantavirus pulmonary syndrome. Andes virus in hamsters almost always causes a disease that is pathologically indistinguishable from fatal hantavirus pulmonary syndrome. The purpose of this study was to assess the pathogenicity of Choclo virus in hamsters. None of 18 hamsters infected with Choclo virus exhibited any symptom of disease. No evidence of inflammation or edema was found in the lungs of the 10 animals killed on days 7, 9, 11, 13, and 16 post-inoculation or in the lungs of the 8 animals killed on day 28 post-inoculation; however, hantavirus antigen was present in large numbers of endothelial cells in the microvasculature of the lungs of the animals killed on days 7, 9, 11, and 13 post-inoculation. These results suggest that infection in the microvasculature of lung tissue alone does not result in the life-threatening pulmonary edema in hamsters infected with Andes virus.     

Toxic effects of dietary selenium in the Syrian hamster

Selenium (Se) toxicity and utilization was evaluated in hamsters fed casein- and torula yeast-based diets. 4-week-old hamsters received semipurified diets for 21 days. In experiment I diets were supplemented with either 0.25, 10, 20, 40 or 80 ppm Se as sodium selenite (SS) and in experiment II diets were supplemented with 0.1, 5.0 or 10.0 ppm as SS or selenomethionine (SM). Blood and tissue Se concentrations and glutathione peroxidase (GSH-Px) activity were measured at the termination of the feeding period. In both studies growth rate was depressed and food consumption decreased in hamsters given diets supplemented with 10 ppm or greater SS. Mortality associated with Se toxicity occurred only in females fed the 80 ppm Se-supplemented diet. Whole blood and tissue Se concentrations rose with increasing dietary Se and occurred up to the 80 ppm Se level in blood. Liver, kidney and lung Se concentrations were higher in hamsters fed SM than for those fed SS. Plasma GSH-Px activity was not significantly affected by increasing dietary Se levels, and hamsters fed dietary Se levels above 10 ppm did not have increased erythrocyte GSH-Px activity associated with increased blood Se concentrations. Liver GSH-Px activity was higher in SM-fed hamsters. The results suggest that dietary Se, fed as SS, becomes toxic for Syrian hamsters at levels of 10 ppm and above.     

Stimulatory effect of RFRP-3 on the gonadotrophic axis in the male Syrian hamster: the exception proves the rule

In seasonal mammals, a distinct photoneuroendocrine circuit that involves the pineal hormone melatonin tightly synchronizes reproduction with seasons. In the Syrian hamster, a seasonal model in which sexual activity is inhibited by short days, we have previously shown that the potent GnRH stimulator, kisspeptin, is crucial to convey melatonin's message; however, the precise mechanisms through which melatonin affects kisspeptin remain unclear. Interestingly, rfrp gene expression in the neurons of the dorsomedial hypothalamic nucleus, a brain region in which melatonin receptors are present in the Syrian hamster, is strongly down-regulated by melatonin in short days. Because a large body of evidence now indicates that RFamide-related peptide (RFRP)-3, the product of the rfrp gene, is an inhibitor of gonadotropin secretion in various mammalian species, we sought to investigate its effect on the gonadotrophic axis in the Syrian hamster. We show that acute central injection of RFRP-3 induces c-Fos expression in GnRH neurons and increases LH, FSH, and testosterone secretion. Moreover, chronic central administration of RFRP-3 restores testicular activity and Kiss1 levels in the arcuate nucleus of hamsters despite persisting photoinhibitory conditions. By contrast RFRP-3 does not have a hypophysiotrophic effect. Overall, these findings demonstrate that, in the male Syrian hamster, RFRP-3 exerts a stimulatory effect on the reproductive axis, most likely via hypothalamic targets. This places RFRP-3 in a decisive position between the melatonergic message and Kiss1 seasonal regulation. Additionally, our data suggest for the first time that the function of this peptide depends on the species and the physiological status of the animal model.