Ultrastructural study of the initial phases of pancreatic carcinoma induced by BOP in the Syrian golden hamster.

A serial study was carried out on the lesions induced by N-nitroso-bis(2-oxopropyl)amine (BOP) in the Syrian golden hamster until the appearance of pancreatic ductal carcinomas. During the initial phase, first findings were cytolysis of acinar cells close to blood vessels and other cells, together with a loss of zymogen granules from the cytoplasm, and an increase in the diameters of the acinar lumens. After week 11 a proliferation of ductule-like cells was observed. We consider that a minimum proliferation of cells at the acinus-ductule junction would give rise to pseudoductules composed of remains of acinar cells together with ductule-like cells.     

Experimental pancreatic carcinogenesis. I. Morphogenesis of pancreatic adenocarcinoma in the Syrian golden hamster induced by N-nitroso-bis(2-hydroxypropyl)amine.

In serial sacrifice experiment, outbred male Syrian golden hamsters were treated once weekly for life with subcutaneous injections of N-nitroso-bis(2-hydroxypropyl) amine (DIPN). The pancreas was examined by high resolution light (1-micro sections) and transmission electron microscopy. Early nonspecific changes in all pancreatic epithelial cellular elements were followed by a progressive proliferation of intra- and interlobular duct cells, with the development of multicentric foci of cystic and papillary cystic adenomas, intraductal carcinomas, and invasive ductal neoplasms. These observations were consistent with multistage morphogenesis of pancreatic adenocarcinoma of ductal origin.     

Stimulation of islet cell proliferation enhances pancreatic ductal carcinogenesis in the hamster model.

Previous studies have shown that some N-nitrosobis (2-oxopropyl)amine (BOP)-induced ductal/ductular pancreatic cancers in the hamster model develop within islets and that streptozotocin (SZ) pretreatment that caused islet degeneration and atrophy inhibits pancreatic cancer induction. Hence, it appears that in this model islets play a significant role in exocrine pancreatic carcinogenesis. To examine whether stimulation of islet cell proliferation (nesidioblastosis) enhances pancreatic exocrine cancer development, we tested the effect of the pancreatic carcinogen BOP in hamsters after induction of nesidioblastosis by cellophane wrapping. Before wrapping, hamsters were treated with SZ to inhibit pancreatic tumor induction in the unwrapped pancreatic tissues. Control groups with a wrapped pancreas did not receive SZ. Six weeks after SZ treatment, all hamsters were treated with BOP (10 mg/kg body weight) weekly for 10 weeks and the experiment was terminated 38 weeks after the last BOP treatment. Many animals recovered from their diabetes at the time when BOP was injected and many more after BOP treatment. Only nine hamsters remained diabetic until the end of the experiment. Both SZ-treated and control groups developed proliferative and malignant pancreatic ductal-type lesions primarily in the wrapped area (47%) but less frequently in the larger segments of the pancreas, including the splenic lobe (34%), gastric lobe (13%), and duodenal lobe (6%). Only a few lesions developed in the unwrapped pancreatic region of nine diabetic hamsters with atrophic islets, whereas seven of these hamsters had tumors in the wrapped area. Histologically, most tumors appeared to originate from islets, many invasive carcinomas had foci of islets, and some tumor cells showed reactivity with anti-insulin. The results show that, in the BOP hamster model, islets are the site of formation of the major fraction of exocrine pancreatic cancer and that induction of nesidioblastosis enhances pancreatic carcinogenesis.     

Early changes in islet hormone secretion in the hamster pancreatic cancer model

The diabetic state that is seen at a high frequency in association with pancreatic cancer is characterized by elevated plasma levels of several islet hormones and by marked insulin resistance. Both the diabetic state and insulin sensitivity improve after tumor removal by sub-total pancreatectomy. Impaired glucose tolerance has also been found in the hamster pancreatic cancer model, but conflicting data regarding islet function have been reported. In order to further investigate islet function and secretion during early development of pancreatic cancer, we measured the concentrations of insulin, glucagon, somatostatin, and islet amyloid polypeptide (IAPP) in plasma, pancreatic tissue, and secretin-stimulated pancreatic juice at 12 and 27 weeks after the ductal-cell-specific carcinogen, BOP had been used to induce tumors in Syrian golden hamsters. At 12 weeks after BOP, plasma glucagon levels were significantly increased. An exaggerated plasma-glucose response and concomitant hyperinsulinemia were observed at 27 but not 12 weeks after BOP. Plasma IAPP concentrations, but not glucagon or somatostatin, were elevated at 27 weeks. Tissue concentrations of IAPP were substantially reduced in BOP-treated hamsters at 27 weeks. No differences in hormone concentrations were seen in pancreatic juice from the two groups at either of the two time points investigated. The study showed that islet hormone changes accompany the early development of pancreatic tumors in the hamster pancreatic model. The hormone changes and apparent insulin resistance resemble the metabolic changes found in humans with pancreatic cancer.     

Streptozotocin and renal amyloidosis in the Syrian hamster.

In the Syrian hamster, administration of the drug streptozotocin was associated with an increased incidence and severity of renal amyloidosis. Some of the more severely affected animals showed a frankly nephrotic picture. Although some of the diseased animals showed decreased levels of serum albumin, no other definite changes in serum proteins were noted, nor was there any evidence of glomerular immunoglobulin or immune complex deposition. None of the lesions previously found after administration of streptozotocin in the Chinese hamster were encountered.     

Daily variations in GABA receptor function in Syrian hamster cerebral cortex

The existence of diurnal changes in postsynaptic expression of γ-aminobutyric acid (GABA) type A receptors was assessed in cerebral cortex of Syrian hamsters by measuring [³H]GABA binding and the influx of ³⁶Cl⁻ in synaptoneurosomes. A diurnal variation in dissociation constant of [³H]GABA binding to cerebral cortex membranes, and the absence of diurnal differences in maximal number of sites, were found. When the nycthemeral changes in muscimol-stimulated ³⁶Cl⁻ uptake by cortical synaptoneurosomes were assessed, a maximum occurred late at night (i.e. 0400 h). At 1600 h, micromolar concentrations of flunitrazepam potentiated significantly the influx of chloride induced by muscimol, while at 0400 h flunitrazepam did not exert any significant effect on ³⁶Cl⁻ uptake. The results indicate that postsynaptic type A GABAergic activity peaked at nocturnal hours in the cerebral cortex of Syrian hamsters.     

Transdisciplinary approach to restore pancreatic islet function

Immunologic Research - The focus of our research is on islet immunobiology. We are exploring novel strategies that could be of assistance in the treatment and prevention of type 1 diabetes, as well...     

Identification of the Syrian hamster cardiomyopathy gene

The BIO14.6 hamster is a widely used model for autosomal recessive cardiomyopathy. These animals die prematurely from progressive myocardial necrosis and heart failure. The primary genetic defect leading to the cardiomyopathy is still unknown. Recently, a genetic linkage map localized the cardiomyopathy locus on hamster chromosome 9qa2.1-b1, excluding several candidate genes. We now demonstrate that the cardiomyopathy results from a mutation in the delta-sarcoglycan gene that maps to the disease locus. This mutation was completely coincident with the disease in backcross and F2 pedigrees. This constitutes the first animal model identified for human sarcoglycan disorders.      

Effects of swimming on dystrophic Syrian hamster heart.

Morphological and histopathological heart changes were determined for sixteen dystrophic Syrian hamsters (B10 14.6 strain) and sixteen normal hamsters. Eight animals were randomly assigned to each of the following groups: dystrophic swim (DYS-SWM), dystrophic sedentary (DSY-SED), normal swim (NOR-SWM), and normal sedentary (NOR-SED). The daily swimming program consisted of an initial 30-minute swim which was gradually extended to 60 minutes by the end of eight weeks. Weights up to 3% body weight were attached during swimming to increase the work load. Sedentary animals received no experimental treatment. Four animals in each group were sacrificed at 4 and 8 weeks after the initiation of treatments. In comparison with the two groups of sedentary animals, the NOR-SWM group had a greater heart weight/body weight ratio at both 4 and 8 weeks (P less than .05), while the DYS-SWM group had an increased ratio only at 8 weeks (P less than .05). Subjective histopathological evaluation of heart lesions showed that the DYS-SED group had many large areas of inflammatory reaction with infrequent diffuse areas of calcification. In contrast, the DYS-SWM group had fewer and smaller areas of inflammatory reaction with moderate amounts of calcification.     

Three-dimensional structure of seminiferous tubules in the Syrian hamster

The hamster is useful for the study of male reproductive biology. However, unlike in the mouse and rat, the gross structure of seminiferous tubules in the hamster is largely unknown. The aim of the present study was to clarify the precise 3-dimensional (3D) structure of seminiferous tubules in hamsters. We reconstructed all seminiferous tubules in 3 and 1 testes from 0-day (P0) and 10-week (adult) Syrian hamsters, respectively, using serial paraffin sections and high-performance 3D reconstruction software. In P0 hamsters, the average numbers of seminiferous tubules, terminating points, branching points, and blind ends per testis were 9.0, 89.7, 93.0, and 0.7, respectively. There were two types of tubules: shorter and dominant ones. The dominant tubules, 2–4 in number per testis and accounting for 86% of the total tubule length, had many terminating and branching points and appeared to be derived from the anastomosis of many shorter tubules. In an adult hamster, there were 11 seminiferous tubules with a total length of 22 m, 98 terminating points, 88 branching points, and 2 blind ends per testis. Three of the 11 tubules were dominant ones, accounting for 83% of the total length, and occupied the testis from the surface over the circumference to the center, while the others were short and occupied only one side of the testis. The amplitude and direction of the curves of tubules were random, and there were no funnel-shaped networks of tubules present, in contrast to the mouse testis. The present study revealed the 3D structure of seminiferous tubules in developing and adult Syrian hamsters, which is different from that in mice and rats.     

Mitochondrion-secretory granules complexes in pancreatic islet B-cells.

Mitochondrion-Secretory Granule Complexes (MSGC) are present in rodent pancreatic islet B-cells, characteristically showing fusion of mitochondria and secretory granules, absence of granule membrane and external mitochondrial membrane at place of contact, often invagination of internal mitochondrial membrane at place of contact forming an electron lucent space directly continuous with the "halo" of the secretory granules, and occurrence of potassium pyroantimonate precipitates in either or both of mitochondria and secretory granules. The MSGC are believed to possess functional significance, possibly playing a role in translocation of ions between mitochondria and secretory granules in the B-cells.     

Morphology and immunohistochemically-defined endocrine function of pancreatic islet cell tumours

Thirty pancreatic islet cell tumours were histologically classified and analysed for their possible peptide hormone content using the immunohistoperoxidase method. Seven tumours contained insulin, six tumours contained gastrin and eight tumours contained glucagon. One tumour contained all three hormones. In the insulin and gastrin-containing tumours, the cells were usually arranged in solid nests of cells, with tubular and acinar formations in about half the cases. In the glucagon-containing tumours the cells were mainly arranged in anastomosing ribbons consisting of one of two layers of small cells. Most of the hormone-containing tumours were argyrophilic using Grimelius' silver reaction. All but one of the glucagon-containing tumours were incidental findings at autopsy. About half of the other tumours had metastasized. It is concluded that a relation exists between the histological pattern of growth and immunohistochemically defined endocrine function of pancreatic islet cell tumours.     

The development of the Syrian hamster cheek pouch

The objective of this study was to provide a detailed account of the morphogenesis and early cytodifferentiation of the hamster cheek pouch. Although the newborn "cheek pouch" is used for in vitro studies of the effects of retinoids and carcinogens, its rudimentary structure has not been adequately described. Complete paraffin serial sections of the heads of 14- and 15-day fetuses were cut in three planes to determine the location and shape of the earliest pouch rudiments. Complete paraffin serial sections were prepared from pouch rudiments dissected from hamsters at birth and at daily intervals from 3 to 12 days postnatal. Semithin Epon sections were examined by light microscopy and ultrathin sections by transmission electron microscopy. The pouch can appear in the fetus as two solid epithelial ingrowths from the lining of the oral cavity. They are the margins of an ingrowing sheet of oral epithelium which becomes leaflike at about the time of birth, as it grows caudad into the tissue of the cheek. The central cells of the ingrowth accumulate large quantities of glycogen before differentiating as a stratum spinosum 5 days after birth. Within the stratum spinosum, groups of cells containing keratohyalin granules initiate the stratum granulosum. Keratinized cells appear within the stratum granulosum areas. Spaces appear between keratinized cells, and the spaces coalesce to form the pouch cavity between 7 and 12 days postnatal. Soon afterward, this cavity opens to the oral cavity to make a pouch, and the ultrastructure of the cheek pouch epithelium closely resembles that of the adult.