azaserine and Carcinoma--Acinar-Cell

In humans, initial events of pancreatic carcinogenesis remain unknown, and the question of whether this cancer, which has a ductal phenotype, exclusively arises from duct cells has been raised. Previous studies have demonstrated that transgenic expression of the CCK2 receptor in acinar cells of ElasCCK2 mice plays a role in the development of pancreatic neoplasia. The aim of our study was to examine initial steps of carcinogenesis in ElasCCK2 mice, adding a supplementary defect by using a chemical carcinogen, azaserine. Results of posttreatment sequential immunohistochemical examinations and quantifications demonstrate that mice responded to azaserine. Transition of acinar cells into duct-like cells expressing Pdx1 and gastrin, as well as proliferation of acinar cells, were transiently observed in both transgenic and control mice. The carcinogen also induced formation of preneoplastic lesions, adenomas, exhibiting properties of autonomous growth. Importantly, expression of the CCK2 receptor increased the susceptibility of pancreas to azaserine. Indeed, treated ElasCCK2 mice exhibited larger areas of pancreatic acinar-ductal transition, increased cellular proliferation as well as larger adenomas areas vs. control mice. These amplified responses may be related to auto/paracrine stimulation of CCK2 receptor by gastrin expressed in newly formed duct-like cells. Our results demonstrate that activation of CCK2 receptor and azaserine result in cumulative effects to favor the emergence of a risk situation that is a potential site for initiation of carcinogenesis.

Topics: Adenoma; Animals; Antimetabolites, Antineoplastic; Azaserine; Bromodeoxyuridine; Carcinogens; Carcinoma, Acinar Cell; Cell Proliferation; Coloring Agents; Homeodomain Proteins; Homozygote; Immunohistochemistry; Inflammation; Lymphocytes; Mice; Mice, Transgenic; Pancreatic Neoplasms; Phenotype; Precancerous Conditions; Receptor, Cholecystokinin B; Receptors, G-Protein-Coupled; Risk; Time Factors; Trans-Activators; Transgenes

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.. 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.. 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%).. 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.

Topics: 2-Pyridinylmethylsulfinylbenzimidazoles; Adenoma; Animals; Anti-Ulcer Agents; Azaserine; Carcinoma in Situ; Carcinoma, Acinar Cell; Disease Models, Animal; Gastrins; Lansoprazole; Male; Omeprazole; Organ Size; Pancreas; Pancreatic Neoplasms; Precancerous Conditions; Rats; Rats, Inbred Lew

To investigate the effects of increasing concentrations of cholecystokinin octapeptide (CCK-8) on a pancreatic acinar adenocarcinoma.. Growth of the tumour was estimated in vivo on rats bearing a subcutaneous pancreatic carcinoma, and in vitro on primary cultured tumour cells. CCK receptors were characterized by binding assays.. CCK-8, administered for 12 successive days, exerted a biphasic action on tumour growth: a dose-dependent stimulation with low doses (0.1 and 0.5 microg/kg) and inhibition with high doses (2 and 4 microg/ kg) as shown by respective increases and decreases in tumor volume, protein, RNA and amylase contents. In cell cultures, [3H]thymidine incorporation was dose-dependently increased with 10-(10) to 10(-8) M CCK-8 and inhibited with 10(-7) M. Both effects were completely suppressed by the CCK-receptor antagonists CR 1409 and L 364,718 (10(-4) M). Binding studies showed the overexpression of two classes of CCK-A receptors of low and high affinity when compared to the normal pancreas which was less sensitive to CCK-8.. CCK-8 exerts a biphasic growth response on the acinar pancreatic carcinoma, mediated by two classes of CCK-A receptors overexpressed in the tumour.

Topics: Animals; Azaserine; Carcinoma, Acinar Cell; Cell Division; Dose-Response Relationship, Drug; Iodine Radioisotopes; Pancreatic Neoplasms; Radioligand Assay; Rats; Rats, Inbred Lew; Receptors, Cholecystokinin; Sincalide; Tumor Cells, Cultured

The hormone gastrin is thought to stimulate the growth of certain pancreatic carcinoma cell lines. We have previously detected the presence of the gastrin receptor in rat pancreatic carcinoma cell lines but not in normal rat pancreas. We had not, however, previously demonstrated that gastrin receptor is expressed in pancreatic carcinomas developing in the rat in vivo. Therefore, in the present study, we examined rat pancreatic tissue at various stages in azaserine-induced pancreatic carcinogenesis for gastrin binding and for the presence of gastrin receptor mRNA to determine the temporal expression pattern of the gastrin receptor during the in vivo development of pancreatic cancer. Autoradiography of pancreatic tissue using (125)I-gastrin-17-I from all azaserine-treated and control animals at 2, 4, 8, and 12 months of age demonstrated no specific gastrin binding. At 18 months of age, normal pancreas, azaserine-induced premalignant pancreatic nodules, and internodular pancreas demonstrated no specific gastrin binding. One of three azaserine-treated animals developed an area of pancreatic acinar cell carcinoma at 18 months of age which exhibited significant specific gastrin binding of 141.8 - 32.8 fmole/gm of tissue. Southern blot analysis of pancreatic RNA isolated from animals at 12 months of age revealed no gastrin receptor mRNA; however, by 18 months of age, gastrin receptor mRNA was present in all azaserine-treated animals but absent in control animals. In summary, specific gastrin binding is present in in vivo azaserine-induced pancreatic acinar cell carcinoma but absent in normal pancreas and azaserine-induced premalignant pancreatic nodules. Gastrin receptor mRNA is first expressed in azaserine-treated rat pancreas at some point between 12 and 18 months of age. These results demonstrate that expression of gastrin receptor is altered in azaserine-treated rat pancreas and may play a role in the development of pancreatic cancer.

Topics: Animals; Autoradiography; Azaserine; Base Sequence; Carcinogens; Carcinoma, Acinar Cell; DNA Primers; Gastrins; Gene Expression; Male; Molecular Sequence Data; Pancreas; Pancreatic Neoplasms; Polymerase Chain Reaction; Precancerous Conditions; Rats; Rats, Inbred Lew; Receptors, Cholecystokinin; RNA, Messenger

Keratin is a member of the intermediate filament family in epithelial cells. Two-dimensional gel electrophoresis of different epithelial cells has shown 20 different keratin polypeptides. Therefore, mapping of the keratin polypeptides can be used to define a specific tissue.. Cytokeratin expression was investigated by using monoclonal antibodies in human surgical specimens and autopsy material of pancreatic, gastric, liver, and colon carcinomas and cholangiocarcinomas, and their metastasis to lymph nodes and liver was examined. In addition, rat acinar cell carcinomas were used to compare cytokeratin expression in ductal vs. acinar cell pancreatic carcinomas.. Human pancreatic ductal carcinomas expressed keratins 7, 8, 18, and 19, whereas the majority of rat acinar carcinomas did not express keratins typical for ducts in rat pancreas. The keratin patterns of gastric and colon carcinomas were identical with keratins 8, 18, and 19. In contrast, hepatocellular carcinomas expressed the same keratin pattern as pancreatic acinar carcinomas with keratins 8 and 18, whereas cholangiocarcinomas expressed keratin 7, 8, 18, and 19, similar to pancreatic ductal carcinomas. Metastasis of pancreatic ductal and colon carcinomas retained their keratin patterns.. Keratin polypeptide typing of unknown malignant cells can be a useful tool for cell identification.

Topics: Animals; Azaserine; Carcinoma, Acinar Cell; Carcinoma, Ductal, Breast; Colonic Neoplasms; Epithelium; Gastrointestinal Neoplasms; Humans; Immunohistochemistry; Intermediate Filaments; Keratins; Male; Neoplasms, Experimental; Pancreatic Neoplasms; Rats; Rats, Inbred Lew; Stomach Neoplasms