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Reidar Fossmark

Publications and source records attributed to Reidar Fossmark.

10 recordsLinked to original sources
PubMed2005

Signet ring cells in gastric carcinomas are derived from neuroendocrine cells.

Adenocarcinomas are malignant tumors with glandular growth and/or supposed intracellular mucin as identified by periodic acid-Schiff (PAS) positivity. Gastric signet ring cell carcinomas are classified as diffuse type. A proportion of diffuse-type adenocarcinomas have previously been suggested to be of neuroendocrine origin. In the present study we examined gastric signet ring cell carcinomas for neuroendocrine differentiation. Of 11 gastric signet ring cell carcinomas, 8 contained areas with PAS-positive signet ring cells that also were immunoreactive for one or several neuroendocrine markers: synaptophysin, chromogranin A, and histidine decarboxylase, the latter an enterochromaffin-like (ECL) cell marker. Whereas PAS positivity was located in the central cytoplasm, neuroendocrine immunoreactivity was often located as a rim surrounding an otherwise non-immunoreactive cytoplasm, presumed to represent the area with PAS-positive material. These findings indicate that signet ring cell carcinomas could be of neuroendocrine origin. We propose that signet ring cell carcinomas develop by gradual dedifferentiation from ECL cells via signet ring cells with neuroendocrine immunoreactivity toward signet ring cells where the cytoplasm mainly consists of PAS-positive material. This finding could have implications for the classification and understanding of gastric carcinogenesis.

Biomarkers↗
PubMed2005

Molecular characterization of rat gastric mucosal response to potent acid inhibition.

Potent acid inhibition with proton pump inhibitors (PPIs) is widely used in clinical medicine, especially for gastroesophageal reflux disease. PPIs cause profound changes in the intragastric environment with near-neutral pH and increase serum concentration of the gastric secretagogue hormone gastrin. Long-term hypergastrinemia increases mucosal thickness and enterochromaffin-like cell density in gastric corpus mucosa and results in development of gastric carcinoids in experimental animals. Our aim was to study responses to potent acid inhibition by characterizing genome-wide gene expression changes in gastric corpus mucosa in rats dosed with the PPI omeprazole. Nine rats received 400 micromol/kg omeprazole daily for 10 wk. Seven rats received vehicle only. Analysis of gastric corpus with microarrays representing 11,848 genes identified 134 genes with changed gene expression levels in omeprazole-dosed rats. Several of the identified genes were previously known to be affected by potent acid inhibition. Of the 62 genes with known functions that changed gene expression levels after PPI dosing, 27 are known to be involved in proliferation and apoptosis and immune, inflammatory, and stress responses. Our study indicates that microarray analysis can detect relevant gene expression changes in the complex gastric tissue, and that cellular processes involved in cell growth and defense responses are strongly affected by PPI dosing. Many genes are identified that were not previously known to be affected by inhibition of gastric acid secretion or that have unknown biological functions. Characterization of the roles of these genes may give new insight into molecular responses to treatment with PPIs.

Animals↗
PubMed2005

Long-term serotonin administration induces heart valve disease in rats.

BACKGROUND: The purpose of this study was to investigate whether rats dosed with serotonin develop changes similar to those seen in human carcinoid heart disease. METHODS AND RESULTS: Ten Sprague-Dawley rats were given serotonin injections subcutaneously once daily for 3 months; controls were given saline. A long-lasting hyperserotoninemia with a >10-fold increase in both platelet-poor plasma and dialysate from the femoral muscles appeared. The animals developed clinical signs such as flushing and loose stools. After 3 months, 6 of 10 rats given serotonin had pathological echocardiographs. Two animals had a combination of aortic and pulmonary valve insufficiency, 1 had isolated aortic valve insufficiency, and 3 had isolated pulmonary valve insufficiency. Histopathological examination revealed shortened and thickened aortic cusps and carcinoidlike plaques characterized by a collection of myofibroblasts within an extracellular matrix of collagen ground substance. Immunostaining for Ki-67 demonstrated an increased number of proliferating subendocardial cells. In the control group, no pathological changes were seen. With the use of reverse-transcription polymerase chain reaction, normal rat aortic cusps were shown to express mRNA for serotonin receptors 5-HT1A, 5-HT2A, and 5-HT2B and the serotonin transporter 5-HTT. CONCLUSIONS: For the first time, long-term serotonin administration was performed in rats. Morphological and echocardiographic changes similar to those seen in human carcinoid heart disease developed. This study demonstrates that serotonin most likely is involved in the pathogenesis of carcinoid heart disease.

Animals↗
PubMed2005

Antiulcer drugs and gastric cancer.

Inhibitors of gastric acid secretion are efficient drugs in the treatment of acid-related diseases. However, by reducing gastric acidity, hypergastrinemia develops. Gastrin regulates its target cell, the enterochromaffin (ECL) cell, both functionally and tropicaly. Long-term hypergastrinemia in whatever species studied, has been shown to induce tumors originating from the ECL cell. In man, at least 10 years of hypergastrinemia, accompanied by high or reduced gastric acidity is necessary to induce ECL cell carcinoids. There are reports indicating development of ECL cell carcinoids after long-term treatment with proton pump inhibitors. Moreover, the ECL cell may give rise to gastric carcinomas of diffuse type, which have increased during the last decades. Furthermore, most of the carcinomas developing in patients with long-lasting hypergastrinemia are of ECL cell origin. Therefore, long-lasting iatrogenic hypergastrinemia induced by potent inhibitors of acid secretion may be expected to increase the occurrence of gastric carcinomas in the future.

Anti-Ulcer Agents↗
PubMed2005

Experimental Helicobacter pylori infection induces antral-predominant, chronic active gastritis in hispid cotton rats (Sigmodon hispidus).

BACKGROUND: The hispid cotton rat has proven to be an excellent animal model for a variety of human infectious disease agents. This study was performed to evaluate the use of the cotton rat as a model of Helicobacter pylori infection. MATERIALS AND METHODS: Thirty-eight inbred cotton rats were orogastrically inoculated with a human strain of H. pylori. Twenty-eight control cotton rats were dosed with vehicle only. Animals were sacrificed at 2, 4, 12, 26, or 38 weeks after inoculation for bacterial and histologic and immunologic examinations. RESULTS: Helicobacter pylori was cultured from the glandular stomach of 89% of the infected cotton rats. The level of colonization was consistently high (approximately 10(4-6) colony-forming units/g tissue). Histologically, the spiral bacteria were demonstrated on the epithelial surface and in the foveolae of the gastric mucosa with highest numbers in the antrum. H. pylori infection was associated with antral-predominant, chronic active gastritis which progressively increased in severity over time. By week 26 of infection, moderate antral gastritis had developed with frequent involvement of the submucosa and formation of lymphocytic aggregates. Splenic T cells from infected cotton rats expressed mRNAs for interferon-gamma, interleukin-4, interleukin-6, and interleukin-10 following in vitro stimulation with H. pylori. Serum levels of H. pylori-specific immunoglobulin G were significantly elevated after 12 weeks of infection. CONCLUSIONS: The H. pylori-infected cotton rat represents a novel animal model that should prove useful for studies of H. pylori-induced chronic active gastritis and factors affecting gastric colonization by this pathogen.

Animals↗
PubMed2005

Dedifferentiation of enterochromaffin-like cells in gastric cancer of hypergastrinemic cotton rats.

The role of enterochromaffin-like (ECL) cells in gastric carcinogenesis is not fully understood. Spontaneous tumours developing in hypergastrinemic female cotton rats have an adenocarcinoma phenotype, but numerous cells in the dysplastic mucosa as well as in the carcinomas are positive for neuroendocrine markers. In the present study of female cotton rats with 2 and 8 months' hypergastrinemia, the oxyntic mucosa of the stomach was examined histologically and immunolabelled for histidine decarboxylase (HDC) and pancreastatin, and hyperplastic and neoplastic ECL cells were evaluated by electron microscopy. These animals developed hyperplasia of the oxyntic mucosa in general and of the ECL cells in particular after 2 months and dysplasia and carcinomas after 8 months. The immunoreactivity of the ECL cells in the oxyntic mucosa was increased at 2 months and declined at 8 months. These histological changes were associated with progressive loss of secretory vesicles and granules in ECL cells. We suggest that ECL cells in hypergastrinemic cotton rats dedifferentiate with time and that the gastric carcinomas may develop from ECL cells.

Animals↗
PubMed2004

ECL-cell derived gastric cancer in male cotton rats dosed with the H2-blocker loxtidine.

Spontaneously hypergastrinemic cotton rats (Sigmodon hispidus) develop tumors that have the phenotype of an adenocarcinoma but most likely originate from the enterochromaffin-like (ECL) cells. Among inbred animals approximately 50% of the females, but <1% of males develop spontaneous gastric carcinomas. Gastrin is the principle carcinogen in this model, as >4 months of hypergastrinemia results in carcinoma, but a gastrin receptor antagonist prevents carcinomas. Carcinomas can also be induced by partial corpectomy. In the present study, the insurmountable H2-receptor antagonist loxtidine (200 mg/kg/day) was given to male cotton rats for 6 months. The loxtidine-dosed animals developed hypergastrinemia, whereas control animals remained normogastrinemic. At termination, 4 of 5 cotton rats had cancer located to the oxyntic mucosa, whereas 1 animal had dysplasia. The gastric mucosa of all of the control animals was normal. In the dysplastic mucosa of loxtidine-dosed animals there was a marked increase in chromogranin A-positive cells, where numerous groups of cells also stained positive with the Sevier-Munger technique. In areas of high proliferation and cancer there were also histidine decarboxylase, chromogranin A, and Sevier-Munger-positive cells, altogether indicating an ECL cell origin of the tumors. This represents an interesting animal model where ECL cell-derived gastric cancer can be induced by pharmacological acid inhibition in 6 months.

Animals↗
PubMed2003

Spontaneous ECL cell carcinomas in cotton rats: natural course and prevention by a gastrin receptor antagonist.

In our inbred strain of cotton rats (Sigmodon hispidus) 50% of the females develop spontaneous ECL cell-derived tumors in the acid-producing part of the stomach due to hypergastrinemia secondary to gastric hypoacidity. Although the mechanism behind the hypoacidity is unknown, the female cotton rat is an excellent model for studying ECL cell-related tumorigenesis. In this study we wanted to explore the malignancy potential of these tumors and the ability of a gastrin receptor antagonist (YF476) to prevent their development. First, nine hypergastrinemic female cotton rats (10 months of age) were diagnosed by laparotomy as having gastric tumors. They were killed 6 months later. Second, 18 female cotton rats (2 months of age) were dosed monthly for 6 months with YF476 (500 micro mol/kg body wt) by s.c. injection, while 21 age-matched animals received vehicle. Samples from each stomach were collected for histology, immunohistochemistry and northern blot analysis. The gastric tumors harbored cells with immunohistochemical features of ECL cells. The tumors were found at times to invade and penetrate the stomach wall and to metastasize to perigastric sites. ECL-derived tumor cells were discovered in peritoneal fluid. At death only 1 out of 18 animals given YF476 displayed carcinomas (invasive growth), compared with 7 out of 21 in the vehicle dosed control group (P = 0.048). The spontaneous gastric tumors in cotton rats derived from ECL cells. The tumors were able to penetrate the stomach wall and to metastasize by intracavital seeding. Gastrin receptor blockade lowered the incidence of such tumors. We propose that the tumors are ECL cell carcinomas and that gastrin is the driving force behind the transformation from normal to malignant ECL cells.

Animals↗
PubMedDate not supplied

Ultrastructure and chromogranin A immunogold labelling of ECL cell carcinoids.

Poorly differentiated neuroendocrine cells can be difficult to recognise. Sensitive methods are needed to label cells that have lost their ultrastructural features and have reduced concentrations of neuroendocrine markers. In gastric neoplasms, enterochromaffin-like cells might dedifferentiate and lose their characteristic granules and secretory vesicles, making detection of such cells increasingly difficult. However, chromogranin A (CgA) immunogold labelling could provide sensitive and specific detection of gastric neuroendocrine cells. We present ultrastructural findings, CgA immunogold labelling as well as conventional immunohistochemical findings of two human enterochromaffin-like cell carcinoids. Electron-dense granules of poorly differentiated cells were less intensely labelled than granules in well-differentiated cells. Granules with atypical shape as well as punctuate granules previously found in neuroendocrine neoplasms were also CgA labelled. The CgA labelling efficacy after antigen retrieval in an alkaline solution was higher after heating in an autoclave at 135 degrees C compared to a microwave at 100 degrees C for both granules and secretory vesicles without significant deterioration of the ultrastructure. In conclusion, the use of CgA immunogold labelling could ensure a specific classification of cells with neuroendocrine granules and be a supplement to immunohistochemical examination of poorly differentiated tumours.

Aged↗