Pathobiology of Gastric Carcinoids and Adenocarcinomas in Rodent Models and Patients: Studies of Gastrocystoplasty, Gender-Related Factors, and Autophagy
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Background: Gastric adenocarcinoma is the fourth most common cancer in the world. Among several etiological factors, gastrin hormone has been considered as a cofactor. Progenitor cells/stem cells and ECL cells are targets of gastrin and have been suggested to be the origin of gastric cancer. Gastric carcinoid (ECLoma) is another example of tumors arising from long-term hypergastrinemia (induced by e.g. proton pump inhibitor). Much progression has been made during the past decades, but there are still limits in our understanding from gastric physiology to the tumorigenesis. For instance, roles of vagus nerve in regulation of gastric acid secretion and trophic effects of gastrin are unclear. Mechanisms behind gender predominance (i.e., females in ECLoma and males in adenocarcinoma) are unknown. Autophagy plays important roles in both cell survival and suicide, little is known about its role in gastric tumorigenesis. Thus, an improved understanding of the pathobiology with emphasis on the biological factors is important for translating research findings and knowledge into clinical managements of these diseases. Aims and hypotheses: The principle objective was to study the pathobiology of gastric carcinoids and adenocarcinomas in rodent models and patients with attempts to understand the roles of vagus nerve, gender-related factors and autophagy. Three hypotheses were tested: 1) Vagus nerve plays a crucial role in gastrin-ECL cell axis. 2) Female sex hormone plays important roles in regulation of ECL cells. 3) Autophagy pathway is impaired in the tumorigenesis of gastric carcinoids and adenocarcinomas. Methods: Gastrocystoplasty with fundectomy was established in rats, and the ECL cells in stomach as well as in bladder were examined. Rats during pregnancy, lactation, estrous cycle, or after nine months treatment with estrogen-like agents (dieldrin and/or toxaphene) were studied with respect to gastrin and ECL cells. Mastomys model of gastric carcinoids (treated with H2 receptor antagonist loxtidine), hypergastrinemic cotton rat model of adenocarcinoma and patients diagnosed as carcinoids or adenocarcinoma were studied with respect to autophagy. Serum gastrin concentration was measured. ECL-cell related parameters, including histamine concentration in the oxyntic mucosa, histidine decarboxylase activity, ultrastructural appearance and secretory organelles, cell numbers were determined. Autophagy pathway was examined by transmission electron microscopy and immunohistochemistry with antibodies against autophagy-related gene protein-6 (ATG 6, also called beclin-1), ATG-5 and ATG-16. Results: Rats subjected to gastrocystoplasty and 90% fundectomy were able to produce acid in the bladder in response to food intake. ECL-cell micronodules with mucosal hyperplasia in the augmented bladder were observed three months postoperatively, and ECL-cell hyperplasia and ECLoma in both the stomach and the segment of oxyntic mucosa developed six months after surgery. The serum gastrin concentration was higher in male than female rats, which was associated with higher HDC activity as well as ECL cell density in females. ECL cells were fully under control of gastrin during pregnancy and lactation and during the estrous cycle, and estrogen-like agents did not induce any changes in the gastrin-ECL cell axis neither in female nor male rats. ECL cells from the ECLoma tissue of Mastomys displayed fewer granules and secretory vesicles (but not microvesicles) in comparison with ECL cells from non-tumor tissue, and were neither hypertrophic nor autophagic (i.e., lack of formation of vacuoles and lipofuscin bodies). There were positive immunostains for ATG-5, ATG-16 and beclin-1 in all tumor-free Mastomys, but negative stains for ATG-5 and ATG-16 in tumor-bearing Mastomys (but only 1 of 5 for beclin-1). Ten patients with gastric carcinoid had similar results as Mastomys. The cotton rats with gastric adenocarcinoma were negative for ATG-5 and ATG-16 in the tumor area and adjacent tissue, but positive in the normal area of the same stomach. Beclin-1 immunostaining was negative in 3 of 5 rats. Ten patients with adenocarcinoma of intestinal type had similar results as the cotton rats. Conclusions: After gastrocystoplasty, gastrin was still capable of stimulating the ECL cells in vagal denervated segment in the augmented bladder, leading to development of ECLoma. The ECL cells in the stomach were activated during lactation but not during pregnancy and they were under control of gastrin but not female hormones. The ECL cells of ECLoma in Mastomys had impaired life cycle of the secretory organelles and autophagy. The impaired autophagy (mainly formation of ATG-5-ATG-12-ATG-16 complex) was found in gastric carcinoids of both Mastomys and patients, and in gastric adenocarcinomas of both hypergastrinemic cotton rats and patients.
UtgiverNorges teknisk-naturvitenskapelige universitet, Det medisinske fakultet, Institutt for kreftforskning og molekylær medisin
SerieDoktoravhandlinger ved NTNU, 1503-8181; 2011:218
Dissertations at the Faculty of Medicine, 0805-7680; 503