The role of gastrin and the ECL cell in gastric carcinogenesis
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Gastrin is pivotal in gastric acid secretion, and also exerts a trophic effect on the oxyntic mucosa. The ECL cell is the only known cell in the oxyntic mucosa with a functional gastrin receptor, and the ECL cell produces histamine in response to gastrin stimulation. Longstanding hypergastrinemia predisposes to ECL neoplasia, which is associated with conditions such as atrophic gastritis and gastrinoma. Other conditions associated with hypergastrinemia include longstanding H. pylori infection and treatment with proton pump inhibitors. A proportion of gastric carcinomas have previously been suggested to be of neuroendocrine origin. This includes the diffuse gastric carcinoma classified according to the Lauren classification. This subgroup has previously been shown to exert ECL cell differentiation. In the diagnostics of neuroendocrine tumours, the detection of neuroendocrine markers such as Chromogranin A (CgA) could be challenging, and this requires adequate sensitivity of the methods applied. Previously signal amplification systems have been applied to immunohistochemistry in order to improve the sensitivity particularly in dedifferentiated tumour cells and the use of probe cocktails have been applied for situ hybridization. In paper I we have evaluated a new commercially available in situ hybridization (ISH) kit, and demonstrated mRNA expression of CgA and histidine decarboxylase (HDC. an ECL cell marker) in both normal oxyntic mucosa cells and in diffuse gastric cancer in dedifferentiated tumour cells. In addition we have been successful in detecting CgA and HDC mRNA in Mongolian gerbils, a species with poorly mapped genome and probe availability. In paper II we have evaluated the exocrine and neuroendocrine properties of diffuse gastric cancer with signet ring cell differentiation. We found no evidence for mucin gene products in the amorphous substance in signet ring cells or in non-signet ring tumour cells. We have found evidence for mRNA and protein expression of CgA, synaptophysin and Regenerating islet derived gene 4 (Reg 4) in both signet ring and non-signet ring tumour cells. These findings strengthen the hypothesis that this tumour group could be of neuroendocrine origin. In paper III we have evaluated the role of gastrin in H. pylori induced gastritis in Mongolian gerbils. We inoculated the gerbils with H. pylori and administered the gastrin receptor antagonist netazepide (YF476) to half of the animals for up to 18 months. The animals that received netazepide had no inflammation despite the presence of H. pylori. The majority of the infected animals that did not receive netazepide had transmural inflammation with thickened gastric mucosa and preneoplastic changes and an increased ECL cell number and ECL cell hyperplasia. These findings indicate that gastrin is pivotal in H. pylori induced gastritis and the pro-inflammatory effect could be mediated by histamine, an ECL cell mediator. In paper IV, a phase II study on netazepide (YF476) in type 1 gastric neuroendocrine tumour was presented. In this study, 8 patients were included in an open-label, pilot, phase II trial. The patients received 50mg netazepide p.o for 12 weeks. All patients had a reduction in carcinoid number and size after 12 weeks and one patient had complete regression of tumours. In addition, all patients had a normalization of serum CgA In conclusion we have demonstrated that gastrin and ECL cell mediators could be paramount in the H. pylori induced gastritis. We have shown abundant neuroendocrine expression in the diffuse type gastric cancer. We have also show that the netazepide is an effective drug in the treatment of type 1 gastric NETs.
UtgiverNorges teknisk-naturvitenskapelige universitet, Det medisinske fakultet, Institutt for kreftforskning og molekylær medisin
SerieDoktoravhandlinger ved NTNU, 1503-8181; 2012:262
Dissertations at the Faculty of Medicine, 0805-7680; 571