| dc.description.abstract | The localization of the gastrin receptor on the enterochromaffin-like (ECL) cells and the dose-response curve for the histamine releasing effect of gastrin have been shown in rats. Furthermore, in this species the trophic effect of gastrin on the ECL cells as well as the acid producing mucosa in general has been demonstrated. Vagotomy reduces the trophic effects of hypergastrinemia on the acid producing mucosa and on the ECL cells in female cotton rats (Sigmodon hispidus). A proportion of these rats are known for developing hypoacidity and hypergastrinemia from two months of age, and among them many later develop adenocarcinomas with ECL cell characteristics. In humans, the trophic effect of hypergastrinemia is apparent in patients with gastrinoma and indirectly by corpus atrophy after removal of antrum in patients operated on because of peptic ulcers. The ECL cell density in the oxyntic mucosa in the rats is higher than in man, presumably due to higher blood gastrin secondary to frequent food intake. Nevertheless, the difference in baseline ECL density between these two species does not invalidate the relevance for man of rat studies with respect to hypergastrinemia. The incidence of adenocarcinomas in female cotton rats is reduced by netazepide (a gastrin receptor antagonist) by binding to gastrin receptors, and octreotide (a somatotatin analogue) by binding to somatostatin receptors subtype 2.
The relation between hypergastrinemia and cancer are not so clear in humans, possibly due to longer tumour latency in species with longer life spans. The simultaneous occurrence of corpus atrophy and hypergastrinemia in patients with chronic autoimmune atrophic gastritis and Helicobacter pylori gastritis makes it difficult to differentiate between the effect of hypergastrinemia and atrophy in epidemiological research. However, there are studies in humans reporting hypergastrinemia in patients with adenocarcinomas of the stomach. Further, it has been reported that gastric neuroendocrine tumours (g-NETs) related to hypergastrinemia may transform into carcinomas. Diffuse gastric cancers with signet cell differentiation have been demonstrated to have ECL cell characteristics, probably indicating that these carcinomas originate from the ECL cells by dedifferentiation.
The prevalence of diffuse gastric cancer and g-NETs seems to be rising. The pathophysiology of these neoplasms is important to investigate in humans. Clinical research may reveal risk factors identifying patients at an early stage and thus improve the outcome of patients with gastric cancer. In paper I, patients operated with proximal gastric vagotomy (PGV) 26-29 years earlier and age and gender matched controls were examined by gastroscopy and mucosal biopsies were taken to evaluate the ECLcell growth in the corpus mucosa. Individuals operated with PGV are known to develop a moderate hypergastrinemia. Despite the elevated fasting gastrin, there was no difference in volume density of neuroendocrine cells compared to controls, and we conclude that vagotomy may prevent ECL cell hyperplasia in humans.
In paper II, patients with non-cardia gastric adenocarcinomas diagnosed between 1992 and 2002 were reviewed retrospectively. Tumour location, histological classification according to Laurens classification and tumour stage were recorded from the medical records and preoperative fasting blood samples were analysed for gastrin, chromogranin A (CgA) and H. pylori antibodies. We found that the hypergastrinemic patients had tumours located in the gastric corpus more frequently than the normogastrinemic patients and that the hypergastrinemic patients in tumours stage 2-4 had shorter survival than normogastrinemic patients at similar stage. We did not find any difference in serum gastrin between the patients with intestinal and diffuse type of adenocarcinomas. Neither did we find any increased proportion of tumour CgA positivity in the group of hypergastrinemic patients. We concluded that hypergastrinemia is associated with adenocarcinomas of the gastric corpus and that the adenocarcinomas developing in hypergastrinemic patients behave more aggressively than the tumours in the normogastrinemic patients. These findings support the hypothesis that hypergastrinemia promotes carcinogenesis and affects biological behaviour of gastric adenocarcinomas.
In paper III, the presentation, treatment and outcome of patients with g-NETs treated at St. Olavs hospital between 1993 and 2013 were reviewed retrospectively. As in other case series, most patients had small and multiple tumours. We found a positive correlation between serum chromogranin A (CgA) and serum gastrin at diagnosis and between tumour size and age at time of diagnoses. Almost 20% of the patients were diagnosed with metastatic disease, more frequently than in most reports. The patients with metastases to lymph nodes and/or liver had larger primary tumours than those without metastases. The mortality was not different between the treatment groups, surgery, medical intervention or observation. However, two patients were diagnosed with gastric adenocarcinomas during follow-up, and two of five patients with metastatic disease had extensive disease dissemination. We concluded that even though patients with g-NETs type 1 usually have a good prognosis, a proportion of the patients develop severe malignant disease due to hypergastrinemia. These patients should undergo endoscopic surveillance and treatment should be considered consecutively.
In paper IV, the clinical course of five patients with g-NETs type 1 on long-term treatment with a gastrin receptor antagonist (netazepide) is described. No adverse events were reported. The number of tumours as well as the size of the largest tumour were reduced in all patients, reflecting the gastrin responsiveness of these neoplasms. Serum CgA, a measure of total ECL cell mass, fell rapidly and remained low during follow up. As expected in these anacidic patients, serum gastrin and volume density of gastrin immunoreactive (IR) cells in the antral part of the stomach remained unchanged. In conclusion, gastrin has a trophic effect on the ECL cells in humans and the effect of gastrin seems to be influenced by vagal innervation. Hypergastrinemia disposes to g-NETs and adenocarcinomas in the gastric corpus, both presumably of ECL cell origin. Tumours developing in hypergastrinemic patients seem to have a more aggressive behaviour than the others. As the level of gastrin in the hypergastrinemic patients varies considerably, we postulate that it is the presence of hypergastrinemia, i.e. the continuous trophic stimulus of gastrin and not the level of gastrin itself that promote cancer genesis. This is in accordance with previous studies in animals. The ECL cell, which is the only cell in the gastric acid producing mucosa with a physiologically important gastrin receptor, seems pivotal in the development and growth of gastric neuroendocrine tumours and gastric adenocarcinomas | nb_NO |
