Gastric cancer in Japanese cotton rats
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The role of gastrin and the enterochromaffin-like (ECL) cell in human gastric carcinogenesis is not fully understood. There are numerous animal models that can be useful when studying this process. One such model is the Japanese cotton rat (Sigmodon hispidus) where a proportion of the females develops spontaneous gastric hypoacidity and hypergastrinemia from age 2-3 months. However, the cause of gastric hypoacidity is unknown. The tumours have an adenocarcinoma phenotype, but there are strong indications that the carcinomas develop from ECL cells. The carcinomas are confined to the gastric corpus, where ECL cells are found. There is pronounced hyperplasia of ECL cells (chromogranin A (CgA), histidine decarboxylase (HDC) and Sevier-Munger (SM) positive) in the oxyntic mucosa of hypergastrinemic animals, and a proportion of the malignant cells is also positive for these neuroendocrine markers. A previous study has shown that these carcinomas develop after 4 months of hypergastrinemia, but can be prevented by a gastrin receptor antagonist. In Paper I, the somatostatin receptor agonist octreotide was given to female cotton rats from age 2 months. Somatostatin has in several studies in other settings been shown to reduce hypergastrinemia. However, in cotton rats the hypergastrinemia was not significantly affected during administration of octreotide, but the development of carcinomas was prevented. This indicates that the antiproliferative effect of octreotide on the ECL cell is important in preventing carcinomas. Characterisation of the spontaneous carcinomas in hypergastrinemic control animals confirmed previous results regarding CgA and SM positivity. In animals with hypergastrinemia and a dysplastic oxyntic mucosa there was a reduction in the number of parietal cells. The female predisposition for spontaneous carcinoma development reported previously is not fully understood. In Paper II, the carcinogenic effect of hypergastrinemia induced by partial corpectomy of male cotton rats was studied. Six months after the operation, more than half of the male cotton rats displayed carcinomas. These carcinomas were histologically similar to spontaneous carcinomas in females, further indicating that gastrin is the principal carcinogen in this model. Long acting anti-secretory drugs raise the gastric pH and induce hypergastrinemia in patients. It was therefore of interest to examine whether administration of the irreversible histamine-2 receptor blocker loxtidine would result in hypergastrinemia and development of carcinomas. In Paper III male cotton rats were dosed with loxtidine for 6 months, which resulted in hypergastrinemia and development of carcinomas in the gastric corpus with CgA, HDC and SM positive cells. In areas of dysplastic mucosa, there was a marked reduction of parietal cells, indicating that the trophic effect of hypergastrinemia also results in loss of parietal cells. Some studies have indicated that a proportion of human adenocarcinomas with neuroendocrine differentiation is actually of neuroendocrine origin. Dedifferentiation of ECL cells during carcinoma development could explain why not all tumour cells are positive for neuroendocrine markers. The ultrastructure of ECL cells in hypergastrinemic cotton rats has not been studied previously and this was therefore of interest. In Paper IV, ECL cells of cotton rats with 2 and 8 months of hypergastrinemia displayed increasing loss of granules and secretory vesicles. Dedifferentiated ECL cells were also found in the tumour tissue. In hypergastrinemic animals, there were more HDC than pancreastatin positive cells, which corresponds with the finding of a loss of granules (containing pancreastatin) during ECL cell dedifferentiation. Altogether, the findings presented in Paper IV support previous suggestions that the carcinomas are ECL cell derived. In conclusion, hypergastrinemic cotton rats have proved to be a useful model when studying the role of gastrin and the ECL cell in gastric carcinogenesis.