Spontaneous enterochromaffin-like cell carcinomas in cotton rats (Sigmodon hispidus) are prevented by a somatostatin analogue.

Abstract

Among inbred female cotton rats (Sigmodon hispidus) 25-50% of the animals develop spontaneous gastric carcinomas; the corresponding figure for male cotton rats is approximately 1%. Animals with carcinomas have hypergastrinaemia and gastric hypo-anacidity and the tumours are derived from enterochromaffin-like (ECL) cells. The mechanism behind the hypo-anacidity is unknown. Carcinomas are found in all female cotton rats with hypergastrinaemia lasting more than 4 months and this represents an excellent animal model for studying gastric carcinogenesis. In this study, the somatostatin analogue octreotide was given to female cotton rats to prevent carcinoma development caused by hypergastrinaemia. Twelve female cotton rats were given monthly injections of long-acting octreotide (5 mg i.m.) for 6 months. A control group of 20 animals was not given injections. Of the 20 control animals, 13 developed hypergastrinaemia and histologically invasive carcinomas or dysplasia. Of the 12 animals in the octreotide group, five developed hypergastrinaemia. None of these five animals developed histological cancer ðP < 0:05Þ; whereas three had dysplasia. However, octreotide did not affect plasma gastrin concentration or antral gastrin mRNA abundance significantly. Dysplasia of the oxyntic mucosa in hypergastrinaemic animals was accompanied by a marked increase in chromogranin A-immunoreactive cells and cells positive for Sevier-Munger staining. The malignant tissue also contained groups of cells with Sevier-Munger staining. In conclusion, octreotide prevented ECL cell carcinomas in hypergastrinaemic cotton rats without lowering the gastrin concentration.

Animal Models to Study the Role of Long‐Term Hypergastrinemia in Gastric Carcinogenesis

“…The animals developing carcinomas were later found to have gastric hypoacidity, secondary hypergastrinemia, and pronounced ECL cell hyperplasia [42]. The oxyntic mucosa in hypergastrinemic cotton rats has marked hyperplasia of chromogranin A, synaptophysin, and HDC immunoreactive cells and a proportion of the tumour cells are chromogranin A, pancreastatin, HDC, and Sevier-Munger positive [42–45]with similar changes found in mRNA expression [46, 47]. Between the age of two and six months, a proportion of female cotton rats develop gastric hypoacidity by an unknown mechanism, and develop carcinomas after approximately four months of hypergastrinemia.…”

“…Between the age of two and six months, a proportion of female cotton rats develop gastric hypoacidity by an unknown mechanism, and develop carcinomas after approximately four months of hypergastrinemia. Several studies have demonstrated the importance of gastrin in tumour development as carcinomas are prevented by injections of a gastrin receptor antagonist (YF476) [43], by removal of antral gastrin by antrectomy [48] or by administration of the somatostatin analogue octreotide [47]. Male cotton rats that are made hypergastrinemic due to either administration of loxtidine [49] or by partial corpectomy [50] also develop carcinomas in the oxyntic mucosa.…”

Gastric cancer: Animal studies on the risk of hypoacidity and hypergastrinemia

“…Animals developing carcinomas have gastric hypoacidity of an unknown cause and secondary hypergastrinemia [63] . The tumors develop from an oxyntic mucosa with marked hyperplasia of chromogranin A, synaptophysin and HDC-immunoreactive cells, and a proportion of the tumor cells are chromogranin A-, pancreastatin-, HDC-and Sevier-Munger-positive [63][64][65][66] . Carcinomas develop after 4 mo of hypergastrinemia, but are prevented by the gastrin receptor antagonist YF486 [64] , demonstrating gastrin is essential in carcinoma development in cotton rats.…”

Dedifferentiation of enterochromaffin‐like cells in gastric cancer of hypergastrinemic cotton rats

“…The carcinomas can also be induced in male cotton rats by long‐term administration of the insurmountable H2 receptor antagonist loxtidine (5) as well as by partial corpectomy (6). The carcinoma development can be prevented by a gastrin‐receptor antagonist (4) or by a somatostatin analogue (7). The oxyntic mucosa surrounding spontaneous as well as induced carcinomas has a marked increase in chromogranin A (CgA)‐ and Sevier‐Munger‐positive cells, demonstrating hyperplasia of enterochromaffin‐like (ECL) cells (4, 7–9).…”

“…The carcinoma development can be prevented by a gastrin‐receptor antagonist (4) or by a somatostatin analogue (7). The oxyntic mucosa surrounding spontaneous as well as induced carcinomas has a marked increase in chromogranin A (CgA)‐ and Sevier‐Munger‐positive cells, demonstrating hyperplasia of enterochromaffin‐like (ECL) cells (4, 7–9). We have argued that ECL cells lose expression of neuroendocrine markers during malignant transformation, explaining why only a proportion of the tumour cells are positive.…”