Effect of endogenous hypergastrinemia on carcinogenesis in the rat esophagus

Abstract

We surgically prepared a hypergastrinemia model in rats and studied the effects of hypergastrinemia on chemically induced carcinogenesis in the esophagus. Operations were performed on 5-week-old male Donryu rats as follows: (1) truncal vagotomy plus pyloroplasty (group V), (2) segmental gastrectomy plus pyloroplasty (group G), (3) antrectomy (group A), and (4) no operation (group C) as a control. From the age of 6 weeks, the animals were given 0.003% N-methyl- N-amylnitrosamine (MAN) solution as drinking water for 8 weeks. After 20 weeks of MAN administration, the animals were bled and killed. The average serum gastrin levels in groups V and G were significantly higher than those groups C or A. There were significant differences between C and V in the incidence of carcinoma, and between V and A in the incidence of carcinoma including severe dysplasia. The incidence of histologically identified lesions per animal was determined, and significant differences were observed between C and both V and G in the incidence of carcinoma including severe dysplasia. Furthermore, we also detected gastrin receptors in the esophageal lesions produced by the oral administration of MAN to rats. The results of the present study suggest that endogenous hypergastrinemia has a positive influence on chemically induced carcinogenesis in the rat esophagus.

Immunohistochemical Examination of Gastrin, Gastrin Precursors, and Gastrin/CCK-2 Receptor in Human Esophageal Squamous Cell Carcinomas

“…Given the finding of potential roles of gastrin precursors in stimulating human cancer growth in vitro [25,43,44] and animal cancer models in vivo [26, 28, It is well known that the effect of amidated gastrin on stimulating gastrointestinal cancer cell growth was mediated by gastrin/CCK2 receptors [15,17,18], a gastringastrin/CCK2 receptor loop was found in some human cancers [15,16,20,24] and targeting of gastrin/CCK2 receptor by peptide or antibody exhibited a therapeutic potential in colonic, pancreatic and hepatocellular carcinoma cell lines in vitro [46]. In animals, gastrin has been found to stimulate normal esophageal epithelium proliferation [31,47,48] and promote carcinogenesis [32]. In Barett's esophagus, gastrin induces proliferation [33], metaplasia [33], and reduced apoptosis [21], which were mediated by upregulated gastrin/CCK2 receptors [21,33].…”

“…Karaki et al [32] reported that hypergastrinemia in rats enhances chemical carcinogen induced esophageal carcinoma. In human, the important role of long-term hypergastrinemia on increasing risk of esophageal cancer has been reported to be mediated by stimulating the growth of Barrett's esophageal epithelium that were via several mechanisms including the activation of the gastrin/CCK2 receptor [30,33] and/or reduction of apoptosis [21].…”

Adenocarcinoma of the rat esophagus in the presence of a proton pump inhibitor: a pilot study

“…A recent study by Karakai et al . showed that squamous cell carcinomas grow more rapidly under the influence of high levels of gastrin, but that there was no differentiation to the adenocarcinomas 78 . Jankowski et al .…”

Changing role ofin vivomodels in columnar-lined lower esophagus

“…Iron supplementation, 52 endogenous hypergastrinemia, 53 alcohol, N ‐nitrosononicotine (NNN), 54 and zinc deficiency act as promoters of esophageal carcinogenesis in the N ‐nitrosamine rat and mouse model 55–57 . Ethanol promotes carcinogenesis through excessive cell proliferation induced by disordered lipid and eicosanoid metabolism 58 …”

“…51 It appears that pancreatic juice is the most potent component of the duodenal refluxate in the promotion of esophageal carcinogenesis in rats. 51 Iron supplementation, 52 endogenous hypergastrinemia, 53 alcohol, N-nitrosononicotine (NNN), 54 and zinc deficiency act as promoters of esophageal carcinogenesis in the N-nitrosamine rat and mouse model. [55][56][57] Ethanol promotes carcinogenesis through excessive cell proliferation induced by disordered lipid and eicosanoid metabolism.…”