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

Abstract

The role of enterochromaffin‐like (ECL) cells in gastric carcinogenesis is not fully understood. Spontaneous tumours developing in hypergastrinemic female cotton rats have an adenocarcinoma phenotype, but numerous cells in the dysplastic mucosa as well as in the carcinomas are positive for neuroendocrine markers. In the present study of female cotton rats with 2 and 8 months' hypergastrinemia, the oxyntic mucosa of the stomach was examined histologically and immunolabelled for histidine decarboxylase (HDC) and pancreastatin, and hyperplastic and neoplastic ECL cells were evaluated by electron microscopy. These animals developed hyperplasia of the oxyntic mucosa in general and of the ECL cells in particular after 2 months and dysplasia and carcinomas after 8 months. The immunoreactivity of the ECL cells in the oxyntic mucosa was increased at 2 months and declined at 8 months. These histological changes were associated with progressive loss of secretory vesicles and granules in ECL cells. We suggest that ECL cells in hypergastrinemic cotton rats dedifferentiate with time and that the gastric carcinomas may develop from ECL cells.

Mixed glandular-neuroendocrine cancer of the gallbladder. Report of a case

“…On the basis of immunohistochemical stainings of gastrointestinal cancer cells it was proved that almost 40% of examined adenocarcinomas were positive for chromogranin and polypeptide hormones, which are characteristic for neuroendocrine tumours [9]. Some investigators suggest the possibility of coincidence of adenocarcinoma and neuroendocrine cancers in gastrointestinal malignancies [10][11][12][13]. In our case the two elements appear rather separated, indicating the presence of two independent tumours of different histotype.…”

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.…”

Consensus Diagnoses and Mode of Action for the Formation of Gastric Tumors in Rats Treated with the Chloroacetanilide Herbicides Alachlor and Butachlor

“…Rats in general have a higher density of ECL cells, achieve high levels of gastrin (>100 pg/ml), and are very responsive to elevations of gastrin (Tuch et al 1992) when compared to humans (Modlin and Sachs 2004;Thake, Iatropoulos, et al 1995;Williams, Iatropoulos, and Enzmann 2008), providing further support that this MOA is not relevant for humans. ECL cell tumors apparently dedifferentiate as they grow (Fossmark et al 2005). This is particularly relevant since in cotton rats the ECL cell tumors can have an adenocarcinoma phenotype with neuroendocrine differentiation (Fossmark et al 2004;Fossmark, Qvigstad, and Waldum 2008) and ECL cell tumors with similar characteristics can also be induced in cotton rats with the H2 receptor blocker, loxtidine (Fossmark et al 2004;Modlin and Kidd 2003).…”

“…Dedifferentiation of ECL cell tumors to fully developed tumors with variable phenotypic characteristics ECL cell tumors have the capacity to dedifferentiate as they grow Fossmark et al 2005) and are known to display a wide variety of histological appearances (Lewin and Appelman 1996). This is particularly relevant since in cotton rats the ECL cell tumors can have an adenocarcinoma phenotype with neuroendocrine differentiation (Fossmark et al 2004(Fossmark et al , 2005 and ECL cell tumors with similar characteristics can also be induced in cotton rats with the H2 blocker loxtidine (Fossmark et al 2004). A glandular tumor phenotype was also described in CD rats after long-term administration of loxtidine (Poynter et al 1985).…”