Gastric Neuroendocrine Tumors With Parietal Cell Atrophy in a Long-term Carcinogenicity Study in Rats

Abstract

Malignant neuroendocrine tumors were diagnosed in the stomach of two out of sixty female Sprague-Dawley rats treated for 89 weeks with a high dose of a novel, small molecule, cannabinoid-1 antagonist. The tumors were associated with parietal cell atrophy accompanied by foveolar hyperplasia of the glandular stomach mucosa. Parietal cell atrophy/foveolar hyperplasia was considered test article related at the high dose, given the higher incidence and severity relative to untreated controls, although the precise mechanism of the parietal cell atrophy was undetermined. Spontaneous gastric neuroendocrine tumors are very rare in rats, and the current cases were considered secondary to parietal cell atrophy causing reduced gastric acid secretion and subsequent overstimulation of gastrin release through a feedback loop.

GFAP-directed Inactivation of Men1 Exploits Glial Cell Plasticity in Favor of Neuroendocrine Reprogramming

“…Previous studies in transgenic mice identified hypergastrinemia-induced changes to the gastric epithelium, including parietal cell atrophy. 39 , 40 Here, we also observed decreased gastric acid levels in the setting of hypergastrinemia in GFAP ΔMen1 mice, consistent with the presence of metaplasia ( Figure 4 , G ). qPCR analysis of other gastric cell types further confirmed decreased expression of the parietal cell-specific marker Atp4b and significant upregulation of Gif, a marker of zymogenic chief cells ( Figure 4 , H–I ).…”