Abstract 1325: Loss of AGR2 results in compromised chief cell differentiation and preneoplastic metaplasia of stomach

Abstract Background: AGR2 represents Anterior Gradient 2, initially discovered in Xenopus where its expression at the anterior pole of the developing embryo induces forebrain and cement gland formation. In salamanders, AGR2 plays a role in nerve-dependent limb regeneration. AGR2 induces foci formation and anchorage independent growth in vitro. Increased AGR2 is observed in adenocarcinoma of the prostate, breast, pancreas, esophagus and ovaries. AGR2 overexpression transforms NIH3T3 cells resulting into tumor xenografts in nude mice. AGR2 induces expression of amphiregullin, EGFR ligand by affecting Hippo signaling pathway. In normal tissues it is expressed in the secretory lineage, paneth, enteroendocrine and goblet cells of the small intestine. AGR2's expression and role in stomach development and disease has not been studied. Stomach consists of three main regions: the fundus, lined with squamous keratinized epithelium, the corpus and the pylorus (glandular stomach). The corpus glands consist of the parietal cells, chief cells, foveolar cells, enterochromaffin cells, neck cells and stem cells. Parietal cells secrete acid for digestion, chief cells make digestive enzyme, pepsinogen and the foveolar cells secrete mucus. Proposed functions of neck cells include a role in mucus secretion or as a progenitor for chief cells. AGR2 is expressed by neck cells in the normal stomach. Hypothesis and methods: AGR2 expression in neck cells is critical for normal development of the stomach. This hypothesis is tested by generating a conditional AGR2 knock out mouse in which the floxed exons are excised with CMV induced expression of Cre-recombinase. Immunohistochemisty with lineage specific antibodies was performed to analyze the phenotype. Results: AGR2 loss results in weight loss and enlarged stomach in the mice. Histological analysis of stomach from AGR2 knock out mice demonstrates that AGR2 expression in the mucus neck cells is dispensable to terminal differentiation of chief cells. Loss of AGR2 results in incomplete maturation of chief cells. AGR2 loss is accompanied with increased cell proliferation in the stomach compared to the litter mate controls. The dividing cells exclude the lineage markers: H-KATPase (parietal cells), Muc5AC (faveolar cells), and intrinsic factor (chief cells). A significant expansion of TFF2 positive cells is observed that is also referred to as Spasmolytic polypeptide-expressing metaplasia (SPEM). In humans, SPEM is associated with precancerous stomach and is observed upon parietal cell loss.TFF2 in the normal stomach is expressed in the neck cells. Previous studies show that loss of parietal cells results in SPEM in the stomach. Loss of AGR2 triggers expansion of TFF2 expressing cells/SPEM before the loss of parietal cells. Conclusions: • AGR2 expression in neck cells is critical for terminal differentiation of chief cells. • Loss of AGR2 results in hyperplasia and SPEM in the stomach Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research; 2012 Mar 31-Apr 4; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2012;72(8 Suppl):Abstract nr 1325. doi:1538-7445.AM2012-1325