Abstract 2251: Loss of epithelial PTEN affects gastric homeostasis and leads to spasmolytic polypeptide-expressing metaplasia in the mouse

Abstract

Abstract AIMS: The phosphatase and tensin homolog (PTEN), a negative regulator of the phosphatidylinositol 3-kinase/ AKT pathway, is one of the most frequently mutated/deleted gene in various human cancers. PTEN has also been shown to regulate numerous cellular processes such as genomic stability, stem cell renewal, senescence and cell differentiation. However, the potential effects of Pten on gastric organogenesis and homeostasis have not yet been explored. The aim of our study is to investigate the role of epithelial Pten signaling in the maintenance and specification of gastric epithelium. METHODS: Using the Cre/loxP system, we have generated a mouse model with a deletion of Pten exclusively in the foregut endoderm (PtenαGEC). Glandular architecture was assessed with H&E staining. Analysis of cell proliferation was performed by immunofluorescence with a PCNA antibody. Gastric cell type patterns from control and mutant mice were analyzed by antibody- specific immunostaining, alcian blue and Periodic Acid Schiff stainings. RESULTS: PtenαGEC mice are viable and have no severe abnormality in gastric organogenesis. Loss of Pten in the stomach epithelium was confirmed by IHC and, as expected, leads to an increase of p-Akt in the mutant gastric glands. Histological analysis by H&E staining demonstrates a disorganized glandular architecture associated with cystic regions in the corpus from 4 months of age. The PtenαGEC mice display a delocalization and upregulation in epithelial proliferation associated to an increase of the glands length. Analysis of the different cell lineages shows an increase in the mucus cell population. Furthermore, chromogranin A immunostaining shows an increase in the number of enteroendocrine cells in Pten mutant mice. Analysis of parietal cells reveals a significant decrease in this cell population in PtenαGEC mice. Surprisingly, zymogenic cells are absent from the glandular epithelium in mutant mice, whereas GSII positive cells, specific for neck cells, are increased and delocalized to the basal region. The latter observations suggest a possible induction of SPEM (spasmolytic polypeptide-expressing metaplasia) in these mice. Furthermore with aging, loss of PTEN leads to an increasing inflammatory process demonstrated by the expression of myeloperoxidase positive cells in the cystic regions and the mesenchyme. CONCLUSION: Altogether, our results indicate that PTEN in the gastric epithelium impacts on gastric gland architecture, negatively regulates the proliferation and plays an important role in the regulation of the cytodifferentiation and maturation of gastric cells. Finally loss epithelial Pten is sufficient for SPEM development and presence of inflammatory markers with age. 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 2251. doi:1538-7445.AM2012-2251