Regulation of gastric metaplasia, dysplasia and neoplasia by Bone Morphogenetic Protein signaling

University Of Michigan At Ann Arbor, Ann Arbor MI

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Abstract

Chronic inflammation contributes to the development of gastric dysplasia and neoplasia. The mechanisms responsible for these events have been only partially characterized. One hypothesis is that inflammation and mucosal injury cause aberrations in the normal biological functions of gastric stem/progenitor cells leading to the development of metaplasia and dysplasia and, ultimately, to neoplasia. Both Intestinal Metaplasia (IM) and spasmolytic polypeptide expressing metaplasia (SPEM) have been associated with inflammation-induced gastric neoplasms. The bone morphogenetic proteins, (BMPs) regulate the growth and differentiation of gastrointestinal tissues. The BMPs are also known to inhibit gastric inflammation, cell proliferation and the growth of gastric neoplasms. The Lgr5 gene marks gastric stem cells and it appears to play a significant role in in the development of gastric cancer. An increased number of Lgr5+ve cells has been detected in gastric tumors. The mechanisms that regulate the function of Lgr5+ve cells and their role in the development of gastric neoplasia are currently unknown. In preliminary studies conducted in mice, we observed Lgr5+ve cells at the base of antral glands and along the lesser curvature, an area that frequently gives rise to gastric neoplasms. We reported that inhibition of BMP signaling in the oxyntic mucosa by transgenic expression of the BMP inhibitor noggin (H+/K+-Nog mice), enhances Helicobacter-induced inflammation and it induces a pro- oncogenic environment characterized by increased epithelial cell proliferation and by the development of SPEM and of dysplastic changes of the gastric mucosa. We also showed that transgenic expression of noggin and deletion of the BMP receptor BMPR1A in Lgr5+ve cells, lead to an increase in Lgr5 gene expression and in the number of Lgr5+ve cells. Lineage tracing studies conducted in the presence of both noggin and H. felis demonstrated expression of markers of SPEM in Lgr5-derived cells. Moreover, deletion of BMPR1A and infection with H. felis, caused the development of dysplasia and of significant cellular changes of the gastric mucosa. The overall goal of this application is to investigate the role of BMP signaling in the regulation of Lgr5 cell homeostasis during gastric inflammation. We will test the hypothesis that inflammation and inhibition/loss of BMP signaling induce the aberrant activation of Lgr5+ve cells that might give rise to metaplastic and dysplastic epithelial lineages, and ultimately, to neoplasias. Toward this goal we will perform lineage-tracing experiments using Lgr5-Cre mice lines crossed to both noggin-tomato reporter mice and to mice carrying floxed alleles of BMPR1A. We will also test the effects of cytokines on the growth and differentiation of gastric organoids, derived from both mice stomachs and human biopsies, in order to define the mechanisms that control the homeostasis of Lgr5 progenitors. To determine the significance of BMP signaling in human diseases, we will measure the expression of BMPs, stem cell markers and of components of the BMP signal transduction pathway in samples derived from patients with gastric cancer, gastritis and intestinal metaplasia.