A cellular key to the gastric inflammation-metaplasia-carcinoma sequence?

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DESCRIPTION (provided by applicant): Gastric cancer is one of the most frequent causes of cancer-related death world wide. Chronic inflammation as a result of Helicobacter pylori infection is an important initiating factor in a sequence that develops over years and progresses from atrophic gastritis, intestinal metaplasia, dysplasia and finally, adenocarcinoma. It has been speculated that the mutational changes that finally result in gastric cancer originate in the stem cell compartment; thus, characterization of gastric stem cells is an important clinical goal. However, the prospective recognition and isolation of gastric stem cells has been heretofore impossible because of the lack of specific markers for these cells. Moreover, the tools necessary to trace the progeny of single gastric progenitor cells (to establish definitively whether these cells give rise to gastric tumors) have not been available. Data presented here show that the mouse villin promoter is active in a subpopulation of gastric cells that exhibit characteristics of progenitor or stem cells; the cells are called pGPC (putative gastric progenitor cells). pGPC arise early in development and are found throughout life in epithelial compartments known to contain stem cells. Lineage tracing experiments in situ suggest that pGPC have multi-lineage potential. Interestingly, interferon gamma (IFNgamma), a potent pro-inflammatory stimulus known to be tightly associated with the development of gastric cancer, causes a robust increase in the number of pGPC. The hypothesis underlying this work is that pGPC are gastric progenitor or stem-like cells and that they play a key role in the "chronic gastritis-intestinal metaplasia-carcinoma" sequence. Thus, the goal of this project is to further characterize pGPC in vivo in murine stomachs and to investigate whether these cells give rise to metaplastic lesions and to gastric tumors. This work can provide major insights into gastrointestinal stem cell biology, an area that has been notoriously difficult to investigate at the single cell level. Moreover, if it is demonstrated that tumors indeed arise from pGPC, this will have enormous implications for the further study and future clinical management of gastric cancer.