178P - Chief cell in stomach have stem cell activity and potential to develop gastric cancer

Abstract

BackgroundRapidly proliferating stomach stem cells have been predicted to be located at the isthmus of both corpus and antrum. We recently identified such stem cells by using 270 bp Runx1 enhancer element, eR1 (Gastroenterol, 2017). In addition, eR1 also marked small number of fully differentiated chief cells in the corpus. We investigated whether chief cells have stem cell activity and can be an origin of gastric cancer, particularly because there are disagreements among the researchers. MethodsWe generated knock-in mice of pepsinogen C-CreERT2 and crossed them with Rosa26-EYFP mice or pepsinogen A-CreERT2 and crossed them with Rosa26-tdTomato mice for lineage tracing. PGC-CreERT2 mice were also crossed with K-rasG12D/+, Trp53flox/flox and Apcflox/floxmice for carcinogenesis model. Those mice were injected with Tamoxifen 2 mg alternate days for 6 timesto activate Cre recombinase in the chief cells. ResultsBy activating Cre recombinase, we showed that relatively small number of chief cells was retro-differentiated into neck, parietal, pit and enteroendocrinecells suggesting that chief cells underwent differentiation in exact reverse order to make a complete gland unit. When K-rasG12Dwas activated by pepsinogen C-CreERT2, induction of metaplasia was observed. Addition of p53 knockout with K-rasG12Dinto chief cells showed increasing number of glands with metaplasia. Furthermore, addition of APC knockout combination with K-rasG12Dand p53f/fshowed invasive intestinal type gastric cancer in the corpus. These results suggest that at least small subfraction of chief cell have stem cell activity and potential to give rise to gastric cancer. Recently, new entity of gastric adenocarcinoma has been proposed which called Gastric adenocarcinoma of fundic gland type (chief cell predominant type). We might have showed those type of gastric carcinogenesis. ConclusionsChief cell in stomach have stem cell activity and potential to develop gastric cancer. Legal entity responsible for the studyThe authors. FundingSingapore Gastric Cancer Consortium. DisclosureAll authors have declared no conflicts of interest.