178PChief cell in stomach have stem cell activity and potential to develop gastric cancer. (24th November 2019)

• Record Type: Journal Article
• Authors: Yamamura, A; Matsuo, J; Lim Yi Hui, M; Liana Heng, D; Kofu, K; Md, Z H; Douchi, D; Yeoh, K G; Kamei, T; Naitoh, T; Osato, M; Unno, M; Ito, Y
• Is Part Of: Annals of oncology. Volume 30(2019)Supplement 9
• Publication Date: 2019-11-24
• Subjects: Oncology -- Periodicals; 616.992
• DOI: 10.1093/annonc/mdz422.055
• Languages: English
• ISSNs: 0923-7534

Abstract

Abstract: Background: Rapidly 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. Methods: We 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-ras G12D/+, Trp53 flox/flox and Apc flox/flox mice for carcinogenesis model. Those mice were injected with Tamoxifen 2 mg alternate days for 6 timesto activate Cre recombinase in the chief cells. Results: By 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-ras G12D was activated by pepsinogen C-CreERT2, induction of metaplasia was observed. Addition of p53 knockout with K-ras G12D into chief cells showed increasing number of glands with metaplasia. Furthermore, addition of APC knockout combination with K-ras G12D and p53 f/f showed 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. Conclusions: Chief cell in stomach have stem cell activity and potential to develop gastric cancer. Legal entity responsible for the study: The authors. Funding: Singapore Gastric Cancer Consortium. Disclosure: All authors have declared no conflicts of interest.