Gastrin Blocks Symmetric Stem-Cell Division and Gastric Tumorigenesis

Although the cell type of origin for gastric cancer has not been pinpointed with certainty, gastric stem cells are considered likely candidates. Chang, Wang, and colleagues found that expression of cholecystokinin 2 receptor (CCK2R), the primary receptor for the peptide hormone gastrin, characterized some DLL1^hiNotch^loNumb⁺ stem cells in mouse gastric antral glands, where these CCK2R⁺ stem cells were observed to primarily undergo asymmetric cell division. The behavior of these CCK2R⁺ cells was regulated by gastrin; specifically, gastrin expression by neighboring endocrine cells (termed G cells) indirectly influenced Notch^loCCK2R⁺ stem cells via Notch signaling, with G cell–dependent gastrin exposure increasing asymmetric cell division associated with stemness and reducing proliferation of CCK2R⁺ cells. Gastrin deficiency caused by loss of gastrin-expressing G cells, however, increased CCK2R⁺ symmetric cell division and cell proliferation, promoting the accumulation of mutations. Interestingly, although CCK2R⁺ cells comprise a small portion of cells in the gastric antrum, they were more likely to contribute to WNT-mediated intestinal metaplasia and tumorigenesis following loss of Apc. Further, carcinogen treatment was associated with G-cell depletion and promoted symmetric cell division by CCK2R⁺ cells as well as stem-cell expansion, effects that were inhibited by exogenous gastrin treatment, and this gastrin treatment also suppressed tumorigenesis and the effects of mutagens on the gastric antrum. With respect to these findings' potential clinical relevance, analysis of tissue and sera from patients with mild (non-atrophic) gastritis, atrophic gastritis, gastritis with hyperplastic polyps, or gastric cancer implied that reduced gastrin expression correlated with progression to antral gastric cancer. Collectively, these results provide a cellular and molecular mechanistic basis for understanding the potential role of CCK2R⁺ cells as the progenitors of gastric cancer and supply evidence supporting the long-debated hypothesis that increased symmetric division of stem cells increases mutation rates and promotes tumorigenesis.

Chang W, Wang H, Kim W, Liu Y, Deng H, Liu H, et al. Hormonal suppression of stem cells inhibits symmetric cell division and gastric tumorigenesis. Cell Stem Cell 2020 Mar 5 [Epub ahead of print].

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