Hormonal Suppression of Stem Cells Inhibits Symmetric Cell Division and Gastric Tumorigenesis

© 2020 Elsevier Inc. Cancer is believed to arise from stem cells, but mechanisms that limit the acquisition of mutations and tumor development have not been well defined. We show that a +4 stem cell (SC) in the gastric antrum, marked by expression of Cck2r (a GPCR) and Delta-like ligand 1 (DLL1), is a label-retaining cell that undergoes predominant asymmetric cell division. This +4 antral SC is Notch1low/ Numb+ and repressed by signaling from gastrin-expressing endocrine (G) cells. Chemical carcinogenesis of the stomach is associated with loss of G cells, increased symmetric stem cell division, glandular fission, and more rapid stem cell lineage tracing, a process that can be suppressed by exogenous gastrin treatment. This hormonal suppression is associated with a marked reduction in gastric cancer mutational load, as revealed by exomic sequencing. Taken together, our results show that gastric tumorigenesis is associated with increased symmetric cell division that facilitates mutation and is suppressed by GPCR signaling. Using lineage-tracing assays and paired-cell analysis, Chang et al. show that murine Cck2r+ +4 antral stem cells undergo predominant asymmetric division and switch to symmetric division under carcinogenic stimulation. Tumorigenesis is associated with increased symmetric cell division that facilitates mutation and is suppressed by GPCR signaling

The Origins of Gastric Cancer From Gastric Stem Cells: Lessons From Mouse Models

The cellular origin of digestive cancers has been a long-standing question in the cancer field. Mouse models have identified long-lived stem cells in most organ systems, including the luminal gastrointestinal tract, and numerous studies have pointed to tissue resident stem cells as the main cellular origin of cancer. During gastric carcinogenesis, chronic inflammation induces genetic and epigenetic alterations in long-lived stem cells, along with expansion of stem cell niches, eventually leading to invasive cancer. The gastric corpus and antrum have distinct stem cells and stem cell niches, suggesting differential regulation of cancer initiation at the 2 sites. In this short review, we discuss recent experimental models and human studies, which provide important insights into the pathogenesis of gastric cancer.National Institutes of Health (U.S.) (grant U54CA126513)National Institutes of Health (U.S.) (grant R01CA093405)National Institutes of Health (U.S.) (grant R01CA120979)National Institutes of Health (U.S.) (grant R01DK052778)National Institutes of Health (U.S.) (grant R35CA210088)National Institutes of Health (U.S.) (grant T32OD010978)National Institutes of Health (U.S.) (grant P30ES002109)National Institutes of Health (U.S.) (grantd P01CA28842)Clyde Wu Family Foundatio