Title

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

Document Type

Journal Article

Publication Date

5-7-2020

Journal

Cell Stem Cell

Volume

26

Issue

5

DOI

10.1016/j.stem.2020.01.020

Keywords

asymmetric division; carcinogenesis; Cck2r; gastric neoplasm; gastrin; gene mutation; notch signaling; stem cell; symmetric division

Abstract

© 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.

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