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

Wenju Chang; Hongshan Wang; Woosook Kim; Yang Liu; Huan Deng; Haibo Liu; Zhengyu Jiang; Zhengchuan Niu; Weiwei Sheng; Osmel Companioni Nápoles; Yihong Sun; Jianmin Xu; Antonia Sepulveda; Yoku Hayakawa; Adam J Bass; Timothy C Wang

doi:10.1016/j.stem.2020.01.020

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

Cell Stem Cell. 2020 May 7;26(5):739-754.e8. doi: 10.1016/j.stem.2020.01.020. Epub 2020 Mar 5.

Authors

Wenju Chang¹, Hongshan Wang², Woosook Kim³, Yang Liu⁴, Huan Deng⁵, Haibo Liu³, Zhengyu Jiang³, Zhengchuan Niu⁶, Weiwei Sheng³, Osmel Companioni Nápoles³, Yihong Sun⁷, Jianmin Xu⁸, Antonia Sepulveda⁹, Yoku Hayakawa¹⁰, Adam J Bass⁴, Timothy C Wang¹¹

Affiliations

¹ Department of General Surgery, Zhongshan Hospital, Fudan University, Shanghai 200032, China; Colorectal Cancer Center of Zhongshan Hospital, Fudan University, Shanghai 200032, China; Division of Digestive and Liver Diseases, Department of Medicine, Columbia University, College of Physicians and Surgeons, New York, NY 10032, USA.
² Department of General Surgery, Zhongshan Hospital, Fudan University, Shanghai 200032, China; Division of Digestive and Liver Diseases, Department of Medicine, Columbia University, College of Physicians and Surgeons, New York, NY 10032, USA; Gastric Cancer Center of Zhongshan Hospital, Fudan University, Shanghai 200032, China.
³ Division of Digestive and Liver Diseases, Department of Medicine, Columbia University, College of Physicians and Surgeons, New York, NY 10032, USA.
⁴ Division of Molecular and Cellular Oncology, Dana Farber Cancer Institute, Harvard Medical School, Boston, MA 02138, USA.
⁵ Division of Digestive and Liver Diseases, Department of Medicine, Columbia University, College of Physicians and Surgeons, New York, NY 10032, USA; The Fourth Affiliated Hospital of Nanchang University, Nanchang 330003, China.
⁶ Department of General Surgery, Zhongshan Hospital, Fudan University, Shanghai 200032, China; Division of Digestive and Liver Diseases, Department of Medicine, Columbia University, College of Physicians and Surgeons, New York, NY 10032, USA.
⁷ Department of General Surgery, Zhongshan Hospital, Fudan University, Shanghai 200032, China; Gastric Cancer Center of Zhongshan Hospital, Fudan University, Shanghai 200032, China.
⁸ Department of General Surgery, Zhongshan Hospital, Fudan University, Shanghai 200032, China; Colorectal Cancer Center of Zhongshan Hospital, Fudan University, Shanghai 200032, China.
⁹ Department of Pathology, Columbia University, College of Physicians and Surgeons, New York, NY 10032, USA.
¹⁰ Department of Gastroenterology, Graduate School of Medicine, The University of Tokyo, Tokyo 113-0033, Japan.
¹¹ Division of Digestive and Liver Diseases, Department of Medicine, Columbia University, College of Physicians and Surgeons, New York, NY 10032, USA. Electronic address: tcw21@columbia.edu.

Abstract

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 Notch1^low/ 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.

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

Publication types

Research Support, N.I.H., Extramural
Research Support, Non-U.S. Gov't

MeSH terms

Carcinogenesis*
Cell Division
Humans
Signal Transduction
Stem Cells*
Stomach

Abstract

Publication types

MeSH terms

Grants and funding