CXCR4-expressing Mist1+ progenitors in the gastric antrum contribute to gastric cancer development

Kosuke Sakitani; Yoku Hayakawa; Huan Deng; Hiroshi Ariyama; Hiroto Kinoshita; Mitsuru Konishi; Satoshi Ono; Nobumi Suzuki; Sozaburo Ihara; Zhengchuan Niu; Woosook Kim; Takayuki Tanaka; Haibo Liu; Xiaowei Chen; Yagnesh Tailor; James G Fox; Stephen F Konieczny; Hiroshi Onodera; Antonia R Sepulveda; Samuel Asfaha; Yoshihiro Hirata; Daniel L Worthley; Kazuhiko Koike; Timothy C Wang

doi:10.18632/oncotarget.22451

CXCR4-expressing Mist1⁺ progenitors in the gastric antrum contribute to gastric cancer development

Oncotarget. 2017 Nov 10;8(67):111012-111025. doi: 10.18632/oncotarget.22451. eCollection 2017 Dec 19.

Authors

Kosuke Sakitani^{1

2}, Yoku Hayakawa^{1

3}, Huan Deng^{1

4}, Hiroshi Ariyama¹, Hiroto Kinoshita³, Mitsuru Konishi³, Satoshi Ono³, Nobumi Suzuki², Sozaburo Ihara², Zhengchuan Niu^{1

5}, Woosook Kim¹, Takayuki Tanaka¹, Haibo Liu¹, Xiaowei Chen¹, Yagnesh Tailor¹, James G Fox⁶, Stephen F Konieczny⁷, Hiroshi Onodera⁸, Antonia R Sepulveda⁹, Samuel Asfaha¹, Yoshihiro Hirata³, Daniel L Worthley¹⁰, Kazuhiko Koike³, Timothy C Wang¹

Affiliations

¹ Division of Digestive and Liver Disease, Department of Medicine, Columbia University, College of Physicians and Surgeons, New York, NY, USA.
² Institute for Adult Diseases, Asahi Life Foundation, Tokyo, Japan.
³ Graduate School of Medicine, The University of Tokyo, Department of Gastroenterology, Tokyo, Japan.
⁴ Department of Pathology, The Fourth Affiliated Hospital of Nanchang University, Nanchang, China.
⁵ Department of General Surgery, Zhongshan Hospital, Fudan University, Shanghai, China.
⁶ Division of Comparative Medicine, Massachusetts Institute of Technology, Boston, MA, USA.
⁷ Department of Biological Sciences, The Purdue Center for Cancer Research, Purdue University, West Lafayette, IN, USA.
⁸ Department of Electrical and Electronic Engineering, The University of Tokyo, Tokyo, Japan.
⁹ Division of Clinical Pathology and Cell Biology, Department of Pathology, Columbia University College of Physicians and Surgeons, New York, NY, USA.
¹⁰ Cancer theme, SAHMRI and Department of Medicine, University of Adelaide, SA, Australia.

Abstract

Mist1 was recently shown to identify a discrete population of stem cells within the isthmus of the oxyntic gland within the gastric corpus. Chief cells at the base of the gastric corpus also express Mist1. The relevance of Mist1 expression as a marker of specific cell populations within the antral glands of the distal stomach, however, is unknown. Using Mist1-CreERT mice, we revealed that Mist1⁺ antral cells, distinct from the Mist1⁺ population in the corpus, comprise long-lived progenitors that reside within the antral isthmus above Lgr5⁺ or CCK2R⁺ cells. Mist1⁺ antral progenitors can serve as an origin of antral tumors induced by loss of Apc or MNU treatment. Mist1⁺ antral progenitors, as well as other antral stem/progenitor population, express Cxcr4, and are located in close proximity to Cxcl12 (the Cxcr4 ligand)-expressing endothelium. During antral carcinogenesis, there is an expansion of Cxcr4⁺ epithelial cells as well as the Cxcl12⁺ perivascular niche. Deletion of Cxcl12 in endothelial cells or pharmacological blockade of Cxcr4 inhibits antral tumor growth. Cxcl12/Cxcr4 signaling may be a potential therapeutic target.

Keywords: cxcl12; cxcr4; gastric cancer; mist1; stem cell.

Abstract

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