CXCR4-expressing Mist1+ progenitors in the gastric antrum contribute to gastric cancer development
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Kosuke Sakitani1,4,*, Yoku Hayakawa1,2,*, Huan Deng1,3, Hiroshi Ariyama1, Hiroto Kinoshita2, Mitsuru Konishi2, Satoshi Ono2, Nobumi Suzuki4, Sozaburo Ihara4, Zhengchuan Niu1,5, Woosook Kim1, Takayuki Tanaka1, Haibo Liu1, Xiaowei Chen1, Yagnesh Tailor1, James G. Fox6, Stephen F. Konieczny7, Hiroshi Onodera8, Antonia R. Sepulveda9, Samuel Asfaha1, Yoshihiro Hirata2, Daniel L. Worthley10, Kazuhiko Koike2 and Timothy C. Wang1
1Division of Digestive and Liver Disease, Department of Medicine, Columbia University, College of Physicians and Surgeons, New York, NY, USA
2Graduate School of Medicine, The University of Tokyo, Department of Gastroenterology, Tokyo, Japan
3Department of Pathology, The Fourth Affiliated Hospital of Nanchang University, Nanchang, China
4Institute for Adult Diseases, Asahi Life Foundation, Tokyo, Japan
5Department of General Surgery, Zhongshan Hospital, Fudan University, Shanghai, China
6Division of Comparative Medicine, Massachusetts Institute of Technology, Boston, MA, USA
7Department of Biological Sciences, The Purdue Center for Cancer Research, Purdue University, West Lafayette, IN, USA
8Department of Electrical and Electronic Engineering, The University of Tokyo, Tokyo, Japan
9Division of Clinical Pathology and Cell Biology, Department of Pathology, Columbia University College of Physicians and Surgeons, New York, NY, USA
10Cancer theme, SAHMRI and Department of Medicine, University of Adelaide, SA, Australia
*These authors contributed equally to this work
Timothy C. Wang, email: firstname.lastname@example.org
Keywords: gastric cancer; stem cell; mist1; cxcr4; cxcl12
Received: October 26, 2017 Accepted: October 30, 2017 Published: November 10, 2017
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.
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