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 AsfahaYoshihiro Hirata, Daniel L. Worthley, Kazuhiko Koike, Timothy C. Wang

Research output: Contribution to journalArticlepeer-review

11 Citations (Scopus)

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.

Original languageEnglish
Pages (from-to)111012-111025
Number of pages14
JournalOncotarget
Volume8
Issue number67
DOIs
Publication statusPublished - 2017
Externally publishedYes

All Science Journal Classification (ASJC) codes

  • Oncology

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