Journal
ONCOTARGET
Volume 8, Issue 67, Pages 111012-111025Publisher
IMPACT JOURNALS LLC
DOI: 10.18632/oncotarget.22451
Keywords
gastric cancer; stem cell; mist1; cxcr4; cxcl12
Categories
Funding
- National Institute of Health [U54CA126513, R01CA093405, R01CA120979, R01DK052778]
- Clyde Wu Family Foundation
- JSPS
- Mitsukoshi health and Welfare Foundation
- Project for Cancer Research And Therapeutic Evolution (P-CREATE) from the Japan Agency of Medical Research and Development, AMED
- KAKENHI [16H06749, 17H05081]
- Kobayashi Foundation for Cancer Research
- Mochida Memorial Foundation for Medical and Pharmacological Research
- Mitsubishi Foundation, Natural Sciences, the Advanced Research and Development Programs for Medical Innovation (PRIME)
- Tokyo Society of Medical Sciences
- Foundation of Jiangxi Educational Committee [20151BAB215008, 20151BBG70200]
- China Scholarship Council
- Grants-in-Aid for Scientific Research [17H05081, 15J00069, 16H06749] Funding Source: KAKEN
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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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