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

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.