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.
Highlights
Gastric cancer is one of the leading causes of cancer death worldwide, and the prognosis for patients with advanced disease remains poor [1, 2]
Mist1 expression has been reported in the gastric corpus [16], we recently found abundant Cre recombination in the antrum of Mist1-CreERT mice, and that Mist1 antral lineages appeared to contribute to tumor development [17]
To clarify Mist1 expression in the stomach in more detail, we looked at an entire longitudinal section of Mist1-CreERT; R26-TdTomato mice 5 days after tamoxifen (TAM) induction (Figure 1A)
Summary
Gastric cancer is one of the leading causes of cancer death worldwide, and the prognosis for patients with advanced disease remains poor [1, 2]. Mist1+ stem cells are regulated by Cxcl12+ endothelial cells and Cxcr4+ innate lymphoid cells (ILCs), and the Cxcl12/Cxcr niche is required for progression to diffuse-type gastric cancer [9]. The gastric corpus and antrum are two different organs, in terms of anatomical and functional differences and their stem cell biology and contribution to carcinogenesis. The contribution of Cxcl12/Cxcr in antral stem cells and other form of gastric cancer has not been fully elucidated. Wnt and Notch signaling have been suggested as important modulators of gastrointestinal stem cells, other critical niche signals that regulate antral stem cells, and that might contribute to the development of cancer, have not been fully explored. We identify Mist expression in antral isthmus progenitors, and define their contribution to the antral lineages and to gastric cancer. We demonstrate a role for Cxcl12/Cxcr signaling in antral tumorigenesis
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