CCK2R identifies and regulates gastric antral stem cell states and carcinogenesis

Yoku Hayakawa, Guangchun Jin, Hongshan Wang, Xiaowei Chen, Christoph B. Westphalen, Samuel Asfaha, Bernhard W. Renz, Hiroshi Ariyama, Zinaida A. Dubeykovskaya, Yoshihiro Takemoto, Yoomi Lee, Ashlesha Muley, Yagnesh Tailor, Duan Chen, Sureshkumar Muthupalani, James G. Fox, Arthur Shulkes, Daniel L. Worthley, Shigeo Takaishi, Timothy C. Wang

    Research output: Contribution to journalArticle

    56 Citations (Scopus)

    Abstract

    Objective Progastrin is the incompletely cleaved precursor of gastrin that is secreted by G-cells in the gastric antrum. Both gastrin and progastrin bind to the CCK2 receptor (Cckbr or CCK2R) expressed on a subset of gastric epithelial cells. Little is known about how gastrin peptides and CCK2R regulate gastric stem cells and carcinogenesis. Interconversion among progenitors in the intestine is documented, but the mechanisms by which this occurs are poorly defined. Design We generated CCK2R-CreERT mice and performed inducible lineage tracing experiments. CCK2R+ antral cells and Lgr5+ antral stem cells were cultured in a three-dimensional in vitro system. We crossed progastrin-overexpressing mice with Lgr5-GFP-CreERT mice and examined the role of progastrin and CCK2R in Lgr5+ stem cells during MNU-induced carcinogenesis. Results Through lineage tracing experiments, we found that CCK2R defines antral stem cells at position +4, which overlapped with an Lgr5neg or low cell population but was distinct from typical antral Lgr5high stem cells. Treatment with progastrin interconverts Lgr5neg or low CCK2R+ cells into Lgr5high cells, increases CCK2R+ cell numbers and promotes gland fission and carcinogenesis in response to the chemical carcinogen MNU. Pharmacological inhibition or genetic ablation of CCK2R attenuated progastrin-dependent stem cell expansion and carcinogenesis. Conclusions CCK2R labels +4 antral stem cells that can be activated and expanded by progastrin, thus identifying one hormonal trigger for gastric stem cell interconversion and a potential target for gastric cancer chemoprevention and therapy.

    Original languageEnglish
    Pages (from-to)544-553
    Number of pages10
    JournalGut
    Volume64
    Issue number4
    DOIs
    Publication statusPublished - Apr 1 2015

    All Science Journal Classification (ASJC) codes

    • Gastroenterology

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    Hayakawa, Y., Jin, G., Wang, H., Chen, X., Westphalen, C. B., Asfaha, S., Renz, B. W., Ariyama, H., Dubeykovskaya, Z. A., Takemoto, Y., Lee, Y., Muley, A., Tailor, Y., Chen, D., Muthupalani, S., Fox, J. G., Shulkes, A., Worthley, D. L., Takaishi, S., & Wang, T. C. (2015). CCK2R identifies and regulates gastric antral stem cell states and carcinogenesis. Gut, 64(4), 544-553. https://doi.org/10.1136/gutjnl-2014-307190