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

    研究成果: ジャーナルへの寄稿記事

    47 引用 (Scopus)

    抄録

    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.

    元の言語英語
    ページ(範囲)544-553
    ページ数10
    ジャーナルGut
    64
    発行部数4
    DOI
    出版物ステータス出版済み - 4 1 2015

    Fingerprint

    Stomach
    Carcinogenesis
    Stem Cells
    Gastrins
    Cholecystokinin B Receptor
    Pyloric Antrum
    Gastrin-Secreting Cells
    Antral
    Chemoprevention
    big gastrin
    Carcinogens
    Stomach Neoplasms
    Intestines
    Cell Count
    Epithelial Cells
    Pharmacology
    Peptides
    Therapeutics
    Population

    All Science Journal Classification (ASJC) codes

    • Gastroenterology

    これを引用

    Hayakawa, Y., Jin, G., Wang, H., Chen, X., Westphalen, C. B., Asfaha, 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

    CCK2R identifies and regulates gastric antral stem cell states and carcinogenesis. / Hayakawa, Yoku; Jin, Guangchun; Wang, Hongshan; Chen, Xiaowei; Westphalen, Christoph B.; Asfaha, Samuel; Renz, Bernhard W.; Ariyama, Hiroshi; Dubeykovskaya, Zinaida A.; Takemoto, Yoshihiro; Lee, Yoomi; Muley, Ashlesha; Tailor, Yagnesh; Chen, Duan; Muthupalani, Sureshkumar; Fox, James G.; Shulkes, Arthur; Worthley, Daniel L.; Takaishi, Shigeo; Wang, Timothy C.

    :: Gut, 巻 64, 番号 4, 01.04.2015, p. 544-553.

    研究成果: ジャーナルへの寄稿記事

    Hayakawa, Y, Jin, G, Wang, H, Chen, X, Westphalen, CB, Asfaha, S, Renz, BW, Ariyama, H, Dubeykovskaya, ZA, Takemoto, Y, Lee, Y, Muley, A, Tailor, Y, Chen, D, Muthupalani, S, Fox, JG, Shulkes, A, Worthley, DL, Takaishi, S & Wang, TC 2015, 'CCK2R identifies and regulates gastric antral stem cell states and carcinogenesis', Gut, 巻. 64, 番号 4, pp. 544-553. https://doi.org/10.1136/gutjnl-2014-307190
    Hayakawa Y, Jin G, Wang H, Chen X, Westphalen CB, Asfaha S その他. CCK2R identifies and regulates gastric antral stem cell states and carcinogenesis. Gut. 2015 4 1;64(4):544-553. https://doi.org/10.1136/gutjnl-2014-307190
    Hayakawa, Yoku ; Jin, Guangchun ; Wang, Hongshan ; Chen, Xiaowei ; Westphalen, Christoph B. ; Asfaha, Samuel ; Renz, Bernhard W. ; Ariyama, Hiroshi ; Dubeykovskaya, Zinaida A. ; Takemoto, Yoshihiro ; Lee, Yoomi ; Muley, Ashlesha ; Tailor, Yagnesh ; Chen, Duan ; Muthupalani, Sureshkumar ; Fox, James G. ; Shulkes, Arthur ; Worthley, Daniel L. ; Takaishi, Shigeo ; Wang, Timothy C. / CCK2R identifies and regulates gastric antral stem cell states and carcinogenesis. :: Gut. 2015 ; 巻 64, 番号 4. pp. 544-553.
    @article{7432090b835a477fb352431f4ed68bfb,
    title = "CCK2R identifies and regulates gastric antral stem cell states and carcinogenesis",
    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.",
    author = "Yoku Hayakawa and Guangchun Jin and Hongshan Wang and Xiaowei Chen and Westphalen, {Christoph B.} and Samuel Asfaha and Renz, {Bernhard W.} and Hiroshi Ariyama and Dubeykovskaya, {Zinaida A.} and Yoshihiro Takemoto and Yoomi Lee and Ashlesha Muley and Yagnesh Tailor and Duan Chen and Sureshkumar Muthupalani and Fox, {James G.} and Arthur Shulkes and Worthley, {Daniel L.} and Shigeo Takaishi and Wang, {Timothy C.}",
    year = "2015",
    month = "4",
    day = "1",
    doi = "10.1136/gutjnl-2014-307190",
    language = "English",
    volume = "64",
    pages = "544--553",
    journal = "Gut",
    issn = "0017-5749",
    publisher = "BMJ Publishing Group",
    number = "4",

    }

    TY - JOUR

    T1 - CCK2R identifies and regulates gastric antral stem cell states and carcinogenesis

    AU - Hayakawa, Yoku

    AU - Jin, Guangchun

    AU - Wang, Hongshan

    AU - Chen, Xiaowei

    AU - Westphalen, Christoph B.

    AU - Asfaha, Samuel

    AU - Renz, Bernhard W.

    AU - Ariyama, Hiroshi

    AU - Dubeykovskaya, Zinaida A.

    AU - Takemoto, Yoshihiro

    AU - Lee, Yoomi

    AU - Muley, Ashlesha

    AU - Tailor, Yagnesh

    AU - Chen, Duan

    AU - Muthupalani, Sureshkumar

    AU - Fox, James G.

    AU - Shulkes, Arthur

    AU - Worthley, Daniel L.

    AU - Takaishi, Shigeo

    AU - Wang, Timothy C.

    PY - 2015/4/1

    Y1 - 2015/4/1

    N2 - 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.

    AB - 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.

    UR - http://www.scopus.com/inward/record.url?scp=84924371079&partnerID=8YFLogxK

    UR - http://www.scopus.com/inward/citedby.url?scp=84924371079&partnerID=8YFLogxK

    U2 - 10.1136/gutjnl-2014-307190

    DO - 10.1136/gutjnl-2014-307190

    M3 - Article

    C2 - 24951258

    AN - SCOPUS:84924371079

    VL - 64

    SP - 544

    EP - 553

    JO - Gut

    JF - Gut

    SN - 0017-5749

    IS - 4

    ER -