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Title: Indispensable role of Notch ligand-dependent signaling in the proliferation and stem cell niche maintenance of APC-deficient intestinal tumors

Abstract

Ligand-dependent activation of Notch signaling is required to maintain the stem-cell niche of normal intestinal epithelium. However, the precise role of Notch signaling in the maintenance of the intestinal tumor stem cell niche and the importance of the RBPJ-independent non-canonical pathway in intestinal tumors remains unknown. Here we show that Notch signaling was activated in LGR5{sup +ve} cells of APC-deficient mice intestinal tumors. Accordingly, Notch ligands, including Jag1, Dll1, and Dll4, were expressed in these tumors. In vitro studies using tumor-derived organoids confirmed the intrinsic Notch activity-dependent growth of tumor cells. Surprisingly, the targeted deletion of Jag1 but not RBPJ in LGR5{sup +ve} tumor-initiating cells resulted in the silencing of Hes1 expression, disruption of the tumor stem cell niche, and dramatic reduction in the proliferation activity of APC-deficient intestinal tumors in vivo. Thus, our results highlight the importance of ligand-dependent non-canonical Notch signaling in the proliferation and maintenance of the tumor stem cell niche in APC-deficient intestinal adenomas. - Highlights: • Notch signaling is activated in LGR5{sup +ve} cells of APC-deficient intestinal tumors. • Lack of Jag1 but not RBPJ disrupts stem cell niche formation in those tumors. • Lack of Jag1 reduces the proliferation activity of APC-deficient intestinal tumors.

Authors:
 [1];  [1];  [2];  [1];  [1];  [3]; ; ; ; ; ; ; ; ; ;  [1];  [4];  [5];  [1];  [1] more »;  [6] « less
  1. Department of Gastroenterology and Hepatology, Graduate School, Tokyo Medical and Dental University, Tokyo (Japan)
  2. (United States)
  3. (Germany)
  4. Department of Advanced Therapeutics in GI Diseases, Tokyo Medical and Dental University, Tokyo (Japan)
  5. Department of Immunology, Tokai University School of Medicine, Isehara (Japan)
  6. (Japan)
Publication Date:
OSTI Identifier:
22696805
Resource Type:
Journal Article
Resource Relation:
Journal Name: Biochemical and Biophysical Research Communications; Journal Volume: 482; Journal Issue: 4; Other Information: Copyright (c) 2016 Elsevier Science B.V., Amsterdam, The Netherlands, All rights reserved.; Country of input: International Atomic Energy Agency (IAEA)
Country of Publication:
United States
Language:
English
Subject:
60 APPLIED LIFE SCIENCES; GOLGI COMPLEXES; IN VIVO; MAINTENANCE; NOTCHES; PLANT GROWTH; SIGNALS; STEM CELLS; TUMOR CELLS

Citation Formats

Nakata, Toru, Shimizu, Hiromichi, Department of Medicine, University of California, San Francisco, San Francisco, CA, Nagata, Sayaka, Ito, Go, Institute of Clinical Molecular Biology, Christian-Albrechts-University Kiel, D-24105 Kiel, Fujii, Satoru, Suzuki, Kohei, Kawamoto, Ami, Ishibashi, Fumiaki, Kuno, Reiko, Anzai, Sho, Murano, Tatsuro, Mizutani, Tomohiro, Oshima, Shigeru, Tsuchiya, Kiichiro, Nakamura, Tetsuya, Hozumi, Katsuto, Watanabe, Mamoru, Okamoto, Ryuichi, and Center for Stem Cell and Regenerative Medicine, Tokyo Medical and Dental University, Tokyo. Indispensable role of Notch ligand-dependent signaling in the proliferation and stem cell niche maintenance of APC-deficient intestinal tumors. United States: N. p., 2017. Web. doi:10.1016/J.BBRC.2016.12.031.
Nakata, Toru, Shimizu, Hiromichi, Department of Medicine, University of California, San Francisco, San Francisco, CA, Nagata, Sayaka, Ito, Go, Institute of Clinical Molecular Biology, Christian-Albrechts-University Kiel, D-24105 Kiel, Fujii, Satoru, Suzuki, Kohei, Kawamoto, Ami, Ishibashi, Fumiaki, Kuno, Reiko, Anzai, Sho, Murano, Tatsuro, Mizutani, Tomohiro, Oshima, Shigeru, Tsuchiya, Kiichiro, Nakamura, Tetsuya, Hozumi, Katsuto, Watanabe, Mamoru, Okamoto, Ryuichi, & Center for Stem Cell and Regenerative Medicine, Tokyo Medical and Dental University, Tokyo. Indispensable role of Notch ligand-dependent signaling in the proliferation and stem cell niche maintenance of APC-deficient intestinal tumors. United States. doi:10.1016/J.BBRC.2016.12.031.
Nakata, Toru, Shimizu, Hiromichi, Department of Medicine, University of California, San Francisco, San Francisco, CA, Nagata, Sayaka, Ito, Go, Institute of Clinical Molecular Biology, Christian-Albrechts-University Kiel, D-24105 Kiel, Fujii, Satoru, Suzuki, Kohei, Kawamoto, Ami, Ishibashi, Fumiaki, Kuno, Reiko, Anzai, Sho, Murano, Tatsuro, Mizutani, Tomohiro, Oshima, Shigeru, Tsuchiya, Kiichiro, Nakamura, Tetsuya, Hozumi, Katsuto, Watanabe, Mamoru, Okamoto, Ryuichi, and Center for Stem Cell and Regenerative Medicine, Tokyo Medical and Dental University, Tokyo. Sun . "Indispensable role of Notch ligand-dependent signaling in the proliferation and stem cell niche maintenance of APC-deficient intestinal tumors". United States. doi:10.1016/J.BBRC.2016.12.031.
@article{osti_22696805,
title = {Indispensable role of Notch ligand-dependent signaling in the proliferation and stem cell niche maintenance of APC-deficient intestinal tumors},
author = {Nakata, Toru and Shimizu, Hiromichi and Department of Medicine, University of California, San Francisco, San Francisco, CA and Nagata, Sayaka and Ito, Go and Institute of Clinical Molecular Biology, Christian-Albrechts-University Kiel, D-24105 Kiel and Fujii, Satoru and Suzuki, Kohei and Kawamoto, Ami and Ishibashi, Fumiaki and Kuno, Reiko and Anzai, Sho and Murano, Tatsuro and Mizutani, Tomohiro and Oshima, Shigeru and Tsuchiya, Kiichiro and Nakamura, Tetsuya and Hozumi, Katsuto and Watanabe, Mamoru and Okamoto, Ryuichi and Center for Stem Cell and Regenerative Medicine, Tokyo Medical and Dental University, Tokyo},
abstractNote = {Ligand-dependent activation of Notch signaling is required to maintain the stem-cell niche of normal intestinal epithelium. However, the precise role of Notch signaling in the maintenance of the intestinal tumor stem cell niche and the importance of the RBPJ-independent non-canonical pathway in intestinal tumors remains unknown. Here we show that Notch signaling was activated in LGR5{sup +ve} cells of APC-deficient mice intestinal tumors. Accordingly, Notch ligands, including Jag1, Dll1, and Dll4, were expressed in these tumors. In vitro studies using tumor-derived organoids confirmed the intrinsic Notch activity-dependent growth of tumor cells. Surprisingly, the targeted deletion of Jag1 but not RBPJ in LGR5{sup +ve} tumor-initiating cells resulted in the silencing of Hes1 expression, disruption of the tumor stem cell niche, and dramatic reduction in the proliferation activity of APC-deficient intestinal tumors in vivo. Thus, our results highlight the importance of ligand-dependent non-canonical Notch signaling in the proliferation and maintenance of the tumor stem cell niche in APC-deficient intestinal adenomas. - Highlights: • Notch signaling is activated in LGR5{sup +ve} cells of APC-deficient intestinal tumors. • Lack of Jag1 but not RBPJ disrupts stem cell niche formation in those tumors. • Lack of Jag1 reduces the proliferation activity of APC-deficient intestinal tumors.},
doi = {10.1016/J.BBRC.2016.12.031},
journal = {Biochemical and Biophysical Research Communications},
number = 4,
volume = 482,
place = {United States},
year = {Sun Jan 22 00:00:00 EST 2017},
month = {Sun Jan 22 00:00:00 EST 2017}
}