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Hedgehog Signals Mediate Anti-Cancer Drug Resistance in Three-Dimensional Primary Colorectal Cancer Organoid Culture

Colorectal cancer is one of the most common causes of cancer death worldwide. In patients with metastatic colorectal cancer, combination treatment with several anti-cancer drugs is employed and improves overall survival in some patients. Nevertheless, most patients with metastatic disease are not cu...

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Autores principales: Usui, Tatsuya, Sakurai, Masashi, Umata, Koji, Elbadawy, Mohamed, Ohama, Takashi, Yamawaki, Hideyuki, Hazama, Shoichi, Takenouchi, Hiroko, Nakajima, Masao, Tsunedomi, Ryouichi, Suzuki, Nobuaki, Nagano, Hiroaki, Sato, Koichi, Kaneda, Masahiro, Sasaki, Kazuaki
Formato: Online Artículo Texto
Lenguaje:English
Publicado: MDPI 2018
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5979580/
https://www.ncbi.nlm.nih.gov/pubmed/29642386
http://dx.doi.org/10.3390/ijms19041098
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author Usui, Tatsuya
Sakurai, Masashi
Umata, Koji
Elbadawy, Mohamed
Ohama, Takashi
Yamawaki, Hideyuki
Hazama, Shoichi
Takenouchi, Hiroko
Nakajima, Masao
Tsunedomi, Ryouichi
Suzuki, Nobuaki
Nagano, Hiroaki
Sato, Koichi
Kaneda, Masahiro
Sasaki, Kazuaki
author_facet Usui, Tatsuya
Sakurai, Masashi
Umata, Koji
Elbadawy, Mohamed
Ohama, Takashi
Yamawaki, Hideyuki
Hazama, Shoichi
Takenouchi, Hiroko
Nakajima, Masao
Tsunedomi, Ryouichi
Suzuki, Nobuaki
Nagano, Hiroaki
Sato, Koichi
Kaneda, Masahiro
Sasaki, Kazuaki
author_sort Usui, Tatsuya
collection PubMed
description Colorectal cancer is one of the most common causes of cancer death worldwide. In patients with metastatic colorectal cancer, combination treatment with several anti-cancer drugs is employed and improves overall survival in some patients. Nevertheless, most patients with metastatic disease are not cured owing to the drug resistance. Cancer stem cells are known to regulate resistance to chemotherapy. In the previous study, we established a novel three-dimensional organoid culture model from tumor colorectal tissues of human patients using an air–liquid interface (ALI) method, which contained numerous cancer stem cells and showed resistance to 5-fluorouracil (5-FU) and Irinotecan. Here, we investigate which inhibitor for stem cell-related signal improves the sensitivity for anti-cancer drug treatment in tumor ALI organoids. Treatment with Hedgehog signal inhibitors (AY9944, GANT61) decreases the cell viability of organoids compared with Notch (YO-01027, DAPT) and Wnt (WAV939, Wnt-C59) signal inhibitors. Combination treatment of AY9944 or GANT61 with 5-FU, Irinotecan or Oxaliplatin decreases the cell viability of tumor organoids compared with each anti-cancer drug alone treatment. Treatment with AY9944 or GANT61 inhibits expression of stem cell markers c-Myc, CD44 and Nanog, likely through the decrease of their transcription factor, GLI-1 expression. Combination treatment of AY9944 or GANT61 with 5-FU or Irinotecan also prevents colony formation of colorectal cancer cell lines HCT116 and SW480. These findings suggest that Hedgehog signals mediate anti-cancer drug resistance in colorectal tumor patient-derived ALI organoids and that the inhibitors are useful as a combinational therapeutic strategy against colorectal cancer.
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spelling pubmed-59795802018-06-10 Hedgehog Signals Mediate Anti-Cancer Drug Resistance in Three-Dimensional Primary Colorectal Cancer Organoid Culture Usui, Tatsuya Sakurai, Masashi Umata, Koji Elbadawy, Mohamed Ohama, Takashi Yamawaki, Hideyuki Hazama, Shoichi Takenouchi, Hiroko Nakajima, Masao Tsunedomi, Ryouichi Suzuki, Nobuaki Nagano, Hiroaki Sato, Koichi Kaneda, Masahiro Sasaki, Kazuaki Int J Mol Sci Article Colorectal cancer is one of the most common causes of cancer death worldwide. In patients with metastatic colorectal cancer, combination treatment with several anti-cancer drugs is employed and improves overall survival in some patients. Nevertheless, most patients with metastatic disease are not cured owing to the drug resistance. Cancer stem cells are known to regulate resistance to chemotherapy. In the previous study, we established a novel three-dimensional organoid culture model from tumor colorectal tissues of human patients using an air–liquid interface (ALI) method, which contained numerous cancer stem cells and showed resistance to 5-fluorouracil (5-FU) and Irinotecan. Here, we investigate which inhibitor for stem cell-related signal improves the sensitivity for anti-cancer drug treatment in tumor ALI organoids. Treatment with Hedgehog signal inhibitors (AY9944, GANT61) decreases the cell viability of organoids compared with Notch (YO-01027, DAPT) and Wnt (WAV939, Wnt-C59) signal inhibitors. Combination treatment of AY9944 or GANT61 with 5-FU, Irinotecan or Oxaliplatin decreases the cell viability of tumor organoids compared with each anti-cancer drug alone treatment. Treatment with AY9944 or GANT61 inhibits expression of stem cell markers c-Myc, CD44 and Nanog, likely through the decrease of their transcription factor, GLI-1 expression. Combination treatment of AY9944 or GANT61 with 5-FU or Irinotecan also prevents colony formation of colorectal cancer cell lines HCT116 and SW480. These findings suggest that Hedgehog signals mediate anti-cancer drug resistance in colorectal tumor patient-derived ALI organoids and that the inhibitors are useful as a combinational therapeutic strategy against colorectal cancer. MDPI 2018-04-06 /pmc/articles/PMC5979580/ /pubmed/29642386 http://dx.doi.org/10.3390/ijms19041098 Text en © 2018 by the authors. Licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license (http://creativecommons.org/licenses/by/4.0/).
spellingShingle Article
Usui, Tatsuya
Sakurai, Masashi
Umata, Koji
Elbadawy, Mohamed
Ohama, Takashi
Yamawaki, Hideyuki
Hazama, Shoichi
Takenouchi, Hiroko
Nakajima, Masao
Tsunedomi, Ryouichi
Suzuki, Nobuaki
Nagano, Hiroaki
Sato, Koichi
Kaneda, Masahiro
Sasaki, Kazuaki
Hedgehog Signals Mediate Anti-Cancer Drug Resistance in Three-Dimensional Primary Colorectal Cancer Organoid Culture
title Hedgehog Signals Mediate Anti-Cancer Drug Resistance in Three-Dimensional Primary Colorectal Cancer Organoid Culture
title_full Hedgehog Signals Mediate Anti-Cancer Drug Resistance in Three-Dimensional Primary Colorectal Cancer Organoid Culture
title_fullStr Hedgehog Signals Mediate Anti-Cancer Drug Resistance in Three-Dimensional Primary Colorectal Cancer Organoid Culture
title_full_unstemmed Hedgehog Signals Mediate Anti-Cancer Drug Resistance in Three-Dimensional Primary Colorectal Cancer Organoid Culture
title_short Hedgehog Signals Mediate Anti-Cancer Drug Resistance in Three-Dimensional Primary Colorectal Cancer Organoid Culture
title_sort hedgehog signals mediate anti-cancer drug resistance in three-dimensional primary colorectal cancer organoid culture
topic Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5979580/
https://www.ncbi.nlm.nih.gov/pubmed/29642386
http://dx.doi.org/10.3390/ijms19041098
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