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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Format: | Article |
Language: | English |
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MDPI AG
2018-04-01
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Series: | International Journal of Molecular Sciences |
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Online Access: | http://www.mdpi.com/1422-0067/19/4/1098 |
id |
doaj-732fc60fef534435926d0d5b42a064c4 |
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record_format |
Article |
collection |
DOAJ |
language |
English |
format |
Article |
sources |
DOAJ |
author |
Tatsuya Usui Masashi Sakurai Koji Umata Mohamed Elbadawy Takashi Ohama Hideyuki Yamawaki Shoichi Hazama Hiroko Takenouchi Masao Nakajima Ryouichi Tsunedomi Nobuaki Suzuki Hiroaki Nagano Koichi Sato Masahiro Kaneda Kazuaki Sasaki |
spellingShingle |
Tatsuya Usui Masashi Sakurai Koji Umata Mohamed Elbadawy Takashi Ohama Hideyuki Yamawaki Shoichi Hazama Hiroko Takenouchi Masao Nakajima Ryouichi Tsunedomi Nobuaki Suzuki Hiroaki Nagano Koichi Sato Masahiro Kaneda Kazuaki Sasaki Hedgehog Signals Mediate Anti-Cancer Drug Resistance in Three-Dimensional Primary Colorectal Cancer Organoid Culture International Journal of Molecular Sciences colorectal cancer Hedgehog signal chemoresistance organoid stem cell |
author_facet |
Tatsuya Usui Masashi Sakurai Koji Umata Mohamed Elbadawy Takashi Ohama Hideyuki Yamawaki Shoichi Hazama Hiroko Takenouchi Masao Nakajima Ryouichi Tsunedomi Nobuaki Suzuki Hiroaki Nagano Koichi Sato Masahiro Kaneda Kazuaki Sasaki |
author_sort |
Tatsuya Usui |
title |
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_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_sort |
hedgehog signals mediate anti-cancer drug resistance in three-dimensional primary colorectal cancer organoid culture |
publisher |
MDPI AG |
series |
International Journal of Molecular Sciences |
issn |
1422-0067 |
publishDate |
2018-04-01 |
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. |
topic |
colorectal cancer Hedgehog signal chemoresistance organoid stem cell |
url |
http://www.mdpi.com/1422-0067/19/4/1098 |
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doaj-732fc60fef534435926d0d5b42a064c42020-11-24T23:06:48ZengMDPI AGInternational Journal of Molecular Sciences1422-00672018-04-01194109810.3390/ijms19041098ijms19041098Hedgehog Signals Mediate Anti-Cancer Drug Resistance in Three-Dimensional Primary Colorectal Cancer Organoid CultureTatsuya Usui0Masashi Sakurai1Koji Umata2Mohamed Elbadawy3Takashi Ohama4Hideyuki Yamawaki5Shoichi Hazama6Hiroko Takenouchi7Masao Nakajima8Ryouichi Tsunedomi9Nobuaki Suzuki10Hiroaki Nagano11Koichi Sato12Masahiro Kaneda13Kazuaki Sasaki14Laboratory of Veterinary Pharmacology, Department of Veterinary Medicine, Faculty of Agriculture, Tokyo University of Agriculture and Technology, 3-5-8 Saiwai-cho, Fuchu, Tokyo 183-8509, JapanLaboratory of Veterinary Pathology, Joint Faculty of Veterinary Medicine, Yamaguchi University, 1677-1 Yoshida, Yamaguchi 753-8515, JapanLaboratory of Veterinary Pharmacology, Joint Faculty of Veterinary Medicine, Yamaguchi University, 1677-1 Yoshida, Yamaguchi 753-8515, JapanLaboratory of Veterinary Pharmacology, Department of Veterinary Medicine, Faculty of Agriculture, Tokyo University of Agriculture and Technology, 3-5-8 Saiwai-cho, Fuchu, Tokyo 183-8509, JapanLaboratory of Veterinary Pharmacology, Joint Faculty of Veterinary Medicine, Yamaguchi University, 1677-1 Yoshida, Yamaguchi 753-8515, JapanLaboratory of Veterinary Pharmacology, School of Veterinary Medicine, Kitasato University, Higashi 23 bancho 35-1, Towada City, Aomori 034-8628, JapanDepartment of Translational Research and Developmental Therapeutics against Cancer, School of Medicine, Yamaguchi University, 1-1-1 Ogushi, Ube, Yamaguchi 755-8505, JapanDepartment of Gastroenterological, Breast and Endocrine Surgery, Graduate School of Medicine, Yamaguchi University, 1-1-1 Ogushi, Ube, Yamaguchi 755-8505, JapanDepartment of Gastroenterological, Breast and Endocrine Surgery, Graduate School of Medicine, Yamaguchi University, 1-1-1 Ogushi, Ube, Yamaguchi 755-8505, JapanDepartment of Gastroenterological, Breast and Endocrine Surgery, Graduate School of Medicine, Yamaguchi University, 1-1-1 Ogushi, Ube, Yamaguchi 755-8505, JapanDepartment of Gastroenterological, Breast and Endocrine Surgery, Graduate School of Medicine, Yamaguchi University, 1-1-1 Ogushi, Ube, Yamaguchi 755-8505, JapanDepartment of Gastroenterological, Breast and Endocrine Surgery, Graduate School of Medicine, Yamaguchi University, 1-1-1 Ogushi, Ube, Yamaguchi 755-8505, JapanLaboratory of Veterinary Pharmacology, Joint Faculty of Veterinary Medicine, Yamaguchi University, 1677-1 Yoshida, Yamaguchi 753-8515, JapanLaboratory of Veterinary Anatomy, Department of Veterinary Medicine, Faculty of Agriculture, Tokyo University of Agriculture and Technology, 3-5-8 Saiwai-cho, Fuchu, Tokyo 183-8509, JapanLaboratory of Veterinary Pharmacology, Department of Veterinary Medicine, Faculty of Agriculture, Tokyo University of Agriculture and Technology, 3-5-8 Saiwai-cho, Fuchu, Tokyo 183-8509, JapanColorectal 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.http://www.mdpi.com/1422-0067/19/4/1098colorectal cancerHedgehog signalchemoresistanceorganoidstem cell |