Conophylline suppresses pancreatic cancer desmoplasia and cancer‐promoting cytokines produced by cancer‐associated fibroblasts
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- Norihiro Ishii
- Division of Hepatobiliary and Pancreatic Surgery Department of General Surgical Science Graduate School of Medicine Gunma University Maebashi Japan
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- Kenichiro Araki
- Division of Hepatobiliary and Pancreatic Surgery Department of General Surgical Science Graduate School of Medicine Gunma University Maebashi Japan
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- Takehiko Yokobori
- Research Program for Omics‐based Medical Science Division of Integrated Oncology Research Gunma University Initiative for Advanced Research (GIAR) Maebashi Japan
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- Kei Hagiwara
- Division of Hepatobiliary and Pancreatic Surgery Department of General Surgical Science Graduate School of Medicine Gunma University Maebashi Japan
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- Dorgormaa Gantumur
- Division of Hepatobiliary and Pancreatic Surgery Department of General Surgical Science Graduate School of Medicine Gunma University Maebashi Japan
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- Takahiro Yamanaka
- Division of Hepatobiliary and Pancreatic Surgery Department of General Surgical Science Graduate School of Medicine Gunma University Maebashi Japan
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- Tadashi Handa
- Department of Diagnostic Pathology Graduate School of Medicine Gunma University Maebashi Japan
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- Mariko Tsukagoshi
- Division of Hepatobiliary and Pancreatic Surgery Department of General Surgical Science Graduate School of Medicine Gunma University Maebashi Japan
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- Takamichi Igarashi
- Division of Hepatobiliary and Pancreatic Surgery Department of General Surgical Science Graduate School of Medicine Gunma University Maebashi Japan
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- Akira Watanabe
- Division of Hepatobiliary and Pancreatic Surgery Department of General Surgical Science Graduate School of Medicine Gunma University Maebashi Japan
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- Norio Kubo
- Division of Hepatobiliary and Pancreatic Surgery Department of General Surgical Science Graduate School of Medicine Gunma University Maebashi Japan
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- Norifumi Harimoto
- Division of Hepatobiliary and Pancreatic Surgery Department of General Surgical Science Graduate School of Medicine Gunma University Maebashi Japan
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- Atsushi Masamune
- Division of Gastroenterology Graduate School of Medicine Tohoku University Sendai Japan
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- Kazuo Umezawa
- Department of Molecular Target Medicine Aichi Medical University School of Medicine Nagakute Japan
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- Hiroyuki Kuwano
- Division of Gastroenterological Surgery Department of General Surgical Science Graduate School of Medicine Gunma University Maebashi Japan
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- Ken Shirabe
- Division of Hepatobiliary and Pancreatic Surgery Department of General Surgical Science Graduate School of Medicine Gunma University Maebashi Japan
説明
<jats:p>Despite recent advances in cancer treatment, pancreatic cancer is a highly malignant tumor type with a dismal prognosis and it is characterized by dense desmoplasia in the cancer tissue. Cancer‐associated fibroblasts (CAF) are responsible for this fibrotic stroma and promote cancer progression. We previously reported that a novel natural compound conophylline (CnP) extracted from the leaves of a tropical plant reduced liver and pancreatic fibrosis by suppression of stellate cells. However, there have been no studies to investigate the effects of CnP on CAF, which is the aim of this work. Here, we showed that CAF stimulated indicators of pancreatic cancer malignancy, such as proliferation, invasiveness, and chemoresistance. We also showed that CnP suppressed CAF activity and proliferation, and inhibited the stimulating effects of CAF on pancreatic cancer cells. Moreover, CnP strongly decreased the various cytokines involved in cancer progression, such as interleukin (IL)‐6, IL‐8, C‐C motif chemokine ligand 2 (CCL2), and C‐X‐C motif chemokine ligand 12 (CXCL12), secreted by CAF. In vivo, CAF promoted tumor proliferation and desmoplastic formation in a mouse xenograft model, CnP reduced desmoplasia of tumors composed of pancreatic cancer cells + CAF, and combination therapy of CnP with gemcitabine remarkably inhibited tumor proliferation. Our findings suggest that CnP is a promising therapeutic strategy of combination therapy with anticancer drugs to overcome refractory pancreatic cancers.</jats:p>
収録刊行物
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- Cancer Science
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Cancer Science 110 (1), 334-344, 2018-12-13
Wiley
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詳細情報 詳細情報について
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- CRID
- 1360848660420610432
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- ISSN
- 13497006
- 13479032
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- データソース種別
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- Crossref
- KAKEN