Conophylline suppresses pancreatic cancer desmoplasia and cancer‐promoting cytokines produced by cancer‐associated fibroblasts

  • Norihiro Ishii
    Division of Hepatobiliary and Pancreatic Surgery Department of General Surgical Science Graduate School of Medicine Gunma University Maebashi Japan
  • Kenichiro Araki
    Division of Hepatobiliary and Pancreatic Surgery Department of General Surgical Science Graduate School of Medicine Gunma University Maebashi Japan
  • Takehiko Yokobori
    Research Program for Omics‐based Medical Science Division of Integrated Oncology Research Gunma University Initiative for Advanced Research (GIAR) Maebashi Japan
  • Kei Hagiwara
    Division of Hepatobiliary and Pancreatic Surgery Department of General Surgical Science Graduate School of Medicine Gunma University Maebashi Japan
  • Dorgormaa Gantumur
    Division of Hepatobiliary and Pancreatic Surgery Department of General Surgical Science Graduate School of Medicine Gunma University Maebashi Japan
  • Takahiro Yamanaka
    Division of Hepatobiliary and Pancreatic Surgery Department of General Surgical Science Graduate School of Medicine Gunma University Maebashi Japan
  • Tadashi Handa
    Department of Diagnostic Pathology Graduate School of Medicine Gunma University Maebashi Japan
  • Mariko Tsukagoshi
    Division of Hepatobiliary and Pancreatic Surgery Department of General Surgical Science Graduate School of Medicine Gunma University Maebashi Japan
  • Takamichi Igarashi
    Division of Hepatobiliary and Pancreatic Surgery Department of General Surgical Science Graduate School of Medicine Gunma University Maebashi Japan
  • Akira Watanabe
    Division of Hepatobiliary and Pancreatic Surgery Department of General Surgical Science Graduate School of Medicine Gunma University Maebashi Japan
  • Norio Kubo
    Division of Hepatobiliary and Pancreatic Surgery Department of General Surgical Science Graduate School of Medicine Gunma University Maebashi Japan
  • Norifumi Harimoto
    Division of Hepatobiliary and Pancreatic Surgery Department of General Surgical Science Graduate School of Medicine Gunma University Maebashi Japan
  • Atsushi Masamune
    Division of Gastroenterology Graduate School of Medicine Tohoku University Sendai Japan
  • Kazuo Umezawa
    Department of Molecular Target Medicine Aichi Medical University School of Medicine Nagakute Japan
  • Hiroyuki Kuwano
    Division of Gastroenterological Surgery Department of General Surgical Science Graduate School of Medicine Gunma University Maebashi Japan
  • 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>

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