1. Academic Validation
  2. Nintedanib inhibits intrahepatic cholangiocarcinoma aggressiveness via suppression of cytokines extracted from activated cancer-associated fibroblasts

Nintedanib inhibits intrahepatic cholangiocarcinoma aggressiveness via suppression of cytokines extracted from activated cancer-associated fibroblasts

  • Br J Cancer. 2020 Mar;122(7):986-994. doi: 10.1038/s41416-020-0744-7.
Takahiro Yamanaka 1 Norifumi Harimoto 2 Takehiko Yokobori 3 Ryo Muranushi 1 Kouki Hoshino 1 Kei Hagiwara 1 Dolgormaa Gantumur 1 Tadashi Handa 4 5 Norihiro Ishii 1 Mariko Tsukagoshi 1 6 Takamichi Igarashi 1 Hiroshi Tanaka 1 Akira Watanabe 1 Norio Kubo 1 Kenichiro Araki 1 Ken Shirabe 1
Affiliations

Affiliations

  • 1 Department of General Surgical Science, Division of Hepatobiliary and Pancreatic Surgery, Gunma University, Graduate School of Medicine, Gunma, Japan.
  • 2 Department of General Surgical Science, Division of Hepatobiliary and Pancreatic Surgery, Gunma University, Graduate School of Medicine, Gunma, Japan. [email protected].
  • 3 Gunma University Initiative for Advanced Research (GIAR), Gunma, Japan.
  • 4 Department of Diagnostic Pathology, Gunma University, Graduate School of Medicine, Gunma, Japan.
  • 5 Department of Social Welfare, Gunma University of Health and Welfare, Gunma, Japan.
  • 6 Department of Innovative Cancer Immunotherapy, Gunma University, Graduate School of Medicine, Gunma, Japan.
Abstract

Background: Intrahepatic cholangiocarcinoma (ICC) is a malignancy that is challenging to treat. Fibroblasts in ICC tissues have been identified as cancer-associated fibroblasts (CAFs) that promote the malignant behaviour of ICC cells. An antifibrotic drug nintedanib has been reported to suppress activated hepatic stellate cells in liver fibrosis.

Methods: We investigated whether nintedanib could suppress the cancer-promoting effect of CAFs derived from ICC tissues in vitro and in vivo.

Results: CAFs promoted the proliferation and invasion of ICC cells. Nintedanib suppressed activated CAFs expressing α-smooth muscle actin (α-SMA) and inhibited the ICC-promoting effects of CAFs. Nintedanib greatly reduced the levels of cancer-promoting cytokines, such as interleukin (IL)-6 (IL-6) and IL-8, secreted by CAFs. An in vivo study demonstrated that nintedanib reduced xenografted ICC growth and activated CAFs expressing α-SMA, and that combination therapy with nintedanib and gemcitabine against CAFs and ICC cells showed the strongest inhibition of tumour growth compared with the control and single-treatment groups.

Conclusions: Nintedanib inhibited the cancer-promoting effect of CAFs via the suppression of CAF activation and secretion of cancer-promoting cytokines. Our findings suggest that therapeutic strategies combining conventional cytotoxic agents with nintedanib targeting CAFs are promising for overcoming refractory ICC with activated CAFs.

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