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- Title
Nintedanib inhibits intrahepatic cholangiocarcinoma aggressiveness via suppression of cytokines extracted from activated cancer-associated fibroblasts.
- Authors
Yamanaka, Takahiro; Harimoto, Norifumi; Yokobori, Takehiko; Muranushi, Ryo; Hoshino, Kouki; Hagiwara, Kei; Gantumur, Dolgormaa; Handa, Tadashi; Ishii, Norihiro; Tsukagoshi, Mariko; Igarashi, Takamichi; Tanaka, Hiroshi; Watanabe, Akira; Kubo, Norio; Araki, Kenichiro; Shirabe, Ken
- Abstract
<bold>Background: </bold>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.<bold>Methods: </bold>We investigated whether nintedanib could suppress the cancer-promoting effect of CAFs derived from ICC tissues in vitro and in vivo.<bold>Results: </bold>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.<bold>Conclusions: </bold>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.
- Publication
British Journal of Cancer, 2020, Vol 122, Issue 7, p986
- ISSN
0007-0920
- Publication type
journal article
- DOI
10.1038/s41416-020-0744-7