Nintedanib inhibits intrahepatic cholangiocarcinoma aggressiveness via suppression of cytokines extracted from activated cancer-associated fibroblasts
Takahiro Yamanaka, Norifumi Harimoto, Takehiko Yokobori, Ryo Muranushi, Kouki Hoshino, Kei Hagiwara, Dolgormaa Gantumur, Tadashi Handa, Norihiro Ishii, Mariko Tsukagoshi, Takamichi Igarashi, Hiroshi Tanaka, Akira Watanabe, Norio Kubo, Kenichiro Araki, Ken Shirabe
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.