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
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DOI：
10.1038/s41416-020-0744-7
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发表时间：
2020-02-04
影响因子：
8.8
通讯作者：
Shirabe, Ken
中科院分区：
文献类型：
--
作者：
Yamanaka, Takahiro;Harimoto, Norifumi;Shirabe, Ken
背景肝内胆管癌（ICC）是一种具有挑战性的恶性肿瘤。ICC组织中的成纤维细胞已被确定为促进ICC细胞恶性行为的癌症相关成纤维细胞（CAFs）。据报道，一种抗纤维化药物尼达尼布可以抑制肝纤维化中活化的肝星状细胞。方法在体外和体内研究尼达尼布是否能抑制ICC组织来源的CAFs的促癌作用。结果CAFs能促进ICC细胞的增殖和侵袭。尼达尼布抑制表达α -平滑肌肌动蛋白（α - sma）的活化CAFs，抑制CAFs促进icc的作用。尼达尼布大大降低了促癌细胞因子的水平，如由caf分泌的白细胞介素(IL)-6 （IL-6）和IL-8。一项体内研究表明，尼达尼布减少了异种移植的ICC生长并激活了表达α - sma的CAFs，与对照和单一治疗组相比，尼达尼布和吉西他滨联合治疗CAFs和ICC细胞对肿瘤生长的抑制作用最强。结论尼达尼布通过抑制CAF的激活和促癌细胞因子的分泌来抑制CAF的促癌作用。我们的研究结果表明，结合传统细胞毒性药物和尼达尼布靶向CAFs的治疗策略有望用活化的CAFs克服难治性ICC。
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 alpha-smooth muscle actin (alpha-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 alpha-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.