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首页> 外文期刊>British Journal of Cancer >Novel therapeutic strategy targeting the Hedgehog signalling and mTOR pathways in biliary tract cancer
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Novel therapeutic strategy targeting the Hedgehog signalling and mTOR pathways in biliary tract cancer

机译：针对胆道癌中刺猬信号和mTOR通路的新型治疗策略

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Background: Activation of the PI3K/mTOR and Hedgehog (Hh) signalling pathways occurs frequently in biliary tract cancer (BTC). Crosstalk between these pathways occurs in other gastrointestinal cancers. The respective signalling inhibitors rapamycin and vismodegib may inhibit BTC synergistically and suppress cancer stem cells (CSCs). Methods: Gene expression profiling for p70S6k and Gli1 was performed with BTC cell lines. Tumour and pathway inhibitory effects of rapamycin and vismodegib were investigated in BTC preclinical models and CSCs. Results: Rapamycin and vismodegib synergistically reduced BTC cell viability and proliferation. This drug combination arrested BTC Mz-ChA-1 cells in the G1 phase but had no significant effect on the cell cycle of BTC Sk-ChA-1 cells. Combined treatment inhibited the proliferation of CSCs and ALDH-positive cells. Nanog and Oct-4 expression in CSCs was decreased by the combination treatment. Western blotting results showed the p-p70S6K, p-Gli1, p-mTOR, and p-AKT protein expression were inhibited by the combination treatment in BTC cells. In an Mz-ChA-1 xenograft model, combination treatment resulted in 80% inhibition of tumour growth and prolonged tumour doubling time. In 4 of 10 human BTC specimens, tumour p-p70S6K and Gli1 protein expression levels were decreased with the combination treatment. Conclusions: Targeted inhibition of the PI3K/mTOR and Hhpathways indicates a new avenue for BTC treatment with combination therapy.
机译：背景：PI3K / mTOR和刺猬（Hh）信号通路的激活在胆道癌（BTC）中经常发生。这些途径之间的串扰在其他胃肠道癌症中发生。各自的信号抑制剂雷帕霉素和vismodegib可以协同抑制BTC并抑制癌症干细胞（CSC）。方法：用BTC细胞株对p70S6k和Gli1进行基因表达谱分析。在BTC临床前模型和CSC中研究了雷帕霉素和vismodegib的肿瘤和途径抑制作用。结果：雷帕霉素和维莫德单抗协同降低BTC细胞活力和增殖。这种药物组合使BTC Mz-ChA-1细胞停滞在G1期，但对BTC Sk-ChA-1细胞的细胞周期没有明显影响。联合治疗抑制了CSCs和ALDH阳性细胞的增殖。通过联合治疗降低了CSC中的Nanog和Oct-4表达。 Western印迹结果表明，联合处理可抑制BTC细胞中p-p70S6K，p-Gli1，p-mTOR和p-AKT蛋白的表达。在Mz-ChA-1异种移植模型中，联合治疗导致80％的肿瘤生长抑制和延长的肿瘤倍增时间。在10个人的BTC标本中的4个中，联合治疗降低了肿瘤p-p70S6K和Gli1蛋白的表达水平。结论：PI3K / mTOR和Hhpathways的靶向抑制为联合治疗BTC治疗提供了新途径。

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