Targeting Stat3 signaling impairs the progression of bladder cancer in a mouse model
Targeting Stat3 signaling impairs the progression of bladder cancer in a mouse model
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DOI：
10.1016/j.canlet.2020.06.018
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发表时间：
2020-10-10
期刊：
影响因子：
9.7
通讯作者：
Terzic, Janos
中科院分区：
文献类型：
--
作者：
Korac-Prlic, Jelena;Degoricija, Marina;Terzic, Janos
膀胱癌是世界上第四种最常见的男性恶性肿瘤，是所有癌症中复发率最高的癌症之一。这种癌症是独一无二的，因为血吸虫引起的慢性炎症可以导致膀胱癌，而卡介苗引起的炎症是这种癌症的治疗基石。促炎性IL-6/STAT3轴的激活通过作用于癌细胞和调节肿瘤微环境来促进不同肿瘤的发生发展。利用遗传学和药理学方法，在小鼠模型中，我们证明了IL-6和STAT3信号在膀胱癌中的重要性。我们的结果表明，WP1066对STAT3的药理抑制有效地延缓了N-丁基-N-(4-羟基丁基)亚硝胺诱导的小鼠膀胱癌的进展和侵袭。此外，IL-6阻断或STAT3抑制均可使膀胱癌对抗PD-L1免疫治疗增敏。综上所述，我们的研究证实了IL-6/STAT3信号在膀胱癌中的重要作用，并为单独或联合抗PD-L1和抗IL-6治疗测试STAT3抑制剂在人MIBC中的治疗潜力奠定了基础。
Bladder cancer is the fourth most commonly diagnosed malignancy in men worldwide and has one of the highest recurrence rates of all cancers. This cancer type is unique because chronic inflammation caused by Schistosoma haematobium can cause bladder cancer, while inflammation induced by Bacillus Calmette Guerin is the therapeutic cornerstone for this cancer type. Activation of proinflammatory IL-6/Stat3 axis promotes the development of different cancers by acting on cancer cells as well as by modulating cancer microenvironment. Using a genetic and pharmacological approach in a mouse model, we demonstrated the importance of IL-6 and Stat3 signaling in bladder cancer. Our findings show that pharmacological inhibition of Stat3 with WP1066 effectively delays progression and invasiveness of bladder cancer in N-butyl-N-(4-hydroxybutyl) nitrosamine-induced mouse model. Moreover, either IL-6 blockade or Stat3 inhibition sensitized bladder cancer to anti-PD-L1 immune therapy. Taken together, our study demonstrates an important role of IL-6/Stat3 signaling in bladder cancer and creates a rationale for testing the therapeutic potential of Stat3 inhibitors in human MIBC both alone or in combination with anti-PD-L1 and anti-IL-6 therapy.