Laboratory for Cancer Research, University of Split School of Medicine, Split, Croatia.
Department of Pathology, University Hospital of Split, Split, Croatia; University of Split School of Medicine, Split, Croatia.
Cancer Lett. 2020 Oct 10;490:89-99. doi: 10.1016/j.canlet.2020.06.018. Epub 2020 Jul 11.
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.
膀胱癌是全球男性中第四大常见的恶性肿瘤，也是所有癌症中复发率最高的癌症之一。这种癌症类型很独特，因为曼氏血吸虫引起的慢性炎症会导致膀胱癌，而卡介苗引起的炎症则是这种癌症类型的治疗基石。促炎细胞因子白细胞介素 6（IL-6）/信号转导和转录激活因子 3（Stat3）轴的激活通过作用于癌细胞以及调节癌症微环境，促进了不同癌症的发展。在小鼠模型中，我们使用遗传和药理学方法证明了 IL-6 和 Stat3 信号在膀胱癌中的重要性。我们的研究结果表明，用 WP1066 抑制 Stat3 的药理学方法可有效延缓 N-丁基-N-（4-羟丁基）亚硝胺诱导的小鼠模型中膀胱癌的进展和侵袭。此外，IL-6 阻断或 Stat3 抑制使膀胱癌对抗 PD-L1 免疫治疗更敏感。综上所述，我们的研究表明 IL-6/Stat3 信号在膀胱癌中起重要作用，并为单独或联合抗 PD-L1 和抗 IL-6 治疗，测试 Stat3 抑制剂在人类肌层浸润性膀胱癌中的治疗潜力提供了依据。
