Department of Urology, Shanghai General Hospital, Shanghai Jiaotong University, Shanghai 200080, China; Departments of Urology and Pathology, University of Rochester Medical Center, Rochester, NY 14642, USA.
Department of Urology, Shanghai General Hospital, Shanghai Jiaotong University, Shanghai 200080, China.
Cancer Lett. 2018 Aug 28;430:215-223. doi: 10.1016/j.canlet.2018.03.045. Epub 2018 Apr 22.
Clinical data indicates that T cells can be recruited to bladder cancer (BCa), yet the impact of T cells on BCa progression remains unclear. In the present study, we found that T cells were recruited more to BCa tissues than to the surrounding normal bladder tissues. Results from an in vitro co-culture system also found that BCa recruited more CD4 T cells than did normal bladder cells. The recruiting of T cells to BCa tissues may increase the proliferation and invasion of BCa cells. Mechanistic studies revealed that infiltrating T cells stimulate BCa estrogen receptor beta (ERβ) signaling and consequently increase the expression of MET proto-oncogene, receptor tyrosine kinase (c-MET), through either direct binding to its promoter or via modulation of IL-1 expression. Interruption of ERβ/c-MET or ERβ/IL-1/c-MET signaling via ERβ-shRNA, IL-1 antagonist, or the c-MET inhibitor, SU11274, could partially reverse the T cell-enhanced BCa cell invasion and proliferation. Finally, the mouse BCa model with xenografted BCa 5637 cells with T (HH) cells confirmed the results of in vitro co-culture studies showing that infiltrating T cells could promote BCa metastasis via modulation of the ERβ/c-MET or ERβ/IL-1/c-MET signaling pathways. These findings may provide a new therapeutic approach to better combat BCa progression via targeting these newly identified signaling pathways.
临床数据表明，T 细胞可以浸润到膀胱癌（BCa）中，但 T 细胞对 BCa 进展的影响尚不清楚。在本研究中，我们发现 T 细胞浸润到 BCa 组织中的数量多于周围正常膀胱组织。体外共培养系统的结果也发现，BCa 招募的 CD4+T 细胞多于正常膀胱细胞。T 细胞浸润到 BCa 组织中可能会增加 BCa 细胞的增殖和侵袭。机制研究表明，浸润的 T 细胞刺激 BCa 雌激素受体β（ERβ）信号，通过直接结合其启动子或通过调节 IL-1 的表达，从而增加原癌基因 MET 受体酪氨酸激酶（c-MET）的表达。通过 ERβ-shRNA、IL-1 拮抗剂或 c-MET 抑制剂 SU11274 阻断 ERβ/c-MET 或 ERβ/IL-1/c-MET 信号通路，可部分逆转 T 细胞增强的 BCa 细胞侵袭和增殖。最后，用携带 T（HH）细胞的异种移植 BCa 5637 细胞的小鼠 BCa 模型证实了体外共培养研究的结果，表明浸润的 T 细胞可以通过调节 ERβ/c-MET 或 ERβ/IL-1/c-MET 信号通路促进 BCa 转移。这些发现可能为通过靶向这些新鉴定的信号通路来更好地对抗 BCa 进展提供一种新的治疗方法。
