Tumor microenvironment B cells increase bladder cancer metastasisviamodulation of the IL-8/androgen receptor (AR)/MMPs signals

// Zhenyu Ou 1, 2, * , Yongjie Wang 1, 2, * , Longfei Liu 1 , Lei Li 2 , Shuyuan Yeh 2 , Lin Qi 1 , Chawnshang Chang 2, 3 1 Departments of Urology and Plastic Surgery, Xiangya Hospital, Central South University, Changsha, China 2 George Whipple Lab for Cancer Research, Departments of Pathology and Urology, University of Rochester Medical Center, Rochester NY, USA 3 Sex hormone Research Center, China Medical University/Hospital, Taichung 404, Taiwan * These authors have contributed equally to this work Correspondence to: Lin Qi, e-mail: Linqi1212@126.com Chawnshang Chang, e-mail: chang@urmc.rochester.edu Keywords: bladder cancer, androgen receptor, B cell, tumor microenvironment, tumor metastasis Received: April 15, 2015      Accepted: July 06, 2015      Published: July 17, 2015 ABSTRACT While B cells in the tumor microenvironment may play important roles in cancer progression, their impacts on the bladder cancer (BCa) metastasis remain unclear. Here we found from human clinical BCa samples that BCa tissues could recruit more B cells than the surrounding normal bladder tissues and the in vitro co-culture assay also demonstrated that B cells could be recruited more easily towards BCa cells compared to normal bladder cells. Chamber invasion and 3D invasion assays showed the recruited B cells could then significantly increase the BCa cell invasion. Mechanism dissection found that recruited B cells could increase IL-8/androgen receptor (AR) signals in BCa cells that could then promote the expression of metastasis genes including MMP1 and MMP13. Blocking the IL-8/AR/MMPs signals either by anti-IL-8 neutralizing antibody, AR-siRNA, or MMPs inhibitors all partially reversed the infiltrating B cells capacity to increase the BCa cell invasion. The in vivo data from orthotopically xenografted BCa mouse model also confirmed that infiltrating B cells could increase BCa cell invasion via increasing AR signals. Together, these results demonstrate the key roles of B cells within the bladder tumor microenvironment that increase the BCa metastasis and may help us to develop the potential therapies via targeting these newly identified IL-8/AR/MMPs signals to better battle the BCa progression.