Recruited mast cells in the tumor microenvironment enhance bladder cancer metastasis via modulation of ERβ/CCL2/CCR2 EMT/MMP9 signals
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Qun Rao1,2,3,*, Yuan Chen2,3,*, Chiuan-Ren Yeh3,*, Jie Ding3, Lei Li3, Chawnshang Chang3, Shuyuan Yeh3
1Department of Gynaecology and Obstetrics, Tongji Medical College/Hospital, Huazhong University of Science and Technology, Wuhan, China
2Sex Hormone Research Center, Department of Urology, Tongji Medical College/Hospital, Huazhong University of Science and Technology, Wuhan, China
3George Whipple Lab for Cancer Research, Departments of Urology and Pathology, University of Rochester Medical Center, Rochester, NY, USA
*These authors have contributed equally to this work
Shuyuan Yeh, e-mail: [email protected]
Keywords: tumor associated immune cells, ERβ antagonist, oncology, carcinogenesis
Received: April 06, 2015 Accepted: September 02, 2015 Published: November 05, 2015
Early clinical studies suggested that infiltrating mast cells could be associated with a poor outcome in bladder cancer (BCa) patients. The mechanisms of how mast cells influence the BCa progression, however, are unclear. Using the human clinical BCa sample survey and in vitro co-culture systems, we found BCa cells could recruit more mast cells than the surrounding non-malignant urothelial cells. The consequences of this better recruitment of mast cells toward BCa cells could then enhance BCa cell invasion. Mechanism dissection revealed that the enhanced BCa cell invasion could function via up-regulation of the estrogen receptor beta (ERβ) in both mast cells and BCa cells, which resulted in the increased CCL2/CCR2/EMT/MMP9 signals. Using the pre-clinical mouse BCa model, we further validated the mast cell-promoted BCa invasion. Interruption of the newly identified ERβ/CCL2/CCR2/EMT/MMP9 pathway via either ERβ-siRNA, ERβ antagonist PHTPP, or CCR2 antagonist can effectively reverse the mast cell-enhanced BCa cells invasion. Together, our finding could lead to the development of an alternative new therapeutic approach to better treat BCa metastasis.
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