title: Recruited mast cells in the tumor microenvironment enhance bladder cancer metastasis via modulation of ERβ/CCL2/CCR2 EMT/MMP9 signals.
abstract: 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.
authors.affiliation: Department of Gynaecology and Obstetrics, Tongji Medical College/Hospital, Huazhong University of Science and Technology, Wuhan, China.|Sex Hormone Research Center, Department of Urology, Tongji Medical College/Hospital, Huazhong University of Science and Technology, Wuhan, China.|George Whipple Lab for Cancer Research, Departments of Urology and Pathology, University of Rochester Medical Center, Rochester, NY, USA.
authors.forename: Qun
authors.initials: Q
authors.lastname: Rao
authors.affiliation: Sex Hormone Research Center, Department of Urology, Tongji Medical College/Hospital, Huazhong University of Science and Technology, Wuhan, China.|George Whipple Lab for Cancer Research, Departments of Urology and Pathology, University of Rochester Medical Center, Rochester, NY, USA.
authors.forename: Yuan
authors.initials: Y
authors.lastname: Chen
authors.affiliation: George Whipple Lab for Cancer Research, Departments of Urology and Pathology, University of Rochester Medical Center, Rochester, NY, USA.
authors.forename: Chiuan-Ren
authors.initials: CR
authors.lastname: Yeh
authors.affiliation: George Whipple Lab for Cancer Research, Departments of Urology and Pathology, University of Rochester Medical Center, Rochester, NY, USA.
authors.forename: Jie
authors.initials: J
authors.lastname: Ding
authors.affiliation: George Whipple Lab for Cancer Research, Departments of Urology and Pathology, University of Rochester Medical Center, Rochester, NY, USA.
authors.forename: Lei
authors.initials: L
authors.lastname: Li
authors.affiliation: George Whipple Lab for Cancer Research, Departments of Urology and Pathology, University of Rochester Medical Center, Rochester, NY, USA.
authors.forename: Chawnshang
authors.initials: C
authors.lastname: Chang
authors.affiliation: George Whipple Lab for Cancer Research, Departments of Urology and Pathology, University of Rochester Medical Center, Rochester, NY, USA.
authors.forename: Shuyuan
authors.initials: S
authors.lastname: Yeh
mesh_terms: D000818:Animals; D017209:Apoptosis; D015153:Blotting, Western; D002465:Cell Movement; D049109:Cell Proliferation; D018932:Chemokine CCL2 / Q000235:genetics / Q000378:metabolism*; D047629:Estrogen Receptor beta / Q000235:genetics / Q000378:metabolism*; D005260:Female; D006801:Humans; D007124:Immunoenzyme Techniques; D008407:Mast Cells / Q000378:metabolism / Q000473:pathology*; D020780:Matrix Metalloproteinase 9 / Q000235:genetics / Q000378:metabolism*; D051379:Mice; D008819:Mice, Nude; D009361:Neoplasm Invasiveness; D027701:Organic Cation Transport Proteins / Q000235:genetics / Q000378:metabolism*; D012333:RNA, Messenger / Q000235:genetics; D060888:Real-Time Polymerase Chain Reaction; D054390:Receptors, CCR2 / Q000235:genetics / Q000378:metabolism*; D020133:Reverse Transcriptase Polymerase Chain Reaction; D014407:Tumor Cells, Cultured; D059016:Tumor Microenvironment; D001749:Urinary Bladder Neoplasms / Q000276:immunology / Q000378:metabolism / Q000556:secondary*; D023041:Xenograft Model Antitumor Assays; D000099254:Organic Cation Transporter 3
chemical_list: D018932:Chemokine CCL2; D047629:Estrogen Receptor beta; D020780:Matrix Metalloproteinase 9; D027701:Organic Cation Transport Proteins; D012333:RNA, Messenger; D054390:Receptors, CCR2; D000099254:Organic Cation Transporter 3; C111835:CCL2 protein, human; C515334:CCR2 protein, human; C579270:MMP9 protein, human
keywords: ERβ antagonist; carcinogenesis; oncology; tumor associated immune cells