title: Infiltrating macrophages promote prostate tumorigenesis via modulating androgen receptor-mediated CCL4-STAT3 signaling.
abstract: Infiltrating macrophages are a key component of inflammation during tumorigenesis, but the direct evidence of such linkage remains unclear. We report here that persistent coculturing of immortalized prostate epithelial cells with macrophages, without adding any carcinogens, induces prostate tumorigenesis and that induction involves the alteration of signaling of macrophage androgen receptor (AR)-inflammatory chemokine CCL4-STAT3 activation as well as epithelial-to-mesenchymal transition and downregulation of p53/PTEN tumor suppressors. In vivo studies further showed that PTEN(+/-) mice lacking macrophage AR developed far fewer prostatic intraepithelial neoplasia (PIN) lesions, supporting an in vivo role for macrophage AR during prostate tumorigenesis. CCL4-neutralizing antibody effectively blocked macrophage-induced prostate tumorigenic signaling and targeting AR via an AR-degradation enhancer, ASC-J9, reduced CCL4 expression, and xenografted tumor growth in vivo. Importantly, CCL4 upregulation was associated with increased Snail expression and downregulation of p53/PTEN in high-grade PIN and prostate cancer. Together, our results identify the AR-CCL4-STAT3 axis as key regulators during prostate tumor initiation and highlight the important roles of infiltrating macrophages and inflammatory cytokines for the prostate tumorigenesis.
authors.affiliation: Authors' Affiliations: George Whipple Lab for Cancer Research, Departments of Pathology, Urology, and Radiation Oncology, The Wilmot Cancer Center, University of Rochester Medical Center, Rochester, New York; Immunology Research Center, National Health Research Institutes, Zhunan, Miaoli County, and Sex Hormone Research Center, China Medical University and Hospital, Taichung, Taiwan.
authors.forename: Lei-Ya
authors.initials: LY
authors.lastname: Fang
authors.forename: Kouji
authors.initials: K
authors.lastname: Izumi
authors.forename: Kuo-Pao
authors.initials: KP
authors.lastname: Lai
authors.forename: Liang
authors.initials: L
authors.lastname: Liang
authors.forename: Lei
authors.initials: L
authors.lastname: Li
authors.forename: Hiroshi
authors.initials: H
authors.lastname: Miyamoto
authors.forename: Wen-Jye
authors.initials: WJ
authors.lastname: Lin
authors.forename: Chawnshang
authors.initials: C
authors.lastname: Chang
mesh_terms: D000818:Animals; D000911:Antibodies, Monoclonal / Q000494:pharmacology; D002471:Cell Transformation, Neoplastic; D002478:Cells, Cultured; D054407:Chemokine CCL4 / Q000378:metabolism*; D003474:Curcumin / Q000031:analogs & derivatives / Q000494:pharmacology; D016207:Cytokines / Q000378:metabolism; D004797:Enzyme-Linked Immunosorbent Assay; D058750:Epithelial-Mesenchymal Transition; D006801:Humans; D007124:Immunoenzyme Techniques; D008264:Macrophages / Q000276:immunology / Q000378:metabolism / Q000473:pathology*; D008297:Male; D051379:Mice; D018345:Mice, Knockout; D051059:PTEN Phosphohydrolase / Q000502:physiology; D011467:Prostate / Q000276:immunology / Q000378:metabolism / Q000473:pathology*; D019048:Prostatic Intraepithelial Neoplasia / Q000276:immunology / Q000378:metabolism / Q000473:pathology*; D011471:Prostatic Neoplasms / Q000276:immunology / Q000378:metabolism / Q000473:pathology*; D011944:Receptors, Androgen / Q000378:metabolism*; D050796:STAT3 Transcription Factor / Q000378:metabolism*; D015398:Signal Transduction
chemical_list: D000911:Antibodies, Monoclonal; D054407:Chemokine CCL4; D003474:Curcumin; D016207:Cytokines; D051059:PTEN Phosphohydrolase; D011944:Receptors, Androgen; D050796:STAT3 Transcription Factor; C471106:ASC-J9 compound; C487757:Pten protein, mouse