*6.1. Carcinogenesis*

Co-culturing of immortalized prostate epithelial cells with macrophages has been observed to induce prostate tumorigenesis, involving the signaling alteration of macrophage AR-inflammatory chemokine CCL4-pSTAT3 activation, EMT, and p53/PTEN tumor suppressor down-regulation [54]. Furthermore, in vivo studies have demonstrated that PTEN(+/ −) mice lacking macrophage AR develop fewer prostatic intraepithelial neoplasia lesions, supporting an important role for macrophage AR signaling during prostate tumorigenesis [54]. CCL4-neutralizing antibodies effectively inhibited macrophage-induced prostate tumorigenic signaling, while CCL4 upregulation was associated with increased Snail expression and p53/PTEN down-regulation in high-grade prostatic intraepithelial neoplasia and prostate cancer [54]. This study identified the AR-CCL4-pSTAT3 axis is a key regulator during prostate tumorigenesis and highlighted the important roles of infiltrating macrophages and inflammatory cytokines during prostate tumorigenesis [54,55].
