Chronic Prostatitis/Chronic Pelvic Pain Syndrome (CP/CPPS) is a chronic inflammatory disease with unclear etiology, high disease burden and increases the risk for prostate cancer (PCa) development at a later age. CP/CPPS and PCa manifest with altered sex hormone signaling and inflammatory dysregulation. Extensive characterization of the PCa stroma showed that tumor-associated macrophages (TAM), mast cells and cancer-associated fibroblasts (CAF) significantly influence disease progression. Tissue biopsies of CP/CPPS patients however are rare, and consequently the stromal contributions to CP/CPPS are less understood.In this study, we examined liquid biopsies (blood and ejaculate) for CP/CPPS-associated changes of estradiol (E2), testosterone and their cognate receptors ERalpha and ERbeta (genes: ESR1, ESR2) as well as the androgen receptor (AR). To examine the role of stromal cells for CP/CPPS and PCa pathogenesis, we characterized mast cell lines (HMC-1/LAD2), in vitro differentiated macrophages (THP-1) and cancer-associated fibroblasts (CAF) from prostatectomy tissue.Our results demonstrated that CP/CPPS associates with elevated E2 concentrations in seminal plasma (SP), as well as systemic (blood) and local (ejaculate) ESR1 downregulation. Stratification of CP/CPPS patients by age could additionally show that testosterone, E2 and their receptors (ERalpha, ERbeta and AR) undergo systemic downregulation in older patients (>40 years). The two mast cell lines (HMC-1/LAD2) differed considerably regarding their estrogen receptor (ERalpha, ERbeta) expression, their basal inflammatory gene expression and their response to E2-stimulation. Macrophage polarization with conditioned media (CM) showed that mast cells and primary CAF affect the macrophage response. Mast cell CM suppressed macrophage expression of transcripts from the tumoricidal M1- response (TNF and HLA-DQA1). CAF CM induced macrophage transcripts (IL-1beta and IL-10) with known associations to prostate carcinogenesis. Our co-culture experiments suggest that macrophages influence stromal/epithelial interactions and facilitate directed cell migration.Altogether, our study helps to clarify the roles of steroid sex hormones and stromal interactions for chronic inflammatory diseases of the prostate.
