Abstract
Androgens are essential for the development, differentiation, growth, and function of the prostate through epithelial–stromal interactions. However, androgen concentrations in the hypertrophic human prostate decrease significantly with age, suggesting an inverse correlation between androgen levels and proliferative diseases of the aging prostate. In elderly males, age- and/or androgen-related stromal remodeling is spontaneously induced, i.e., increased fibroblast and myofibroblast numbers, but decreased smooth muscle cell numbers in the prostatic stroma. These fibroblasts produce not only growth factors, cytokines, and extracellular matrix proteins, but also microRNAs as stromal paracrine signals that stimulate prostate epithelial cell proliferation. Surgical or chemical castration is the standard systemic therapy for patients with advanced prostate cancer. Androgen deprivation therapy induces temporary remission, but the majority of patients eventually progress to castration-resistant prostate cancer, which is associated with a high mortality rate. Androgen deprivation therapy-induced stromal remodeling may be involved in the development and progression of castration-resistant prostate cancer. In the tumor microenvironment, activated fibroblasts stimulating prostate cancer cell proliferation are called carcinoma-associated fibroblasts. In this review, we summarize the role of stromal paracrine signals in proliferative diseases of the aging human prostate and discuss the potential clinical applications of carcinoma-associated fibroblast-derived exosomal microRNAs as promising biomarkers.
Highlights
The prostate is a male accessory sex gland found only in mammals
Regarding the role of transforming growth factor α (TGFα), we demonstrated that the number of basal epithelial cells in the prostate of TGFα-overexpressing mice was increased [70]
We reported that primary cultured PCaSC-8 and/or PCaSC-9 cells derived from different human prostate cancer (PCa) specimens displayed a significantly higher mRNA expression of COL1A1, TNC, epidermal growth factor (EGF), FGF2, FGF7, HGF, and IGF1 [96]
Summary
The prostate is a male accessory sex gland found only in mammals. Its main function is to produce a major proportion of the seminal fluid. Androgens act on epithelial cells to produce growth factors, cytokines, and miRNAs that mediate stromal functions, including proliferation and differentiation [8,9,10]. 20 years since their clinical use was introduced, α1 -blockers are considered useful in the treatment of BPH They suppress functional contraction of prostatic smooth muscle cells by blocking signaling from the α1 -adrenoceptors distributed in this muscle. Justulin et al reported that when rats were given repeated doses of doxazosin, an α1 -blocker, they exhibited an accumulation of collagen fibers in the prostatic stroma and a reduction in smooth muscle cells [35] Based on this finding, they suggested the possibility that continued oral treatment with doxazosin would alter stromal structure and components, reducing the efficacy of α1 -blockers [35]. In the ECM, fibroblasts, osteoblasts, odontoblasts, and other types of cells induce the expression of COL1A1 and COL1A2 (genes encoding type I collagen) in the presence of TGF-β, resulting in the stimulation of type I collagen formation [37]
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