Prostate-specific antigen (PSA) is currently the most useful biomarker for detection of prostate cancer (PCa). The ability to measure serum PSA levels has affected all aspects of PCa management over the past two decades. The standard initial systemic therapy for advanced PCa is androgen-deprivation therapy (ADT). Although PCa patients with metastatic disease initially respond well to ADT, they often progress to castration-resistant prostate cancer (CRPC), which has a high mortality rate. We have demonstrated that time to PSA nadir (TTN) after primary ADT is an important early predictor of overall survival and progression-free survival for advanced PCa patients. In in vivo experiments, we demonstrated that the presence of fibroblasts in the PCa tumor microenvironment can prolong the period for serum PSA decline after ADT, and enhance the efficacy of ADT. Clarification of the mechanisms that affect TTN after ADT could be useful to guide selection of optimal PCa treatment strategies. In this review, we discuss recent in vitro and in vivo findings concerning the involvement of stromal–epithelial interactions in the biological mechanism of TTN after ADT to support the novel concept of “tumor regulating fibroblasts”.

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.

Renal cell carcinoma (RCC) is an angiogenesis-dependent and hypoxia-driven malignancy. As a result, several targeting agents are being investigated. However, the efficacy of current regimens is generally insufficient for their toxicity and poor overall response rates. We have recently reported that naftopidil exerts growth-inhibitory effects on human prostate cancer cells. In this study, we investigated the biochemical mechanisms by which naftopidil produces growth-inhibitory and antiangiogenic effects on RCC. We first tested the effects of naftopidil on the proliferation of ACHN and Caki-2 RCC cells. Next, we set up a model simulating the tumor microenvironment, in which ACHN cells were grafted onto the renal capsule of mice. We then tested the effects of naftopidil on human umbilical vein endothelial cells' cell proliferation and Matrigel plug vascularization. Finally, to establish the antitumor activity of naftopidil on RCC, we tested the antitumor effects of naftopidil on excised tumor specimens from 20 patients with RCC that were grafted beneath the renal capsule of mice. Naftopidil showed similar in vitro growth-inhibitory effects on all cell lines. Fluorescence-activated cell sorting analysis revealed an increase in G₁ cell-cycle arrest in all naftopidil-treated cell lines. In vivo tumorigenic studies showed a significant reduction of ACHN tumor weight, Ki-67 index, and microvessel density (MVD) in naftopidil-treated mice. Naftopidil attenuated neovascularization in an in vivo Matrigel plug assay. Studies in mouse xenograft models also showed a significant MVD reduction in naftopidil-treated excised human RCC. The growth-inhibitory effects of naftopidil suggest it may be a novel anticancer agent and a potential preventive option for RCC. Cancer Prev Res; 6(9); 1000–6. ©2013 AACR.

There is currently no consensus on the correlations between androgen concentrations in prostate tissue and blood and stage and pathological grade of prostate cancer. In this study, we used a newly-developed ultra-sensitive liquid-chromatography tandem mass spectrometry method to measure testosterone (T) and dihydrotestosterone (DHT) concentrations in blood and needle biopsy prostate specimens from patients with prostate cancer. We analyzed androgen levels in 196 men diagnosed with prostate cancer. All patients had undergone systematic needle biopsy, and an additional needle biopsy from the peripheral zone was conducted for the simultaneous determination of T and DHT. We analyzed the relationships between T and DHT levels in tissue and blood and Gleason score, clinical stage, and percentage of positive biopsy cores, using multivariate analysis. The median T and DHT levels in blood were 3551.0 pg/mL and 330.5 pg/mL, respectively. There was a strong correlation between serum T and DHT. The median T and DHT levels in prostate tissue were 0.5667 pg/mg and 7.0625 pg/mg, respectively. In multivariate analysis, serum prostate-specific antigen and tissue T levels were significantly associated with poor prognosis; high T levels in prostate tissue were significantly related to high Gleason score (p = 0.041), advanced clinical stage (p = 0.002), and a high percentage of positive biopsy cores (p = 0.001). The results of this study indicate that high T levels in prostate tissue are related to high Gleason score, advanced clinical stage, and a high percentage of positive biopsy cores in patients with prostate cancer. T level in needle biopsy specimens may therefore be a useful prognostic factor in prostate cancer patients.