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.

The dipeptide prolyl-hydroxyproline promotes cellular homeostasis and lamellipodiadriven motility via active β1-integrin in adult tendon cells

Abstract:Patients with metastatic castration-resistant prostate cancer (mCRPC) have poor outcomes. Docetaxel (DTX)-based therapy is a current standard treatment for patients with mCRPC. Approaches combining conventional chemotherapeutic agents and nanoparticles (NPs), particularly iron oxide NPs, may overcome the serious side effects and drug resistance, resulting in the establishment of new therapeutic strategies. We previously reported the combined effects of

Patients with metastatic castration-resistant prostate cancer (mCRPC) have a poor prognosis. Docetaxel (DTX)-based therapy is one of current standard treatments for mCRPC since 2004 although cabazitaxel, abiraterone acetate, and enzalutamide are three agents recently approved for the treatment of mCRPC. Although DTX-based chemotherapy has been shown to improve the quality of life in patients with the advanced disease, this needs to be improved because of limitations by lack of specificity, toxicity, and progression of docetaxel-resistance. Thus, combination of docetaxel with other compounds or drugs is needed to overcome these problems. We have investigated usefulness of magnetic iron oxide nanoparticles (MNPs- Fe3O4) for cancer diagnosis and therapy, showing that MNPs- Fe3O4 may modify the effect of chemotherapy in prostate cancer cells in vitro. The purpose of this study was to analyze the combined effect of docetaxel and MNPs- Fe3O4 on prostate cancer cell lines, DU145 and PC-3 and clarify their mechanisms. Electron microscopy, flow cytometry and Western blotting were used to study apoptosis and autophagic cell death with/without an autophagic inhibitor. Our results showed that MNPs- Fe3O4 produced reactive oxygen species (ROS) and 8-OHdG, and the combination of docetaxel and MNPs- Fe3O4 inhibited cancer cell growth and induced apoptosis and autophagic cell death. Although docetaxel induced nuclear factor-kappaB (NF-KB) expression, combination of docetaxel and MNPs inhibited NF-KB expression. These results suggest that MNPs- Fe3O4 may enhance effect of docetaxel on prostate cancer cells via ROS generation and inhibition of NF-KB signaling, leading to new tumor ablation therapies.<!–EndFragment–> Citation Format: Kanako Kojima, Sanai Takahashi, Shungo Saito, Tadashi Nittami, Eri Usugi, Kenichiro Ishii, Yoshifumi HIrokawa, Masatoshi Watanabe. Magnetic iron oxide nanoparticles induce apoptosis and autophagic cell death in prostate cancer cells treated with docetaxel via ROS generation and NF-KB signaling [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr 4827.

Chemotherapy is one of treatment options for castration-resistant prostate cancer. Especially, docetaxel-based chemotherapy has been shown to improve the quality of life in patients with the advanced disease. However, this needs to be improved because of limitations by lack of specificity, toxicity, and progression of docetaxel-resistance. Thus, combination of docetaxel with other compounds or drugs is needed to overcome these problems. Magnetic iron oxide nanoparticles (MgNPs, Fe3O4) have been investigated for nanomedicine such as drug delivery, cancer diagnosis and therapy. We have also shown that MgNPs would modify the effect of chemotherapy in prostate cancer cells in vitro. The purpose of this study was to analyze the combined effect of docetaxel and non-/carboxyl-modified magnetic nanoparticles (MgNPs/MgNPs-COOH) on a prostate cancer cell line, DU145 and clarify their mechanisms. While only MgNPs produced reactive oxygen species (ROS) and 8-OHdG, MgNPs-COOH did neither produce ROS nor 8-OHdG. The combination of docetaxel and MgNPs-COOH more effectively inhibited cancer cell growth and induced apoptosis compared with combination of docetaxel and MgNPs. Although docetaxel induced NF-kappa B expression, combination of docetaxel and MgNPs inhibited NF-kappa B expression compared with combination of MgNPs-COOH and docetaxel. However, both combinations increased p-Akt expression. These results suggest that MgNPs/MgNPs-COOH may enhance effect of docetaxel on prostate cancer cells via NF-kappa B signaling, however different factors may be involved in these phenomena, leading to new tumor ablation therapies. Citation Format: Kanako Kojima, Saho Hashimoto, Rina Sakamaki, Sanai Takahashi, Risa Kasakura, Ryo Maruyama, Tadashi Nittami, Hitoshi Ishiguro, Hiroji Uemura, Masatoshi Watanabe. Magnetic iron oxide nanoparticles enhance anti-tumor effect of docetaxel on prostate cancer cells via ROS generation and NF-kappa B signaling. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr 4813.