Background: Pirfenidone (PFD), which is an antifibrotic agent used for treatment of idiopathic pulmonary fibrosis, induces G0/G1 cell cycle arrest in fibroblasts. We hypothesized that PFD-induced G0/G1 cell cycle arrest might be achieved in other types of cells, including cancer cells. Here we investigated the effects of PFD on the proliferation of pancreatic cancer cells (PCCs) in vitro. Method: Human skin fibroblasts ASF-4-1 cells and human prostate stromal cells (PrSC) were used as fibroblasts. PANC-1, MIA PaCa-2, and BxPC-3 cells were used as human PCCs. Cell cycle and apoptosis were analyzed using flow cytometer. Results: First, we confirmed that PFD suppressed cell proliferation of ASF-4-1 cells and PrSC and induced G0/G1 cell cycle arrest. Under these experimental conditions, PFD also suppressed cell proliferation and induced G0/G1 cell cycle arrest in all PCCs. In PFD-treated PCCs, expression of p21 was increased but that of CDK2 was not clearly decreased. Of note, PFD did not induce significant apoptosis among PCCs. Conclusions: These results demonstrated that the antifibrotic agent PFD might have antiproliferative effects on PCCs by inducing G0/G1 cell cycle arrest. This suggests that PFD may target not only fibroblasts but also PCCs in the tumor microenvironment of pancreatic cancer.

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.

Activation of tumor–stromal interactions is considered to play a critical role in the promotion of tumorigenesis. To discover new therapeutic targets for hormone-refractory prostate tumor growth under androgen ablation therapy, androgen-sensitive LNCaP cells and the derived sublines, E9 (androgen-low-sensitive), and AIDL (androgen-insensitive), were recombined with androgen-dependent embryonic rat urogenital sinus mesenchyme (UGM). Tumors of E9+UGM and AIDL+UGM were approximately three times as large as those of LNCaP+UGM. Tumors grown in castrated hosts exhibited reduced growth as compared with those in intact hosts. However, in castrated hosts, E9+UGM and AIDL+UGM tumors were still approximately twice as large as those of LNCaP+UGM. Cell proliferation in tumors of E9+UGM and AIDL+UGM grown in castrated host, was significantly higher than that in tumors of LNCaP+UGM. In vitro, expression of fibroblast growth factor (FGF)-2 and IGF-I, but not FGF-7 mRNA, was significantly reduced in UGM under androgen starvation. In cell culture, E9 cells were responsive to FGF-2 and FGF-7 stimulation, while AIDL responded to FGF-7 and IGF-1. Expression of FGFR1 and FGFR2 was considerably higher in E9 than those in LNCaP, similarly expression of FGFR2 and IGF-IR were elevated in AIDL. These data suggest that activation of prostate cancer cell growth through growth factor receptor expression may result in the activity of otherwise androgen-independent stromal growth factor signals such as FGF-7 under conditions of androgen ablation.