Isaac Yi Kim

Background: Androgen ablation is the first-line therapy for patients with metastatic prostate cancer (CaP). However, castration resistance will eventually emerge. In the present study, we have investigated the role of bone morphogenetic protein-6 (BMP-6) in the development of castration-resistant prostate cancer (CRPC) in the context of bone metastases. Methods: We initially investigated the clinical course of 158 men with advanced CaP who were treated with primary androgen deprivation therapy. To elucidate the underlying mechanism of CRPC in the context of bone metastases, we examined the impact of bone stromal cells on CaP in the absence of androgens using a co-culture model. Results: In the 158 patients, we found that the median time to prostate-specific antigen progression was significantly shorter when bone metastases were present (14 months (95% CI, 10.2–17.8 months) vs 57 months (95% CI, 19.4–94.6 months)). These results suggest that bone–tumour interactions may accelerate castration resistance. Consistent with this hypothesis, in vitro co-cultures demonstrated that CaP cells proliferated under an androgen-depleted condition when incubated with bone stromal cells. Mechanistically, gene expression analysis using quantitative polymerase chain reaction arrays showed a dramatic induction of BMP-6 by CaP cell lines in the presence of bone stromal cells. Further studies revealed that WNT5A derived from bone stromal cells induced the expression of BMP-6 by CaP cells; BMP-6 in turn stimulated cellular proliferation of CaP cells in an androgen-deprived media via a physical interaction between Smad5 and β-catenin. Intracellularly, WNT5A increased BMP-6 expression via protein kinase C/NF-κB pathway in CaP cell lines. Conclusions: These observations suggest that bone–CaP interaction leads to castration resistance via WNT5A/BMP-6 loop.

INTRODUCTION: Overexpression of bone morphogenetic protein‐6 (BMP‐6) has been reported in human prostate cancer tissues. Previously we have demonstrated that BMP‐6 enhances prostate cancer growth in mice and not in tissue culture. Herein, we have investigated the mechanism of BMP‐6's pro‐tumorigenic effect in prostate cancer.METHODS: Tramp C2 murine and LNCaP human prostate cancer cell lines were co‐cultured with RAW 264.7 and THP‐1 cells, respectively. IL‐1α knockout mice were used to confirm the role of BMP‐6/IL‐1α loop in vivo. Lastly, conditional macrophage null mice cd11b‐DTR was used.RESULTS: The results demonstrated that BMP‐6 induced the expression of IL‐1α in macrophages via a cross‐talk between NF‐κB1 p50 and Smad1. When endothelial cells were treated with conditioned media harvested from macrophages incubated with BMP‐6, tube formation was detected. In the presence of IL‐1α neutralizing antibody, endothelial tube formation was blocked. In vivo, tumor growth and neovascularization decreased significantly when BMP‐6 was expressed in IL‐1α knockout and conditional macrophage‐null mice.CONCLUSIONS: Prostate cancer‐derived BMP‐6 stimulates tumor‐associated macrophages to produce IL‐1α through a crosstalk between Smad1 and NF‐κB1; IL‐1α, in turn, promotes angiogenesis and prostate cancer growth. Prostate 74:121–133, 2014.

Purpose: To investigate the efficacy of hyaluronic acid-carboxymethylcellulose (HACM) in facilitating early recovery of erectile function (EF) after radical prostatectomy, we report our initial experience of HACM use on the neurovascular bundle (NVB) after robot-assisted radical prostatectomy (RARP). Patients and Methods: Between 2008 and 2010, 459 consecutive patients who underwent RARP with bilateral nerve-sparing technique were included in this study. Patients were classified into two groups: HACM (group 1; n=162) and non-HACM (group 2; n=287). HACM was delivered to the anatomic location of the NVB after prostate removal. We retrospectively analyzed the surgical outcomes including EF, continence, and perioperative complications. Results: At 6 months after surgery, EF recovery rate was 28.5% in group 1 and 17.4% in group 2 (P=0.006). In a subgroup analysis consisting of 225 patients with a preoperative International Index of Erectile Function Short Survey (IIEF)-5 score ≥20, the difference in EF recovery at 6 months was significant with 62.8% in group 1 and 27.0% in group 2 (P=0.002), respectively. HACM use was an independent predictor for EF recovery at 6 months after surgery (odds ratio, 2.735; 95% confidence interval, 1.613–4.638; PConclusions: HACM use around the NVBs is safe and facilitates early recovery of EF after nerve-sparing RARP. HACM use is more effective in patients with normal preoperative sexual function.

Few studies have analyzed factors that influence longitudinal changes in patient-perceived satisfaction during the recovery period following robot-assisted radical prostatectomy (RARP) for prostate cancer. We investigated variables that were associated with patient-perceived satisfaction after RARP using the expanded prostate cancer index composite (EPIC) survey. Of 175 men who underwent RARP between 2010 and 2011, 140 men completed the EPIC questionnaire preoperatively and 3, 6 and 12 months postoperatively. On the basis of the EPIC question no. 32 (item number 80), patients were divided into four groups according to the pattern of satisfaction change at postoperative 3 and 12 months: satisfied to satisfied (group 1); satisfied to dissatisfied (group 2); dissatisfied to satisfied (group 3); and dissatisfied to dissatisfied (group 4). Longitudinal changes in EPIC scores over time in each group and differences in EPIC scores of each domain subscale between groups at each follow-up were analyzed. A linear mixed model with generalized estimating equation approach was used to identify independent factors that influence overall satisfaction among repeated measures from same patients. On the basis of the pattern of satisfaction change, groups 1, 2, 3 and 4 had 103 (74.3%), 21 (15.0%), 11 (7.9%) and 5 (2.9%) patients, respectively. The factor that was associated with overall satisfaction was urinary bother (UB) (β=0.283, 95% confidence interval (0.024, 0.543 ); P=0.033) adjusted for other factors under consideration. UB was the independent factor influencing patient-perceived satisfaction after RARP. During post-RARP follow-up, physician should have the optimal management for the patient’s UB.

Lymph nodes in the prostatic anterior fat pad rarely harbor metastatic disease. Therefore, the characteristics of patients with prostatic anterior fat pad lymph node metastasis are not well described in the literature. We identified the perioperative characteristics and assessed the clinical outcomes of patients with prostatic anterior fat pad lymph node metastasis. At 8 tertiary care centers a total of 4,261 patients underwent complete removal and pathological analysis of the prostatic anterior fat pad. We describe preoperative and pathological characteristics, and clinical management and outcomes in patients with metastatic disease to the prostatic anterior fat pad. Metastatic disease to the prostatic anterior fat pad lymph nodes was detected in 40 patients (0.94%), of whom 37 (92.5%) had intermediate or high risk features preoperatively. Most patients with prostatic anterior fat pad metastases underwent concomitant pelvic lymph node dissection, and adjuvant therapy with radiation, androgen ablation and/or chemotherapy. A total of 27 patients (67.5%) with prostatic anterior fat pad metastatic disease were up-staged as a result of prostatic anterior fat pad pathological analysis, of whom 14 (51.8%) remained free of biochemical recurrence with observation and/or definitive adjuvant/salvage therapy. Most patients with prostatic anterior fat pad metastatic disease had intermediate to high risk features preoperatively. In some patients with such lymph node metastasis removing these lymph nodes resulted in prolonged biochemical recurrence-free survival. Therefore, we recommend that the prostatic anterior fat pad be removed in all patients undergoing radical prostatectomy. However, pathological analysis of the prostatic anterior fat pad may be limited to patients with intermediate to high risk oncological features preoperatively.

Dysregulated bone morphogenetic proteins (BMP) may contribute to the development and progression of renal cell carcinoma (RCC). Herein, we report that BMP-6 promotes the growth of RCC by interleukin (IL)-10–mediated M2 polarization of tumor-associated macrophages (TAM). BMP-6–mediated IL-10 expression in macrophages required Smad5 and STAT3. In human RCC specimens, the three-marker signature BMP-6/IL-10/CD68 was associated with a poor prognosis. Furthermore, patients with elevated IL-10 serum levels had worse outcome after surgery. Together, our results suggest that BMP-6/macrophage/IL-10 regulates M2 polarization of TAMs in RCC. Cancer Res; 73(12); 3604–14. ©2013 AACR.

Bone morphogenetic protein (BMP) is a pleiotropic growth factor that has been implicated in inflammation and prostate cancer (CaP) progression. We investigated the potential role of BMP‐6 in the context of macrophages and castration‐resistant prostate cancer. When the androgen‐responsive murine (Tramp‐C1 and PTENCaP8) and human (LNCaP) CaP cell lines were cocultured with macrophages in the presence of dihydrotestosterone, BMP‐6 increased androgen‐responsive promoter activity and cell count significantly. Subsequent studies revealed that BMP‐6 increased the expression level of androgen receptor (AR) mRNA and protein in CaP cell lines only in the presence of macrophages. Simultaneously, the AR antagonists bicalutamide and MDV3100 partially or completely blocked BMP‐6‐induced macrophage‐mediated androgen hypersensitivity in CaP cells. Abolishing interleukin‐6 signaling with neutralizing antibody in CaP/macrophage cocultures inhibited the BMP‐6‐mediated AR upregulation in CaP cells. Using Tramp‐C1 and PTENCaP8 cells with a tetracycline‐inducible expression of BMP‐6, the induction of BMP‐6 in vivo resulted in a significant resistance to castration. However, this resistance was blocked after the removal of macrophages with clodronate liposomes. Taken together, these results show that BMP‐6 induces castration resistance by increasing the expression of AR through macrophage‐derived interleukin‐6.

Castration-resistant prostate cancer (CRPC) remains a major clinical challenge, given the mechanistic heterogeneity due to a complex signal transduction network. Enzalutamide (MDV-3100), recently approved by the U.S. Food and Drug Administration (FDA) at a dose of 160 mg/day for the treatment of CRPC, blocks androgen signaling by directly binding to the androgen receptor (AR) and inhibiting nuclear translocation and coactivator recruitment of the ligand-receptor complex. In preclinical studies, enzalutamide has been shown to block the binding of AR to DNA, resulting in apoptosis and retardation of tumor growth. Clinically, a phase I/II study (N = 140) revealed that enzalutamide had an optimal safety profile and significant antitumor activity in patients with CRPC regardless of prior chemotherapy. In the AFFIRM phase III trial (N = 1,199), oral enzalutamide significantly improved survival in men with metastatic CRPC after chemotherapy. Currently, a phase III trial (PREVAIL) is under way to determine the effectiveness of enzalutamide in patients who have not received prior docetaxel chemotherapy.

Radium Ra 223 dichloride (Xofigo®, formerly Alpharadin) is one of the representative α-particle-emitting isotopes that delivers radiation with a higher biological effect to a more localized area. Preclinical studies in mouse, rat and canine models have demonstrated that radium Ra 223 dichloride has a definite skeletal affinity and antitumor effect with a relatively low toxicity on bone marrow. More recently, in a large randomized phase III trial (ALSYMPCA), patients with bone metastasis and castration-resistant prostate cancer (CRPC) received six cycles of 50 kBq/kg of radium Ra 223 dichloride in 4-week intervals. In these men, radium Ra 223 dichloride improved the median overall survival by 3.6 months when compared to the placebo group. Collectively, these results suggest that radium Ra 223 dichloride is a promising candidate for managing bone metastases in patients with CRPC.