Kouji Izumi

Prostate cancer stromal cells and LNCaP cells coordinately activate the androgen receptor through synthesis of testosterone and dihydrotestosterone from dehydroepiandrosterone

One of the mechanisms through which advanced prostate cancer (PCa) usually relapses after androgen deprivation therapy (ADT) is the adaptation to residual androgens in PCa tissue. It has been observed that androgen biosynthesis in PCa tissue plays an important role in this adaptation. In the present study, we investigated how stromal cells affect adrenal androgen dehydroepiandrosterone (DHEA) metabolism in androgen-sensitive PCa LNCaP cells. DHEA alone had little effect on prostate-specific antigen (PSA) promoter activity and the proliferation of LNCaP cells. However, the addition of prostate stromal cells or PCa-derived stromal cells (PCaSC) increased DHEA-induced PSA promoter activity via androgen receptor activation in the LNCaP cells. Moreover, PCaSC stimulated the proliferation of LNCaP cells under physiological concentrations of DHEA. Biosynthesis of testosterone or dihydrotestosterone from DHEA in stromal cells and LNCaP cells was involved in this stimulation of LNCaP cell proliferation. Androgen biosynthesis from DHEA depended upon the activity of various steroidogenic enzymes present in stromal cells. Finally, the dual 5alpha-reductase inhibitor dutasteride appears to function not only as a 5alpha-reductase inhibitor but also as a 3beta-hydroxysteroid dehydrogenase inhibitor in LNCaP cells. Taken together, this coculture assay system provides new insights of coordinate androgen biosynthesis under the microenvironment of PCa cells before and after ADT, and offers a model system for the identification of important steroidogenic enzymes involved in PCa progression and for the development of the corresponding inhibitors of androgen biosynthesis.

Androgen Receptor Roles in the Development of Benign Prostate Hyperplasia

Benign prostate hyperplasia (BPH) is a major cause of lower urinary tract symptoms, with an increased volume of transitional zone and associated with increased stromal cells. It is known that androgen/androgen receptor (AR) signaling plays a key role in development of BPH, and that blockade of this signaling decreases BPH volume and can relieve lower urinary tract symptoms, but the mechanisms of androgen/AR signaling in BPH development remain unclear, and the effectiveness of current drugs for treating BPH is still limited. The detailed mechanisms of androgen/AR signaling need to be clarified, and new therapies are needed for better treatment of BPH patients. This review focuses on roles of AR in epithelial and stromal cells in BPH development. In epithelial cells, AR may contribute to BPH development via epithelial cell-stromal cell interaction with alterations of epithelial-mesenchymal transition, leading to proliferation of stromal cells. Data from several mouse models with selective knockout of AR in stromal smooth-muscle cells and/or fibroblasts indicate that the AR in stromal cells can also promote BPH development. In prostatic inflammation, AR roles in infiltrating macrophages and epithelial and stromal cells have been linked to BPH development, which has led to discovery of new therapeutic targets. For example, targeting AR with the novel AR degradation enhancer, ASC-J9 offers a potential therapeutic approach against BPH development.

Tranilast inhibits hormone refractory prostate cancer cell proliferation and suppresses transforming growth factor β1-associated osteoblastic changes

Tranilast is a therapeutic agent used in treatment of allergic diseases, although it has been reported to show anti‐tumor effects on some cancer cells. To elucidate the effects of tranilast on prostate cancer, we investigated the mechanisms of its anti‐tumor effect on prostate cancer.

Current Outcome of Patients With Ureteral Stents for the Management of Malignant Ureteral Obstruction

PURPOSE We analyzed the prognostic factors associated with overall survival and predictive factors of stent failure in patients treated with an indwelling retrograde ureteral stent for malignant ureteral obstruction. MATERIALS AND METHODS Among 186 Japanese patients treated with an indwelling retrograde ureteral stent for ureteral obstruction from January 2005 to March 2010, 61 with malignant ureteral obstruction and 95 ureteral units were analyzed retrospectively. RESULTS Median survival was estimated at 228 days. Unfavorable prognostic factors of overall survival were no treatment after indwelling retrograde ureteral stent placement (p = 0.023) and a serum creatinine before indwelling retrograde ureteral stent placement of 1.2 mg/dl or greater (p = 0.016). Overall survival differed significantly among cancer groups (p <0.001) as did stent failure-free survival (p = 0.011). Overall survival differed significantly among 3 risk groups divided according to the score calculated with regard to prognostic factors (p <0.001). CONCLUSIONS Gynecologic cancer was a significant favorable predictor of stent failure-free survival. Patients treated with an indwelling retrograde ureteral stent for malignant ureteral obstruction were divided into 3 groups, which showed significant differences in overall survival. This risk classification may help urologists predict survival time.

Risedronate Recovers Bone Loss in Patients With Prostate Cancer Undergoing Androgen-deprivation Therapy

OBJECTIVES To perform a prospective observational study between risedronate and no risedronate (control) groups to determine the effectiveness of risedronate against bone loss in patients with prostate cancer (PCa) receiving androgen-deprivation therapy (ADT). ADT for PCa has iatrogenic complications (eg, bone loss and fracture). METHODS We enrolled 60 Japanese patients with PCa who were receiving ADT or were newly scheduled for ADT. The lumbar spine bone mineral density (BMD) was determined by dual-energy x-ray absorptiometry. Patients with a BMD <90% of the young adult mean received risedronate. We analyzed 29 and 27 patients in the risedronate and control groups, respectively. The BMD, urinary deoxypyridinoline, and serum bone alkaline phosphatase were measured as bone turnover markers at 6 and 12 months. RESULTS The BMD/young adult mean ratio correlated inversely with the duration of ADT. The initial mean BMD was significantly lower in the risedronate group than in the control group (1.02 +/- 0.19 vs 1.19 +/- 0.16 g/cm(2)). We focused on patients treated with ADT for >6 months. The mean percentage of changes in the BMD/young adult mean ratio of the risedronate and control groups was +2.6 +/- 4.5% and -2.8 +/- 2.6% after 1 year, respectively (P = .0001). The urinary deoxypyridinoline and bone alkaline phosphatase in the risedronate group decreased significantly after 12 months compared with the levels in the controls. CONCLUSIONS The results of our study have shown that oral administration of risedronate is effective for the recovery of ADT-induced bone loss in patients with PCa.

Adrenal androgen levels as predictors of outcome in castration‐resistant prostate cancer patients treated with combined androgen blockade using flutamide as a second‐line anti‐androgen

Objectives:  To analyze the clinical effects of flutamide as a second‐line anti‐androgen for combined androgen blockade in patients with castration‐resistant prostate cancer (CRPC) initially treated with bicalutamide as a first‐line anti‐androgen.

Increases in bone turnover marker levels at an early phase after starting zoledronic acid predicts skeletal-related events in patients with prostate cancer with bone metastasis.

Study Type – Prognosis (case series)

A Case of Bone, Lung, Pleural and Liver Metastases from Renal Cell Carcinoma Which Responded Remarkably Well to Zoledronic Acid Monotherapy

Herein, we report a rare case in which bisphosphonate zoledronic acid (ZA) effectively treated not only multiple bone metastases but also lung, pleural and liver metastases from renal cell carcinoma (RCC). Recently, ZA is used to treat skeletal-related events (SREs) such as bone pain caused by bone metastasis from many kinds of cancer. The patient in the present report had multiple bone metastases from RCC. Remarkable improvement of the bone metastasis was observed following treatment with ZA at a dosage of 4 mg administered once every 4 weeks. Moreover, lung, pleural and liver metastases also diminished markedly in size in response to the treatment. The metastases have shown no progression for 20 months since starting the ZA treatment. We believe that the present report is the first of its kind announcing that ZA monotherapy has been effective for lung, pleural and liver metastases from RCC.

CTEN/tensin 4 expression induces sensitivity to paclitaxel in prostate cancer

Recently, we established paclitaxel‐resistant prostate cancer cell lines (PC‐3‐TxR and DU145‐TxR). To determine the mechanisms of paclitaxel resistance in PC‐3‐TxR cells, we compared the gene expression profiles between PC‐3 and PC‐3‐TxR cells. Our results indicated that expression of the C‐terminal tensin like protein (CTEN, tensin 4) gene was down‐regulated by 10‐fold in PC‐3‐TxR cells. We investigated the possibility that CTEN overexpression restores paclitaxel sensitivity.

Chronological urodynamic evaluation of changing bladder and urethral functions after robot-assisted radical prostatectomy

OBJECTIVE To examine chronological changes in urethral and bladder functions before, immediately after, and 1 year after robot-assisted radical prostatectomy (RARP), urodynamic studies were prospectively performed. METHODS Sixty-three consecutive patients underwent pressure-flow studies, urethral pressure profiles, and abdominal leak point pressure (ALPP) tests 1-2 days before, immediately after, and 1 year after RARP. RESULTS The mean bladder compliance was 28.3 mL/cm H₂O before RARP; it worsened to 16.3 mL/cm H₂O immediately after RARP and recovered to 27.1 mL/cm H₂O at 1 year. The mean detrusor pressure at maximum flow rate was 61.9 cm H₂O before RARP; it decreased to 34.3 cm H₂O immediately after RARP and remained at 35.6 cm H₂O at 1 year. The mean maximum urethral closure pressure was 84.2 cm H₂O before RARP; it decreased to 33.4 cm H₂O immediately after RARP and recovered to 63.0 cm H₂O at 1 year. Intrinsic sphincter deficiency (ISD) evaluated by the ALPP test was observed in 53 patients immediately after RARP, although no patient showed ISD before RARP. ISD remained in 7 patients at 1 year. Both ALPP and maximum urethral closure pressure at 1 year were significant factors for continence in multivariate analysis. CONCLUSION Urethral sphincter and bladder function worsen immediately after RARP and recover over time. The bladder storage function after RARP returns to almost the same level before RARP, and the voiding function improves compared with the condition before RARP; however, the urethral sphincter function does not return to its preoperative level. Urethral sphincter dysfunction is considered the main factor for urinary incontinence after RARP.