Shujie Xia

Endothelial Cells Enhance Prostate Cancer Metastasis via IL-6→Androgen Receptor→TGF-β→MMP-9 Signals

Although the potential roles of endothelial cells in the microvascules of prostate cancer during angiogenesis have been documented, their direct impacts on the prostate cancer metastasis remain unclear. We found that the CD31-positive and CD34-positive endothelial cells are increased in prostate cancer compared with the normal tissues and that these endothelial cells were decreased upon castration, gradually recovered with time, and increased after prostate cancer progressed into the castration-resistant stage, suggesting a potential linkage of these endothelial cells with androgen deprivation therapy. The in vitro invasion assays showed that the coculture of endothelial cells with prostate cancer cells significantly enhanced the invasion ability of the prostate cancer cells. Mechanism dissection found that coculture of prostate cancer cells with endothelial cells led to increased interleukin (IL)-6 secretion from endothelial cells, which may result in downregulation of androgen receptor (AR) signaling in prostate cancer cells and then the activation of TGF-β/matrix metalloproteinase-9 (MMP-9) signaling. The consequences of the IL-6→AR→TGFβ→MMP-9 signaling pathway might then trigger the increased invasion of prostate cancer cells. Blocking the IL-6→AR→TGFβ→MMP-9 signaling pathway either by IL-6 antibody, AR-siRNA, or TGF-β1 inhibitor all interrupted the ability of endothelial cells to influence prostate cancer invasion. These results, for the first time, revealed the important roles of endothelial cells within the prostate cancer microenvironment to promote the prostate cancer metastasis and provide new potential targets of IL-6→AR→TGFβ→MMP-9 signals to battle the prostate cancer metastasis. Mol Cancer Ther; 12(6); 1026–37. ©2013 AACR.

Activated androgen receptor promotes bladder cancer metastasis via Slug mediated epithelial-mesenchymal transition

Androgen receptor (AR) has been indicated to be involved in bladder cancer progression. We showed androgen induced epithelial-mesenchymal transition (EMT) in AR-positive bladder cancer cells and promoted tumor metastasis in xenograft models. We subsequently identified that Slug was the mediator of EMT induced by androgen. Furthermore, upregulation of Slug was due to activation of Wnt/β-catenin signaling in response to androgen. Finally, expression of AR showed strong correlation with loss of E-cadherin, higher expression of Slug and nuclear accumulation of β-catenin in bladder tumor tissues. Taken together, our results suggest AR signaling promotes bladder cancer metastasis through Slug mediated EMT.

Human Wharton’s jelly-derived mesenchymal stromal cells reduce renal fibrosis through induction of native and foreign hepatocyte growth factor synthesis in injured tubular epithelial cells

IntroductionBased on some well-documented reports, we attempted to clarify the antifibrotic mechanisms of human Wharton’s-jelly-derived mesenchymal stromal cells (WJ-MSCs) from the perspective of induction of hepatocyte growth factor (HGF) expression in tubular epithelial cells (TECs).MethodsA rat model of acute kidney injury (AKI) was established through unilateral renal ischemia for 1 hour. Two days later, a single intravenous cell or vehicle injection, or contralateral nephrectomy, was performed. Rats were sacrificed at 1 day, 1 week, 4 weeks, or 6 weeks after the intervention. Renal fibrosis was evaluated by Masson trichrome staining and Sircol collagen assay. The upregulation of α-smooth muscle actin (α-SMA) versus E-cadherin expression was adopted as an indicator of tubular epithelial-mesenchymal transition (EMT). Gene and protein expression of HGF or transforming growth factor-beta1 (TGF-β1) was determined by real-time polymerase chain reaction (RT-PCR) and Western blot, respectively. HGF expression in TECs was detected with immunostaining. In vitro, rat TECs subjected to hypoxia injury were incubated with or without conditioned medium (CM) from WJ-MSCs for 1, 3, 24, or 48 hours. Rat or human HGF synthesis in TECs was assessed with immunostaining, RT-PCR, or ELISA.ResultsCell delivery or nephrectomy led to abrogation of renal scarring. At the incipient period of AKI, through induction of HGF expression, either of them remarkably promoted the upregulation of HGF versus TGF-β1 expression in damaged kidney. Rat TECs were not only the principal cells expressing HGF but also exhibited human HGF expression after cell infusion. During fibrogenesis, the downregulation of HGF versus TGF-β1 expression was greatly prevented by WJ-MSCs or kidney removal, thereby resulting in tubular EMT delay. In vitro, after 24 or 48 hours of incubation, CM not only robustly induced the upregulation of rat HGF gene expression in TECs but substantially amplified the release of rat HGF. Under the induction of CM, human HGF mRNA and protein were detected in rat TECs.ConclusionsWJ-MSCs contribute to tubular EMT delay and the alleviation of renal fibrosis. Induction of native and foreign HGF synthesis in damaged TECs at the initial stage of AKI leads to recovery of the disturbed balance of HGF/TGF-β1 during scar formation, being one of the vital mechanisms.

miR-200b suppresses cell proliferation, migration and enhances chemosensitivity in prostate cancer by regulating Bmi-1.

microRNAs (miRNAs) are a class of small non-coding RNAs that can post-transcriptionally regulate gene expression and play critical roles in many important biological processes. The role of miRNAs in prostate cancer (PCa) development and pathogenesis remains largely unknown. In the present study, we showed that miR-200b was downregulated in clinical prostatic tumors when compared to normal prostate tissue and in advanced PCa cell lines when compared to normal epithelial prostatic cells. Enforced miR-200b expression suppressed PCa cell proliferation and migration and enhanced chemosensitivity to docetaxel by targeting B-cell-specific Moloney murine leukemia virus insertion site 1 (Bmi-1). Bmi-1 was detected at higher levels in PCa, and knockdown of Bmi-1 showed similar effects as miR-200b overexpression in PCa cells. Moreover, we confirmed that these effects were correlated with increased levels of E-cadherin and P16 and a reduction in vimentin expression and expression of stem cell markers (CD44 and OCT4). These findings suggest that miR-200b plays vital roles as a tumor-suppressor by targeting Bmi-1 and may be a promising therapeutic target for PCa treatment.

Treatment of Large Impacted Proximal Ureteral Stones: Randomized Comparison of Percutaneous Antegrade Ureterolithotripsy versus Retrograde Ureterolithotripsy

PURPOSE We compared the safety and efficacy of percutaneous antegrade ureterolithotripsy with retrograde ureterolithotripsy for large impacted proximal ureter stones in a prospective randomized manner. MATERIALS AND METHODS A total of 91 patients with large impacted proximal ureteral stones, defined as stones >1 cm in size located between the ureteropelvic junction and the lower border of the fourth lumbar vertebra, were prospectively randomized for antegrade (44) or retrograde (47) ureterolithotripsy. Failure of the procedure (conversion to an open procedure), intraoperative and postoperative morbidity, operative time, hospital stay, stone clearance at discharge home, and follow-up were analyzed in each group. RESULTS The main complications were bleeding (2.3%; 1 of 43) for the antegrade procedure and ureteral injury (2.3%; 1 of 44) for the retrograde procedure. Percutaneous antegrade ureterolithotripsy was associated with longer operative times (75.4+/-11.8 v 30.6+/-7.8 minutes; P<0.001), longer hospital stay (6.3+/-0.5 v 2.1+/-0.4 days; P<0.001), and a longer interval to return to normal activities (7.8+/-0.7 v 2.7+/-0.6 days; P<0.001). Nevertheless, the percutaneous antegrade procedure had a higher stone-free rate both at discharge home (95.3% v 79.5%; P=0.027), and 1 month post-procedure (100% v 86.4%; P=0.026). CONCLUSIONS Percutaneous antegrade ureterolithotripsy is a valuable treatment modality for impacted proximal ureteral calculi larger than 1 cm, and achieves higher stone-free rates than those of retrograde ureteroscopy with holmium:YAG laser lithotripsy. The drawbacks of the antegrade procedure are longer operative time and hospital stay.

Androgen receptor in human prostate cancer-associated fibroblasts promotes prostate cancer epithelial cell growth and invasion

The androgens and androgen receptor (AR) play key roles in the prostate cancer (PCa) development and progression via epithelium-stroma cross talk. Prostate cancer-associated fibroblasts (CAFs) are dominant components in PCa stroma and are essential in the malignant progression by supporting tumorigenesis and metastasis. However, the AR roles in CAFs are still obscure. We isolated and immortalized the CAFs from human PCa tissues and found the CAFs are AR positive. We then knocked down their AR with siRNA and co-cultured the resultant CAFs with PCa cell line PC3. The MTT, invasion, and colony formation assays were performed to study the PC3 biological behavior. The results showed that the PCa epithelial growth, invasion, and colony formation abilities decreased when knocking down the CAFs AR. By using the real-time quantitative polymerase chain reaction, we found the IGF1, FGF7, FGF10, SDF1, HGF, and TGFb2 expression levels decreased in the AR knocked down CAFs. These results suggested that the AR in CAFs promoted PCa epithelial growth and invasion via regulating a series of growth factors. Targeting the AR in CAFs might be a potential therapeutic option for PCa in future.

Increased Infiltrated Macrophages in Benign Prostatic Hyperplasia (BPH) ROLE OF STROMAL ANDROGEN RECEPTOR IN MACROPHAGE-INDUCED PROSTATE STROMAL CELL PROLIFERATION

Background: Macrophages are key players in the pathogenesis of benign prostatic hyperplasia (BPH). But, molecular mechanisms by which macrophages promote prostate cell proliferation remain unclear. Results: Macrophages can enhance the growth of prostate stromal cells via an androgen receptor (AR)-CCL3-dependent pathway. Conclusion: CCL3 is an AR downstream regulator of macrophages in promoting prostate stromal cell growth. Significance: AR and CCL3 could be targets of opportunity for new therapeutic approaches for the treatment of BPH. Infiltrated macrophages may play important roles in the development and progression of benign prostatic hyperplasia (BPH), but the underlying mechanisms remain largely unknown. We found increased macrophages infiltration in human and mouse BPH tissues. By establishing a co-culture transwell system, we found increased migration of macrophages and proliferation of prostate stromal cells during co-culture. Importantly, stromal androgen receptor (AR) could enhance the migration of macrophages and macrophage-mediated stromal cell proliferation. We identified CCL3 as an AR downstream player, and found CCL3 levels were notably increased in human and mouse BPH prostates. Ablation of prostate stromal AR in a mouse BPH model significantly reduced CCL3 expression levels in prostates. Consistently, targeting AR via an AR degradation enhancer, ASC-J9§, or neutralization of CCL3 with an antibody, resulted in suppression of macrophage migration and prostate stromal cell growth. Our study provides mechanistic insights on the regulation of prostate stromal cells by macrophages via stromal AR/CCL3 signaling pathways, which could potentially allow the development of therapeutic approaches for battling BPH with persistent inflammation.

An overview of prostate diseases and their characteristics specific to Asian men

In this paper, we reviewed the features of common prostate diseases, such as benign prostatic hyperplasia (BPH), prostate cancer (PCa) and chronic prostatitis (CP) that are specific to Asian men. Compared to the Westerners, Asians exhibit particular characteristics of prostate diseases. Through summarizing the epidemiology, symptomatology, diagnostics and therapeutics of these diseases, we find that Asians have a lower incidence of PCa than whites, but the incidences of BPH and CP are similar. Asian men with CP often suffer from fewer disease sites, but have a higher frequency of pain during urination rather than after sexual climax. Prostate-specific antigen (PSA) is a widely used marker for the diagnosis of PCa in both Asian and Western countries. Although the PSA level may be lower in Asians, the threshold used is based on whites. After reviewing the treatments available for these diseases, we did not find a fundamental difference between Asians and whites. Furthermore, the selection for the most appropriate treatment based on the individual needs of patients remains a challenge to urologists in Asia. After considering the traits of prostate diseases that are specific to Asian men, we hope to pave the way for the development of specific diagnostic and therapeutic strategies targeted specifically to Asian men.

Transurethral anatomical enucleation of the prostate with Tm:YAG support (ThuLEP): review of the literature on a novel surgical approach in the management of benign prostatic enlargement

AbstractPurpose Retrograde transurethral anatomical enucleation of the prostate is gaining momentum as a new concept in transurethral surgery of benign prostatic hyperplasia. Its adaptation is boosted by the familiarity of urologists with the finger-assisted anatomical enucleation of the adenoma during open prostatectomy and the combination of this well-established concept with the minimal invasive characteristics of transurethral surgery. The thulium laser appears as an ideal energy source for such operation. In this work, current evidence on thulium laser-assisted anatomical enucleation of the prostate (ThuLEP) is being reviewed. Materials and MethodsA comprehensive literature review was performed on Medline, PubMed, and Cochrane databases retrieving all literature on thulium laser-assisted prostatectomy between 2006 and 2015. Experimental studies, review articles and editorial comments as well as studies on thulium laser-assisted approaches other than ThuLEP (i.e., ThuVEP, ThuVAP or ThuVARP) were excluded from the analysis.ResultsIn total, six original articles on either surgical technique or clinical outcomes were retrieved. With regard to functional results, ThuLEP presented no significant differences toward the standard treatment (TURP/HoLEP) arm in two randomized controlled trials and favorable outcomes in available prospective cohorts. Observed morbidity was minimum and comparable with the rest of transurethral literature.ConclusionsThuLEP literature is still very limited. Based on the available data, the approach is safe and effective, demonstrating favorable outcomes, comparable with the current standard treatment options. Further documentation of ThuLEP outcomes is necessary to define the optimum indications of this novel technique.

Ureteral Reconstruction Using Autologous Tubular Grafts for the Management of Ureteral Strictures and Defects: An Experimental Study

Objective: To investigate whether the peritoneal cavity could function as a bioreactor to produce autologous tubular grafts for ureteral reconstruction in beagles. Materials and Methods: 8-Fr Silastic tubes were implanted into the peritoneal cavities of 6 female beagles. At 3 weeks, the tubes were harvested and the tubular tissue covering the tubes was gently everted. A segment 3 cm in length of the right mid-ureter, involving two thirds of its diameter, was removed parallel to the ureteral axis, leaving a third of the ureteral wall. A 5-Fr double-J stent was inserted into the ureter through the created defect, and two thirds of the graft were anastomosed to both edges of the ureteral defect. One third of the graft was overlapped with the retained normal ureter and anastomosed to the external surface of the lumens. Thus, the graft was partly encapsulated by the remainder of ureteral wall. The stent was maintained for 6 weeks and removed. Excretory urography was performed at 8 (n = 3) and 12 weeks (n = 3), postoperatively. Meanwhile, the neoureter was harvested and analyzed. The left ureter served as the control and a simple intubated ureterotomy was performed. Results: Histological analysis of the tubular tissue demonstrated transversely arranged myofibroblasts and an outer layer of mesothelium. The tissue was easily everted and transplanted as a ureteral graft. Eight weeks postoperatively, the neoureter demonstrated normal ureteral architecture, composed of multilayers of urothelium surrounded by smooth muscle bundles, which became increasingly organized with time. Excretory urography indicated no stenosis or hydronephrosis. Conclusions: These results show that autologous tubular tissue grown within the recipients’ peritoneal cavity can be used for ureteral reconstruction in the beagle model.