BackgroundProstate is susceptible to infection and pro-inflammatory agents in a man’s whole life. Chronic inflammation might play important roles in the development and progression of prostate cancer. Mesenchymal stem cells (MSCs) are often recruited to the tumor microenvironment due to local inflammation. We have asked whether stimulation of MSCs by pro-inflammatory cytokines could promote prostate tumor growth. The current study investigated the possible involvement of MSCs stimulated by pro-inflammatory cytokines in promotion and angiogenesis of prostate cancer through relative pathway in vitro and in vivo.MethodsA syngeneic mouse model of C57 was established. The murine prostate cancer cells (RM-1) mixing with MSCs treated with tumor necrosis factor alpha (TNF-α) and interferon gamma (IFN-γ) or vehicle were subcutaneously injected into C57 mice. Tumor volume of C57 mouse model was estimated and serum level of platelet-derived growth factor (PDGF) and vascular endothelial growth factor (VEGF) was test by Enzyme-linked Immunosorbent Assay (ELISA). A hen egg test-chorioallantoic membrane (HET-CAM) assay was applied to test the effect of conditioned media of stimulated MSCs in chorioallantoic membrane angiogenesis. Short interfering RNA (siRNA) knocked down either hypoxia-inducible factor-1alpha (HIF-1α) or nuclear factor-erythroid-2-related factor 2 (NRF2) were employed. mRNA of PDGF and VEGF in MSCs, as well as NRF2 and HIF-1α was test by Real time polymerase chain reaction (PCR) analyses. Protein expression levels of PDGF and VEGF from conditioned medium, NRF2, HIF-1α, as well as PDGF and VEGF in MSCs were detected by Western blot analysis.ResultsMSCs treated with TNF-α and IFN-γ promote tumor growth in C57 syngeneic mouse model, correlating with increased serum level of PDGF, VEGF. HET-CAM assay shows the angiogenic effect of conditioned medium of MSCs pre-treated with the pro-inflammatory cytokines. mRNA and protein levels of two pro-angiogenic factors (PDGF and VEGF) and key hypoxia regulators (HIF-1α and NRF2) in MSCs were induced after MSCs’ pretreatment. siRNA knockdown either HIF-1α or NRF2 results reduction of PDGF and VEGF expression.ConclusionsMSCs stimulated by pro-inflammatory cytokines increase the expression of PDGF and VEGF via the NRF2-HIF-1α pathway and accelerate prostate cancer growth in mice.Electronic supplementary materialThe online version of this article (10.1186/s12885-017-3879-z) contains supplementary material, which is available to authorized users.

Cystitis glandularis (CG) has been hypothesized as a potential precursor of adenocarcinoma, although this remains controversial. The present study reports data accumulated from 166 cases of cystitis glandularis with follow-up periods ranging between 0.5 and 17 years. The association between intestinal and typical CG and bladder carcinoma was retrospectively evaluated. The patients included in the present study had presented with typical (n=155) or intestinal (n=11) CG between 1994 and 2010. Of those patients, concurrent carcinoma of the bladder was identified in 15 (9.0%) patients, including two cases of squamous cell carcinoma and 1 case of sarcoma. The cases of carcinoma were identified either prior to or concurrently with the diagnosis of CG. Follow-up was available for 9/11 (81.8%) patients with intestinal CG. Nine months following transurethral fulguration, 8/11 (72.7%) patients were in complete remission and 1/11 (9.1%) complained of urgency and dysuria; two patients were lost to follow-up. The follow-up of the patients ranged from 0.7 to 4.5 years (median, 2.67 years; mean, 2.82 years). No evidence of subsequent carcinoma was identified in any of the patients during the follow-up of the intestinal and typical CG groups. In addition, there was no evidence of carcinoma subsequent to CG in either of the typical or intestinal CG groups. The results did not support that CG increases the future risk of malignancy in the short term and repeated cystoscopies over a short period of time are not recommended.

Mesenchymal stem cells (MSCs) play an important role in the development of human prostate cancer (PCa). However, the role of MSCs in the transformation of androgen-dependent human PCa cells into androgen-independent manner has been poorly understood. In this study, we investigated the underlying mechanism of MSCs in promoting PCa cells from androgen-dependent into androgen-independent manner. Firstly, we demonstrated that MSCs could affect the transformation of androgen-dependent human PCa cells into androgen-independent manner in vivo and in vitro. Then we found a substantial expression of TGF-β in MSCs. TGF-β blockade could significantly inhibit the promotive function of MSCs in PCa cells. Besides that, we also demonstrated androgen might inhibit the expression of TGF-β in MSCs. Furthermore, we found that either overexpression of SSEA-4 or the number of SSEA-4 positive MSCs in PCa tissues was associated with a shorter cancer-free survival interval (CFSI) and a worse overall survival (OS). Our results suggest that androgen blockade treatment in clinical PCa therapy may elicit the expression of TGF-β in MSCs, which will result in the transformation of androgen-dependent human PCa cells into androgen-independent manner.

Prostate cancer (PCa) has become the second leading cause of male cancer-related mortality in the United States. Mesenchymal stem cells (MSCs) are able to migrate to tumor tissues, and are thus considered to be novel antitumor carriers. However, due to their immunosuppressive nature, the application of MSCs in PCa therapy remains limited. In this study, we investigated the effect of MSCs overexpressing an NAD-dependent deacetylase sirtuin 1 (MSCs-Sirt1) on prostate tumor growth, and we analyzed the underlying mechanisms. Our results show that MSCs accelerate prostate tumor growth, whereas MSCs-Sirt1 significantly suppresses tumor growth. Natural killer (NK) cells and macrophages are the prominent antitumor effectors of the MSCs-Sirt1-induced antitumor activity. IFN-γ and C-X-C motif chemokine ligand 10 (CXCL10) are highly expressed in MSCs-Sirt1 mice. The antitumor effect of MSCs-Sirt1 is weakened when CXCL10 and IFN-γ are inhibited. These results show that MSCs-Sirt1 can effectively inhibit prostate cancer growthrecruiting NK cells and macrophages in a tumor inflammatory microenvironment.

Estrogen-related receptor α (ERRα) belongs to the superfamily of nuclear orphan receptors. However, the role of ERRα in bladder cancer remains unknown. This study examined the expression of ERRα in bladder cancer tissues and explored the molecular mechanisms of ERRα in bladder cancer progression. The expression of ERRα in bladder cancer tissues from 61 patients was determined by immunohistochemistry. We performed quantitative realtime polymerase chain reaction assay to detect the gene expression levels and carried out Western blot assay to measure protein levels. In vitro functional assays, including colony formation, Cell Counting Kit-8, Transwell invasion, and migration assays, were performed to detect bladder cancer cell growth, proliferation, invasion, and migration, respectively. Flow cytometry was used to determine the cell apoptotic rate of bladder cancer cells. Among the 61 detected bladder cancer tissues, 39 bladder cancer tissues showed positive ERRα immunoreactivity. Higher ERRα immunoreactivity score was significantly associated with TNM stage, tumor grade, distant metastasis, and poor survival in patients with bladder cancer. Univariate and multivariate analyses showed that ERRα immunoreactivity was an independent prognostic factor for overall survival in patients with bladder cancer. ERRα was found to be upregulated in bladder cancer cell lines, and knockdown of ERRα suppressed bladder cancer cell growth, proliferation, invasion, and migration; promoted bladder cancer cell apoptosis; and inhibited the epithelial-mesenchymal transition of bladder cancer cells. On the other hand, bladder cancer cell proliferation, invasion, and migration were significantly enhanced after cells were transfected with an ERRα-overexpressing vector. In vivo tumor growth and metastasis assays showed that ERRα knockdown resulted in remarkable inhibition of tumor growth and tumor metastasis in nude mice. Collectively, our results suggest that J Cell Biochem. 2019;120:13841-13852.wileyonlinelibrary.com/journal/jcb

The objective of the present study was to explore the association between muscarinic cholinergic signaling and urothelial bladder tumors. Possible associations among overactive bladder (OAB) symptoms and bladder tumors were retrospectively investigated using a multicenter Chinese database with prospectively collected data since 2010. Firstly, it was demonstrated that OAB symptoms, such as urgency, were more severe in patients with invasive bladder cancer and were associated with a reduced prognosis. Following this, muscarinic cholinergic receptor 3 (M3R) expression in urothelium was determined to be lower in invasive cancer tissue than in adjacent non-cancerous tissue, yet M3R upregulation was associated with a reduced progression free survival (PFS) time. Additionally, it was also demonstrated that muscarinic cholinergic receptor 2 (M2R) was upregulated in the sub-urothelium, and this was also associated with a reduced PFS time. Furthermore, it was determined that cholinesterase and acetylcholinesterase were lower in invasive cancer than in non-invasive cancer. In conclusion, the results indicated that M3R expression was downregulated in invasive bladder cancer, which may have a role as a protective anti-oncogene, in contrast to its oncogenic role in numerous other cancer types. Therefore, muscarinic cholinergic signaling may be a novel therapeutic target for treating bladder cancer.

Purpose This study investigated the clinical significance of postoperative neutrophil-to-lymphocyte ratio (NLR) changes in bladder cancer recurrence. Patients and Methods For evaluating the predictive value of postoperative dynamic change of NLR, a retrospective cohort study was performed to analyze 213 patients with bladder cancer who underwent surgical treatment from January 2013 to December 2019 at the Affiliated Tumor Hospital of Guangxi Medical University. Baseline characteristics and recurrence-free survival (RFS) were statistically compared, and a multivariate analysis was used to identify prognostic factors. Results Compared with preoperative NLR levels, postoperative decreased NLR in 130 patients and postoperative increased NLR in 83 patients were detected. The 1-, 3- and 5-year RFS rates were 88.0%, 75.4% and 75.4% in the decreased postoperative NLR group, respectively, and 51.2%, 25.8% and 16.1% in the increased postoperative NLR group, respectively (P < 0.05). Kaplan–Meier curves showed that the cumulative DFS rate in the increased group was significantly lower than that in the decreased group (P < 0.05). The preoperative NLR showed significant difference with postoperative NLR in the total cohort, high-grade non-muscle-invasive bladder cancer (HG-NMIBC) and muscle-invasive bladder cancer (MIBC) group, while there was no significant difference between postoperative NLR and NLR of recurrence or last follow-up. Multivariate analysis suggested that postoperative-preoperative NLR was an independent predictor for RFS (HR=6.206, 95% CI: 3.826–10.067, P < 0.001) in the total cohort, RFS (HR=9.373, 95% CI: 2.724–32.245, P < 0.001) in the LG-NMIBC group, RFS rates (HR=6.873, 95% CI: 2.486–18.999, P < 0.001) in the HG-NMIBC group and RFS rates (HR=6.109, 95% CI: 2.847–13.109, P < 0.001) in the MIBC group. Conclusion The dynamic change of postoperative NLR is a potential marker for the early detection of bladder cancer recurrence. Patients with increased NLR after surgery tend to have higher risk of recurrence.

This study aimed to investigate the effects and mechanisms of water-soluble Semen cassiae polysaccharide (SCP) on retinitis pigmentosa (RP) in rats. Dne hundred rats were randomly divided into control, model, and 50, 100 and 200 mg/kg SCP groups. The 50, 100 and 200 mg/kg SCP groups were treated with 50, 100 and 200 mg/kg SCP for 5 days, respectively. Dn the sixth day, the model, and 50, 100 and 200 mg/kg SCP groups were treated with N-nitroso-N-methylurea (MNU). After 12 h and 5 days, the electroretinogram, retinal thickness, apoptosis of retinal photoreceptor cells, and expressions of apoptosis related protein in retina tissue were determined. Results showed that, after 12 h and on 5 days from MNU treatment, compared with model group, the a-wave and b-wave amplitude and retinal thickness in SCP groups were significantly increased, the apoptosis rate of retinal photoreceptor cells was significantly decreased, the Bcl-2 protein expression level in retinal tissue was significantly increased, and the Bax and Caspase-3 protein level were significantly decreased (all P < 0.05). On conclusion, SCP has obvious protective effects on RP in rats. The mechanism may be related to it regulation of Bcl-2, Bax and Caspase-3 protein expression in retina tissue.Practical Application: Water-soluble polysaccharide isolated from Semen cassiae may be applied to prevention and treatment of retinitis pigmentosa.