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Current organoid models are limited by their inability to mimic mature organ architecture and associated tissue microenvironments 1 , 2 . Here we create multilayer bladder ‘assembloids’ by reconstituting tissue stem cells with stromal components to represent an organized architecture with an epithelium surrounding stroma and an outer muscle layer. These assembloids exhibit characteristics of mature adult bladders in cell composition and gene expression at the single-cell transcriptome level, and recapitulate in vivo tissue dynamics of regenerative responses to injury. We also develop malignant counterpart tumour assembloids to recapitulate the in vivo pathophysiological features of urothelial carcinoma. Using the genetically manipulated tumour-assembloid platform, we identify tumoural FOXA1, induced by stromal bone morphogenetic protein (BMP), as a master pioneer factor that drives enhancer reprogramming for the determination of tumour phenotype, suggesting the importance of the FOXA1–BMP–hedgehog signalling feedback axis between tumour and stroma in the control of tumour plasticity. Multilayer 3D reconstitution of bladder stem cells with stromal cells enables recapitulation of the architecture and molecular functions of bladder tissue.

The conventional strategy for cancer gene therapy offers limited control of specificity and efficacy. A possible way to overcome these limitations is to construct logic circuits. Here we present modular AND gate circuits based on CRISPR-Cas9 system. The circuits integrate cellular information from two promoters as inputs and activate the output gene only when both inputs are active in the tested cell lines. Using the luciferase reporter as the output gene, we show that the circuit specifically detects bladder cancer cells and significantly enhances luciferase expression in comparison to the human telomerase reverse transcriptase-renilla luciferase construct. We also test the modularity of the design by replacing the output with other cellular functional genes including hBAX , p21 and E-cadherin . The circuits effectively inhibit bladder cancer cell growth, induce apoptosis and decrease cell motility by regulating the corresponding gene. This approach provides a synthetic biology platform for targeting and controlling bladder cancer cells in vitro . Tools derived from synthetic biology offer powerful means to refine drug delivery and disease detection. Liu et al . engineer a logical AND gate using CRISPR-Cas9 to drive gene expression only cells in which two promoters are active, and use it to selectively inhibit the growth of bladder cancer cells in vitro .

The association between opium use and bladder cancer has been investigated in many studies, with varying reporting results reported. This study aims to estimate the total odds ratio for the association between bladder cancer and opium consumption using meta-analysis. The study was designed according to PRISMA guidelines. Two independent researchers searched for the relevant studies using PubMed, Web of Science, Scopus, OVID, Embase, and Google Scholar. After systematic screening of the studies identified during the first step, Cochrane risk of bias tool was determined for the selected studies. The case-control and the cohort studies were investigated to assess risk of bladder cancer due to opium use. In addition, the cross-sectional studies were analysed separately to assess frequency of opium consumption. These estimates were combined using the inverse variance method. Fixed or random effect models were applied to combine the point odds ratios. The heterogeneity between the primary results was assessed using the Cochran test and I-square index. The suspected factors for heterogeneity were investigated using meta-regression models. An Egger test was conducted to identify any probable publication bias. Forest plots illustrated the point and pooled estimates. All analyses were performed using Stata version 14 software and RevMan version 5.3. We included 17 primary studies (11 case-control, one cohort and five cross-sectional) in the final meta-analysis. The total odds ratios (95% confidence intervals) for developing bladder cancer by opium use alone, and concurrent use of opium and cigarettes were estimated as 3.85 (3.05-4.87) and 5.7 (1.9-16.3) respectively. The odds ratio (95% confidence interval) for opium use with or without cigarette smoking was estimated as 5.3 (3.6-7.7). This meta-analysis showed that opium use similar to cigarette smoking and maybe with similar mechanisms can be a risk factor for bladder cancer. It is therefore expected to be a risk factor for other cancers.

ATP-binding cassette transporter G1 (ABCG1) promotes cholesterol efflux from cells and regulates intracellular cholesterol homeostasis. Here we demonstrate a role of ABCG1 as a mediator of tumour immunity. Abcg1 −/− mice have dramatically suppressed subcutaneous MB49-bladder carcinoma and B16-melanoma growth and prolonged survival. We show that reduced tumour growth in Abcg1 −/− mice is myeloid cell intrinsic and is associated with a phenotypic shift of the macrophages from a tumour-promoting M2 to a tumour-fighting M1 within the tumour. Abcg1 −/− macrophages exhibit an intrinsic bias towards M1 polarization with increased NF-κB activation and direct cytotoxicity for tumour cells in vitro . Overall, our study demonstrates that the absence of ABCG1 inhibits tumour growth through modulation of macrophage function within the tumour, and illustrates a link between cholesterol homeostasis and cancer. ABCG1 transporter pumps cholesterol out of the cell. Here, the authors show that ABCG1-deficient mice have reduced tumour growth due to a switch of the tumour-associated macrophages from a tumour-promoting to tumour-suppressing phenotype, and are protected from the pro-tumorigenic effects of a Western-like diet.

Bladder cancer prognosis is closely linked to the underlying differentiation state of the tumor, ranging from the less aggressive and most-differentiated luminal tumors to the more aggressive and least-differentiated basal tumors. Sequencing of bladder cancer has revealed that loss-of-function mutations in chromatin regulators and mutations that activate receptor tyrosine kinase (RTK) signaling frequently occur in bladder cancer. However, little is known as to whether and how these two types of mutations functionally interact or cooperate to regulate tumor growth and differentiation state. Here, we focus on loss of the histone demethylase UTX (also known as KDM6A) and activation of the RTK FGFR3, two events that commonly cooccur in muscle invasive bladder tumors. We show that UTX loss and FGFR3 activation cooperate to disrupt the balance of luminal and basal gene expression in bladder cells. UTX localized to enhancers surrounding many genes that are important for luminal cell fate, and supported the transcription of these genes in a catalytic-independent manner. In contrast to UTX, FGFR3 activation was associated with lower expression of luminal genes in tumors and FGFR inhibition increased transcription of these same genes in cell culture models. This suggests an antagonistic relationship between UTX and FGFR3. In support of this model, UTX loss-of-function potentiated FGFR3- dependent transcriptional effects and the presence of UTX blocked an FGFR3-mediated increase in the colony formation of bladder cells. Taken together, our study reveals how mutations in UTX and FGFR3 converge to disrupt bladder differentiation programs that could serve as a therapeutic target.

Bladder cancer (BC) is the tenth most common cancer worldwide with a high recurrence rate, morbidity and mortality. Therefore, chemoprevention and improved treatment of BC are of paramount importance. Epidemiological studies suggest that adequate vitamin A intake may be associated with reduced BC risk. In addition, retinoids, natural and synthetic derivatives of vitamin A, are intensively studied in cancer research due to their antioxidant properties and their ability to regulate cell growth, differentiation, and apoptosis. Findings from in vivo and in vitro models of BC show great potential for the use of retinoids in the chemoprevention and treatment of BC. However, translation to the clinical practice is limited. In this narrative review we discuss: (i) vitamin A and retinoid metabolism and retinoic acid signalling, (ii) the pathobiology of BC and the need for chemoprevention, (iii) the epidemiological evidence for the role of dietary vitamin A in BC, (iv) mechanistic insights obtained from in vivo and in vitro models, (v) clinical trials of retinoids and the limitations of retinoid use, (vi) novel systems of retinoid delivery, and (vii) components of retinoid signalling pathways as potential novel therapeutic targets.

Urinary incontinence of idiopathic nature is a common complication of bladder cancer, yet, the mechanisms underlying changes in bladder contractility associated with cancer are not known. Here by using tensiometry on detrusor smooth muscle (DSM) strips from normal rats and rats with bladder cancer induced by known urothelial carcinogen, N-butyl-N-(4-hydroxybutyl)nitrosamine (BBN), we show that bladder cancer is associated with considerable changes in DSM contractility. These changes include: (1) decrease in the amplitude and frequency of spontaneous contractions, consistent with the decline of luminal pressures during filling, and detrusor underactivity; (2) diminution of parasympathetic DSM stimulation mainly at the expense of m-cholinergic excitatory transmission, suggestive of difficulty in bladder emptying and weakening of urine stream; (3) strengthening of TRPV1-dependent afferent limb of micturition reflex and TRPV1-mediated local contractility, promoting urge incontinence; (4) attenuation of stretch-dependent, TRPV4-mediated spontaneous contractility leading to overflow incontinence. These changes are consistent with the symptomatic of bladder dysfunction in bladder cancer patients. Considering that BBN-induced urothelial lesions in rodents largely resemble human urothelial lesions at least in their morphology, our studies establish for the first time underlying reasons for bladder dysfunction in bladder cancer.

Amentoflavone has been shown to be effective against a variety of cancer cells, but its role in bladder cancer remains unclear. Thus, the aim of this study is to evaluate whether amentoflavone may induce toxicity effect of bladder cancer. Herein, we evaluated amentoflavone effects in a human bladder cancer cell line TSGH8301 in vitro. Amentoflavone caused significant cytotoxicity in TSGH8301 cells at a concentration as low as 200 μM. FAS/FASL-dependent extrinsic apoptosis and mitochondria-dependent intrinsic apoptosis were observed in amentoflavone-treated cells in a dose-dependent manner. Levels of several proapoptotic proteins, such as FAS, FAS-ligand and BAX (B-cell lymphoma 2 associated X) were increased following amentoflavone treatment. Meanwhile, anti-apoptotic MCL-1 (myeloid cell leukemia sequence 1) and cellular FLICE-inhibitory protein (C-FLIP) protein levels were reduced. Additionally, angiogenesis and proliferation-related proteins, including matrix metalloproteinase (MMP)-2, -9, vascular endothelial growth factor (VEGF), urokinase-type plasminogen actvator (uPA) and cyclin D1 were diminished by amentoflavone. Amentoflavone induced toxicity of bladder cancer by inhibiting tumor progression and inducing apoptosis signaling transduction.

Background To explore the prognostic significance of preoperative prognostic nutritional index (PNI) in bladder cancer after radical cystectomy and compare the prognostic ability of inflammation-based indices. Methods We retrospectively analyzed data for 516 patients with bladder cancer who underwent radical cystectomy in our institution between 2006 to 2012. Clinicopathologic characteristics and inflammation-based indices (PNI, neutrophil/lymphocyte ratio [NLR], platelet/lymphocyte ratio [PLR], lymphocyte/monocyte ratio [LMR]) were evaluated by pre-treatment measurements. Overall survival (OS) and progression-free survival (PFS) were estimated by the Kaplan–Meier method and compared by log-rank test. Multivariate analysis with a Cox proportional hazards model was used to confirm predictors identified on univariate analysis. The association between clinicopathological characteristics and PNI or NLR was tested. Results Among the 516 patients, the median follow-up was 37 months (interquartile range 20 to 56). On multivariate analysis, PNI and NLR independently predicted OS (PNI: hazard ratio [HR] = 1.668, 95% CI: 1.147–2.425, P  = 0.007; NLR: HR = 1.416, 95% CI:1.094–2.016, P  = 0.0149) and PFS (PNI: HR = 1.680, 95% CI:1.092–2.005, P  = 0.015; NLR: HR = 1.550, 95% CI:1.140–2.388, P  = 0.008). Low PNI predicted worse OS for all pathological stages and PFS for T1 and T2 stages. Low PNI was associated with older age (>65 years), muscle-invasive bladder cancer, high American Society of Anesthesiologists grade and anemia. Conclusion PNI and NLR were independent predictors of OS and PFS for patients with bladder cancer after radical cystectomy and PNI might be a novel reliable biomarker for bladder cancer.

BackgroundUrinary bladder cancer (UBC) is considered one of the most prevalent malignant tumors worldwide. Complementary and integrative approaches for the treatment of bladder cancer, such as the intake of isoflavonoid phytoestrogens, are of increasing interest due to the risk of mortality and long-term morbidity associated with surgical procedures. The biological effects of prunetin, one of the less-studied phytoestrogens, have not yet been examined in this respect. Therefore, this study aimed to explore the efficacy of prunetin on UBC cells (RT-4).Methods and resultsThe cytotoxicity and nitric oxide synthase activities of prunetin were determined in cell cultures. The expression of apoptosis-related genes was determined with RT-PCR. Cell cycle assays were performed using a flow cytometer and cellular apoptotic rate was measured. The results suggested that prunetin has cytotoxic effects at 21.11 µg/mL on RT-4 cells. Flow cytometry analysis showed that prunetin induced apoptosis and arrested th cell cycle in the G0/G1 phase. Prunetin exposure was associated with increases in CASP3 and TNF-α gene expression in RT-4 cells at doses of 21.11 and 42.22 µg/mL, respectively. Strong nitric oxide inhibition was observed at IC50 of 5.18 µg/mL under macrophage mediated inflammatory circumstances.ConclusionsPrunetin possesses anti-cancer properties and may be a candidate compound for the prevention of UBC. This is the first study that evaluated prunetin for its in vitro antitumor activities, clarified its possible apoptotic molecular mechanism and provided novel insights into its anti-inflammatory nature and effects on the expression of related key genes.