Subject(s)
Carcinoma, Renal Cell , Kidney Neoplasms , Humans , Kidney Neoplasms/genetics , Kidney Neoplasms/diagnosis , Kidney Neoplasms/pathology , Carcinoma, Renal Cell/genetics , Carcinoma, Renal Cell/diagnosis , Carcinoma, Renal Cell/pathology , Carcinoma, Transitional Cell/genetics , Carcinoma, Transitional Cell/diagnosis , Carcinoma, Transitional Cell/pathology , Incidental Findings , Urinary Bladder Neoplasms/genetics , Urinary Bladder Neoplasms/diagnosis , Urinary Bladder Neoplasms/pathology , Early Detection of Cancer , Urologic Neoplasms/genetics , Urologic Neoplasms/diagnosis , Urologic Neoplasms/pathologyABSTRACT
INTRODUCTION: Previously, in a randomised trial we demonstrated bipolar transurethral resection of bladder tumor (TURBT) could achieve a higher detrusor sampling rate than monopolar TURBT. We hereby report the long-term oncological outcomes following study intervention. METHODS: This is a post-hoc analysis of a randomized phase III trial comparing monopolar and bipolar TURBT. Only patients with pathology of non-muscle invasive bladder cancer (NMIBC) were included in the analysis. Per-patient analysis was performed. Primary outcome was recurrence-free survival (RFS). Secondary outcomes included progression-free survival (PFS), cancer-specific survival (CSS) and overall survival (OS). RESULTS: From the initial trial, 160 cases were randomised to receive monopolar or bipolar TURBT. 24 cases of non-urothelial carcinoma, 22 cases of muscle-invasive bladder cancer, and 9 cases of recurrences were excluded. A total of 97 patients were included in the analysis, with 46 in the monopolar and 51 in the bipolar group. The median follow-up was 97.1 months. Loss-to-follow-up rate was 7.2%. Regarding the primary outcome of RFS, there was no significant difference (HR = 0.731; 95%CI = 0.433-1.236; P = 0.242) between the two groups. PFS (HR = 1.014; 95%CI = 0.511-2.012; P = 0.969), CSS (HR = 0.718; 95%CI = 0.219-2.352; P = 0.584) and OS (HR = 1.135; 95%CI = 0.564-2.283; P = 0.722) were also similar between the two groups. Multifocal tumours were the only factor that was associated with worse RFS. CONCLUSION: Despite the superiority in detrusor sampling rate, bipolar TURBT was unable to confer long-term oncological benefits over monopolar TURBT.
Subject(s)
Cystectomy , Transurethral Resection of Bladder , Urinary Bladder Neoplasms , Aged , Female , Humans , Male , Middle Aged , Cystectomy/methods , Prospective Studies , Transurethral Resection of Bladder/methods , Treatment Outcome , Urethra , Urinary Bladder Neoplasms/surgery , Urinary Bladder Neoplasms/pathology , Urinary Bladder Neoplasms/mortalityABSTRACT
Muscle invasive bladder cancers (BCs) can be divided into 2 major subgroups-basal/squamous (BASQ) tumors and luminal tumors. Since Pparg has low or undetectable expression in BASQ tumors, we tested the effects of rosiglitazone, Pparg agonist, in a mouse model of BASQ BC. We find that rosiglitazone reduces proliferation while treatment with rosiglitazone plus trametinib, a MEK inhibitor, induces apoptosis and reduces tumor volume by 91% after 1 month. Rosiglitazone and trametinib also induce a shift from BASQ to luminal differentiation in tumors, which our analysis suggests is mediated by retinoid signaling, a pathway known to drive the luminal differentiation program. Our data suggest that rosiglitazone, trametinib, and retinoids, which are all FDA approved, may be clinically active in BASQ tumors in patients.
Subject(s)
Apoptosis , Cell Proliferation , Disease Models, Animal , Pyridones , Pyrimidinones , Rosiglitazone , Urinary Bladder Neoplasms , Animals , Urinary Bladder Neoplasms/drug therapy , Urinary Bladder Neoplasms/pathology , Urinary Bladder Neoplasms/genetics , Pyridones/pharmacology , Pyridones/therapeutic use , Pyrimidinones/pharmacology , Pyrimidinones/therapeutic use , Rosiglitazone/pharmacology , Rosiglitazone/therapeutic use , Mice , Apoptosis/drug effects , Humans , Cell Proliferation/drug effects , Cell Line, Tumor , Antineoplastic Agents/pharmacology , Antineoplastic Agents/therapeutic use , Neoplasm Invasiveness , Female , PPAR gamma/metabolism , PPAR gamma/agonists , Thiazolidinediones/pharmacology , Thiazolidinediones/therapeutic use , Cell Differentiation/drug effects , Signal Transduction/drug effects , Retinoids/pharmacology , Retinoids/therapeutic useABSTRACT
BACKGROUND: Sarcomatoid urothelial carcinoma (SUC) is a rare and highly malignant form of bladder cancer with a poor prognosis. Currently, there is limited information on the imaging features of bladder SUC and reliable indicators for distinguishing it from conventional urothelial carcinoma (CUC). The objective of our study was to identify the unique imaging characteristics of bladder SUC and determine factors that aid in its differential diagnosis. MATERIALS AND METHODS: This retrospective study enrolled 22 participants with bladder SUC and 61 participants with CUC. The clinical, pathologic, and CT/MRI data from both groups were recorded, and a comparison was conducted using univariate analysis and multinomial logistic regression for distinguishing SUC from CUC. RESULTS: The majority of SUCs were located in the trigone of the bladder and exhibited large tumor size, irregular shape, low ADC values, Vesical Imaging-Reporting and Data System (VI-RADS) score ≥ 4, the presence of necrosis, and an invasive nature. Univariate analysis revealed significant differences in terms of tumor location, shape, the maximum long-axis diameter (LAD), the short-axis diameter (SAD), ADC-value, VI-RADS scores, necrosis, extravesical extension (EVE), pelvic peritoneal spread (PPS), and hydronephrosis/ureteral effusion (p < .001 ~ p = .037) between SUCs and CUCs. Multinomial logistic regression found that only SAD (p = .014) and necrosis (p = .003) emerged as independent predictors for differentiating between SUC and CUC. The model based on these two factors achieved an area under curve (AUC) of 0.849 in ROC curve analysis. CONCLUSION: Bladder SUC demonstrates several distinct imaging features, including a high incidence of trigone involvement, large tumor size, and obvious invasiveness accompanied by necrosis. A bladder tumor with a large SAD and evidence of necrosis is more likely to be SUC rather than CUC.
Subject(s)
Carcinoma, Transitional Cell , Magnetic Resonance Imaging , Tomography, X-Ray Computed , Urinary Bladder Neoplasms , Humans , Urinary Bladder Neoplasms/diagnostic imaging , Urinary Bladder Neoplasms/pathology , Diagnosis, Differential , Male , Female , Aged , Retrospective Studies , Magnetic Resonance Imaging/methods , Middle Aged , Tomography, X-Ray Computed/methods , Carcinoma, Transitional Cell/diagnostic imaging , Carcinoma, Transitional Cell/pathology , Aged, 80 and over , AdultABSTRACT
Grading and staging are the most important prognostic factors for both non-invasive and invasive urothelial carcinomas, and are also one of the most common difficulties encountered by pathologists in the daily diagnostic practice of urothelial carcinoma. Recently, the International Society of Urological Pathology organized a survey and questionnaire conference on various issues related to the diagnosis, grading, and staging of urothelial carcinoma, and ultimately formed a series of consensus opinions. This article briefly summarizes the consensus opinions of this series, and combines them with the current pathological diagnosis status of urothelial carcinoma in China. It briefly comments on how to apply this series of consensus opinions in the daily diagnostic practice of pathologists, deeply understand relevant diagnostic problems, and carry out relevant clinical pathological research to further solve problems.
Subject(s)
Carcinoma, Transitional Cell , Neoplasm Grading , Urinary Bladder Neoplasms , Humans , Urinary Bladder Neoplasms/pathology , Carcinoma, Transitional Cell/pathology , Neoplasm Staging , Urothelium/pathologySubject(s)
Solitary Fibrous Tumors , Urinary Bladder Neoplasms , Humans , Solitary Fibrous Tumors/pathology , Solitary Fibrous Tumors/metabolism , Solitary Fibrous Tumors/genetics , Solitary Fibrous Tumors/surgery , Urinary Bladder Neoplasms/pathology , Urinary Bladder Neoplasms/metabolism , Urinary Bladder Neoplasms/genetics , Urinary Bladder Neoplasms/surgery , Antigens, CD34/metabolism , Diagnosis, Differential , STAT6 Transcription Factor/metabolism , STAT6 Transcription Factor/genetics , Repressor Proteins/genetics , Repressor Proteins/metabolism , MaleABSTRACT
Bladder cancer is a common malignancy worldwide, posing a substantial healthcare challenge. Current standard treatment regimens are primarily based on cisplatin, but their success is often limited by cisplatin resistance and associated toxicities. Therefore, there is an urgent need to develop effective and less toxic therapies as alternatives to cisplatin. We screened the activity of FDA-approved anti-cancer drugs on a panel of cisplatin-resistant bladder cancer cell lines. Based on initial responses, cabazitaxel was selected for further evaluation of its inhibitory effects on the phenotypic properties of these cells. Cabazitaxel, primarily used for metastatic castration-resistant prostate cancer, demonstrated remarkable efficacy in inhibiting colony formation, proliferation, and migration of cisplatin-resistant bladder cancer cells. This study highlights the potential of drug repurposing as a cost-effective and efficient strategy to overcome drug resistance in bladder cancer.
Subject(s)
Antineoplastic Agents , Cisplatin , Drug Resistance, Neoplasm , Taxoids , Urinary Bladder Neoplasms , Humans , Urinary Bladder Neoplasms/drug therapy , Urinary Bladder Neoplasms/pathology , Drug Resistance, Neoplasm/drug effects , Cisplatin/pharmacology , Cisplatin/therapeutic use , Taxoids/pharmacology , Taxoids/therapeutic use , Antineoplastic Agents/pharmacology , Antineoplastic Agents/therapeutic use , Cell Line, Tumor , Cell Proliferation/drug effects , Cell Movement/drug effectsSubject(s)
Cullin Proteins , Epithelial-Mesenchymal Transition , Urinary Bladder Neoplasms , Wnt Signaling Pathway , Humans , Urinary Bladder Neoplasms/pathology , Urinary Bladder Neoplasms/metabolism , Urinary Bladder Neoplasms/genetics , Cullin Proteins/metabolism , Cullin Proteins/genetics , Neoplasm Metastasis , beta Catenin/metabolism , AnimalsABSTRACT
OBJECTIVE: We present a novel technique to perform single-port (SP) robot-assisted partial cystectomy with excision of the urachal remnant and bilateral pelvic lymph node dissection for urachal adenocarcinoma (1-7). MATERIALS AND METHODS: A 41-year-old male presented to the clinic for multiple episodes of hematuria and mucousuria. Office cystoscopy revealed a small solitary tumor at the dome of the bladder, with a diagnostic bladder biopsy revealing a tubule-villous bladder adenoma. Cross-sectional imaging of the chest/abdomen/pelvis revealed a 4.5 cm cystic mass arising from the urachus without evidence of local invasion and metastatic spread. He underwent SP robotic-assisted partial cystectomy with excision of the urachal remnant and bilateral pelvic lymph node dissection. Surgical steps include: 1) peritoneal incision to release the urachus and drop bladder 2) identification of urachal tumor 3) intraoperative live cystoscopic identification of bladder mass and scoring of tumor margins using Toggle Pro feature 4) tumor excision with partial cystectomy 5) cystorrhaphy 6) bilateral pelvic lymph node dissection 7) peritoneal interposition flap to mitigate lymphocele formation. RESULTS: Surgery was successful, with no intraoperative complications, an operative time of 100 minutes, and estimated blood loss of 20 mL. The patient was discharged on post-op day one, and the Foley catheter removed one week after surgery. Final pathology revealed a 7.5 cm infiltrating urachal muscle-invasive adenocarcinoma of the bladder (pT2b). Negative surgical margins were achieved. CONCLUSIONS: Single-port robot-assisted partial cystectomy for urachal adenocarcinoma is safe and can achieve equivalent oncologic outcomes to the standard of care with minimally invasive and open techniques.
Subject(s)
Adenocarcinoma , Cystectomy , Lymph Node Excision , Robotic Surgical Procedures , Urinary Bladder Neoplasms , Humans , Male , Adenocarcinoma/surgery , Adenocarcinoma/pathology , Robotic Surgical Procedures/methods , Cystectomy/methods , Urinary Bladder Neoplasms/surgery , Urinary Bladder Neoplasms/pathology , Adult , Lymph Node Excision/methods , Treatment Outcome , Operative Time , Reproducibility of ResultsABSTRACT
INTRODUCTION: Bladder cancer (BC) is a prevalent malignancy with high recurrence rates. Patient-derived bladder cancer organoids (BCO) pose as a promising approach in both, disease modeling and individualized treatment screening. The aim of this study was to investigate the transcriptomic plasticity in BCOs as a function of cultivation times to define ideal time periods for the applications envisioned. METHODS: Tumor samples of three patients with pathologically confirmed non-muscle invasive and muscle-invasive bladder cancer were included in this study and expanded as BCOs. RNA expression was investigated at different time periods of cells in culture using differential gene expression for overall transcript expression and quantitative real-time PCR (qRT-PCR) for pathological relevant markers. RESULTS: Differential gene expression of the BCO lines was investigated across passages 1-4, in passages 5-9 and above 9, respectively. Analysis of the entire transcriptome of the respective BCO lines revealed consistent profiles without significant alterations throughout the cultivation and expansion procedure. Notably, key transcripts like TP53, PIK3CA, BRCA1, among others, exhibited stable expression levels in the quantitative RNA analysis during the cultivation period. CONCLUSION: The robust transcriptome during BCO cultivation advocates for the use of earlier passages of BCOs in personalized medicine providing a time-efficient drug screening option to accelerate the counseling of patients' treatment options. Higher passages of BCOs still hold the potential in topics demanding for expanded cell masses such as medical device development and others.
Subject(s)
Organoids , Urinary Bladder Neoplasms , Humans , Urinary Bladder Neoplasms/genetics , Urinary Bladder Neoplasms/pathology , Urinary Bladder Neoplasms/metabolism , Organoids/metabolism , Gene Expression Regulation, Neoplastic , Male , Transcriptome , Tumor Cells, Cultured , FemaleABSTRACT
BACKGROUND: Although immunotherapy shows tremendous potential in the treatment of bladder cancer (BLCA), the overall prognosis and response rates to immunotherapy in BLCA remain suboptimal. METHODS: We performed an extensive evaluation of glycosyltransferase expression patterns in BLCA patients by analyzing 210 glycosyltransferase-related genes. Subsequently, we established correlations between these glycosyltransferase patterns, prognosis, and tumor microenvironment (TME) phenotypes. To offer personalized patient assessments, we developed a glycosyltransferase risk score that accurately predicts prognosis, TME phenotypes, and molecular subtypes. Importantly, we developed a RNA-seq cohort, named Xiangya cohort, to validate our results. RESULTS: Two distinct patterns of glycosyltransferase expression were identified, corresponding to inflamed and noninflamed TME phenotypes, and demonstrated the potential to predict prognosis. We developed and validated a comprehensive risk score that accurately predicted individual patient prognosis in the TCGA-BLCA cohort. Additionally, we constructed a nomogram that integrated the risk score with several key clinical factors. Importantly, this risk score was successfully validated in external cohorts, including the Xiangya cohort and GSE48075. Furthermore, we discovered a positive correlation between this risk score and tumor-infiltrating lymphocytes in both the TCGA-BLCA and Xiangya cohorts, suggesting that patients with a higher risk score exhibited an inflamed TME phenotype and were more responsive to immunotherapy. Finally, we observed that the high and low risk score groups were consistent with the luminal and basal subtypes of BLCA, respectively, providing further validation of the risk score's role in the TME in terms of molecular subtypes. CONCLUSIONS: Glycosyltransferase patterns exhibit distinct TME phenotypes in BLCA. Our comprehensive risk score provides a promising approach for prognostic prediction and assessment of immunotherapy efficacy, offering valuable guidance for precision medicine.
Subject(s)
Glycosyltransferases , Immunotherapy , Nomograms , Phenotype , Tumor Microenvironment , Urinary Bladder Neoplasms , Humans , Urinary Bladder Neoplasms/genetics , Urinary Bladder Neoplasms/therapy , Urinary Bladder Neoplasms/immunology , Urinary Bladder Neoplasms/pathology , Urinary Bladder Neoplasms/mortality , Tumor Microenvironment/immunology , Tumor Microenvironment/genetics , Prognosis , Immunotherapy/methods , Glycosyltransferases/genetics , Glycosyltransferases/metabolism , Male , Female , Lymphocytes, Tumor-Infiltrating/immunology , Lymphocytes, Tumor-Infiltrating/metabolism , Biomarkers, Tumor/genetics , Middle Aged , Risk Assessment , Aged , Gene Expression Regulation, Neoplastic , Risk FactorsABSTRACT
BACKGROUND: A second look trans-urethral resection of the bladder (re-TUR) is recommended after the diagnosis of T1 high grade (T1HG) bladder cancer. Few studies have evaluated the results of re-TUR after a first en bloc resection (EBR) and none of them have specifically reported the pathological results on the field of previous T1 disease. OBJECTIVE: To report the rate of upstaging and the rate of residual disease (RD) on the field of T1HG lesions resected with EBR. MATERIALS AND METHODS: Between 01/2014 and 06/2022, patients from 2 centers who had a re-TUR after an EBR for T1HG urothelial carcinoma were retrospectively included. Primary endpoint was the rate of RD including the rate of upstaging to T2 disease on the scar of the primary resection. Secondary endpoints were the rate of any residual disease outside the field. RESULTS: Seventy-five patients were included. No muscle invasive bladder cancer lesions were found after re-TUR. Among the 16 patients who had a RD, 4 were on the resection scar. All of these lesions were papillary and high grade. RD outside the field of the first EBR was observed in 12 patients. CONCLUSION: After EBR of T1HG disease, none of our patients had an upstaging to MIBC. However, the rate of RD either on and outside the field of the EBR remains quite significant. We suggested that predictive factors of residual papillary disease (number of tumors at the initial TUR and concomitant CIS) might be suitable to select patient who will benefit of the re-TUR.
Subject(s)
Carcinoma, Transitional Cell , Cystectomy , Neoplasm Staging , Neoplasm, Residual , Reoperation , Urinary Bladder Neoplasms , Humans , Urinary Bladder Neoplasms/surgery , Urinary Bladder Neoplasms/pathology , Retrospective Studies , Male , Aged , Female , Cystectomy/methods , Carcinoma, Transitional Cell/surgery , Carcinoma, Transitional Cell/pathology , Middle Aged , Aged, 80 and overABSTRACT
BACKGROUND: Muscle-invasive bladder cancer (MIBC) is a prevalent and aggressive malignancy. Ferroptosis and cuproptosis are recently discovered forms of programmed cell death (PCD) that have attracted much attention. However, their interactions and impacts on MIBC overall survival (OS) and treatment outcomes remain unclear. METHODS: Data from the TCGA-BLCA project (as the training set), cBioPortal database, and GEO datasets (GSE13507 and GSE32894, as the test sets) were utilized to identify hub ferroptosis/cuproptosis-related genes (FRGs and CRGs) and develop a prognostic signature. Differential expression analysis (DEA) was conducted, followed by univariate and multivariate Cox's regression analyses and multiple machine learning (ML) techniques to select genetic features. The performance of the ferroptosis/cuproptosis-related signature was evaluated using Kaplan-Meier (K-M) survival analysis and receiver-operating characteristics (ROC) curves. Mutational and tumour immune microenvironment landscapes were also explored. Real-time quantitative reverse transcription polymerase chain reaction (RT-qPCR) experiments confirmed the expression patterns of the hub genes, and functional assays assessed the effects of SCD knockdown on cell viability, proliferation, and migration. RESULTS: DEA revealed dysregulated FRGs and CRGs in the TCGA MIBC cohort. SCD, DDR2, and MT1A were identified as hub genes. A prognostic signature based on the sum of the weighted expression of these genes demonstrated strong predictive efficacy in the training and test sets. Nomogram incorporating this signature accurately predicted 1-, 3-, and 5-year survival probabilities in the TCGA cohort and GSE13507 dataset. Copy number variation (CNV) and tumour immune microenvironment analysis revealed that high risk score level groups were associated with immunosuppression and lower tumour purity. The associations of risk scores with immunotherapy and chemical drugs were also explored, indicating their potential for guiding treatment for MIBC patients. The dysregulated expression patterns of three hub genes were validated by RT-qPCR experiments. CONCLUSIONS: Targeting hub FRGs and CRGs could be a promising therapeutic approach for MIBC. Our prognostic model offers a new framework for MIBC subtyping and can inform personalized therapeutic strategies.
Subject(s)
Ferroptosis , Mutation , Tumor Microenvironment , Urinary Bladder Neoplasms , Humans , Urinary Bladder Neoplasms/genetics , Urinary Bladder Neoplasms/pathology , Urinary Bladder Neoplasms/mortality , Ferroptosis/genetics , Prognosis , Tumor Microenvironment/genetics , Biomarkers, Tumor/genetics , Male , Gene Expression Regulation, Neoplastic , Neoplasm Invasiveness , Female , Gene Expression Profiling , Nomograms , Kaplan-Meier Estimate , Cell Line, TumorABSTRACT
We aimed to build a deep learning-based pathomics model to predict the early recurrence of non-muscle-infiltrating bladder cancer (NMIBC) in this work. A total of 147 patients from Xuzhou Central Hospital were enrolled as the training cohort, and 63 patients from Suqian Affiliated Hospital of Xuzhou Medical University were enrolled as the test cohort. Based on two consecutive phases of patch level prediction and WSI-level predictione, we built a pathomics model, with the initial model developed in the training cohort and subjected to transfer learning, and then the test cohort was validated for generalization. The features extracted from the visualization model were used for model interpretation. After migration learning, the area under the receiver operating characteristic curve for the deep learning-based pathomics model in the test cohort was 0.860 (95% CI 0.752-0.969), with good agreement between the migration training cohort and the test cohort in predicting recurrence, and the predicted values matched well with the observed values, with p values of 0.667766 and 0.140233 for the Hosmer-Lemeshow test, respectively. The good clinical application was observed using a decision curve analysis method. We developed a deep learning-based pathomics model showed promising performance in predicting recurrence within one year in NMIBC patients. Including 10 state prediction NMIBC recurrence group pathology features be visualized, which may be used to facilitate personalized management of NMIBC patients to avoid ineffective or unnecessary treatment for the benefit of patients.
Subject(s)
Deep Learning , Neoplasm Recurrence, Local , Urinary Bladder Neoplasms , Humans , Urinary Bladder Neoplasms/pathology , Neoplasm Recurrence, Local/pathology , Male , Female , Middle Aged , Aged , ROC Curve , Neoplasm Invasiveness , Non-Muscle Invasive Bladder NeoplasmsABSTRACT
Programmed cell death (PCD) is a process that eliminates infected, damaged, or possibly neoplastic cells to sustain homeostatic multicellular organisms. Although long noncoding RNAs (lncRNAs) are involved in various types of PCD and regulate tumor growth, invasion, and migration, the role of PCD-related lncRNAs in bladder cancer still lacks systematic exploration. In this research, we integrated multiple types of PCD as pan-PCD and identified eight pan-PCD-related lncRNAs (LINC00174, HCP5, HCG27, UCA1, SNHG15, GHRLOS, CYB561D2, and AGAP11). Then, we generated a pan-PCD-related lncRNA prognostic signature (PPlncPS) with excellent predictive power and reliability, which performed equally well in the E-MTAB-4321 cohort. In comparison with the low-PPlncPS score group, the high-PPlncPS score group had remarkably higher levels of angiogenesis, matrix, cancer-associated fibroblasts, myeloid cell traffic, and protumor cytokine signatures. In addition, the low-PPlncPS score group was positively correlated with relatively abundant immune cell infiltration, upregulated expression levels of immune checkpoints, and high tumor mutation burden (TMB). Immunogenomic profiles revealed that patients with both low PPlncPS scores and high TMB had the best prognosis and may benefit from immune checkpoint inhibitors. Furthermore, for patients with high PPlncPS scores, docetaxel, staurosporine, and luminespib were screened as potential therapeutic candidates. In conclusion, we generated a pan-PCD-related lncRNA signature, providing precise and individualized prediction for clinical prognosis and some new insights into chemotherapy and immune checkpoint inhibitor therapy for bladder cancer.
Subject(s)
Gene Expression Regulation, Neoplastic , RNA, Long Noncoding , Urinary Bladder Neoplasms , Urinary Bladder Neoplasms/genetics , Urinary Bladder Neoplasms/immunology , Urinary Bladder Neoplasms/drug therapy , Urinary Bladder Neoplasms/pathology , Humans , RNA, Long Noncoding/genetics , Prognosis , Biomarkers, Tumor/genetics , Apoptosis/genetics , Gene Expression Profiling , Immune Checkpoint Inhibitors/therapeutic useABSTRACT
Lymph node (LN) metastasis is the dominant cause of death in bladder cancer (BCa) patients, but the underlying mechanism remains largely unknown. In recent years, accumulating studies have confirmed that bidirectional mitochondria-nucleus communication is essential for sustaining multiple function of mitochondria. However, little has been studied regarding whether and how the translocation of mitochondrial proteins is involved in LN metastasis. In this study, we first identified that the SUMO E3 ligase MUL1 was significantly downregulated in LN-metastatic BCa tissues and correlated with a good prognosis. Mechanistically, MUL1 SUMOylated HSPA9 at the K612 residue, leading to HSPA9 export from mitochondria and interaction with SUZ12 and in the nucleus. Consequently, MUL1 induced the ubiquitination-mediated degradation of SUZ12 and EZH2 and induced downstream STAT3 pathway inhibition in a HSPA9-dependent manner. Importantly, mutation of HSPA9 SUMO-conjugation motifs limited the translocation of mitochondrial HSPA9 and blocked the HSPA9-SUZ12 and HSPA9-EZH2 interactions. With mutation of the HSPA9 K612 site, the suppressive role of MUL1 overexpression was lost in BCa cells. Further in vitro and in vivo assays revealed that MUL1 inhibits the metastasis and proliferation of BCa cells. Overall, our study reveals a novel function and molecular mechanism of SUMO E3 ligases in LN metastasis.
Subject(s)
HSP70 Heat-Shock Proteins , Lymphatic Metastasis , Ubiquitin-Protein Ligases , Urinary Bladder Neoplasms , Urinary Bladder Neoplasms/metabolism , Urinary Bladder Neoplasms/pathology , Urinary Bladder Neoplasms/genetics , Humans , Ubiquitin-Protein Ligases/metabolism , Ubiquitin-Protein Ligases/genetics , HSP70 Heat-Shock Proteins/metabolism , HSP70 Heat-Shock Proteins/genetics , Cell Line, Tumor , Mitochondria/metabolism , Animals , Mice , Mice, Inbred BALB C , Mice, Nude , Male , Sumoylation , Female , Mitochondrial ProteinsABSTRACT
BACKGROUND: Urinary bladder cancer, is the 10th most common global cancer, diagnosed in over 600,000 people causing 200,000 deaths annually. Artemisinin and its derivatives are safe compounds that have recently been proven to possess potent anti-tumor effects in vivo, through inhibition of cancer cell growth. The aim of this study is to assess the efficiency of artemisinin as a cancer treatment alone and as a pre-treatment fore cisplatin therapy for high grade urothelial carcinoma. METHODS: Sixty male albino mice were divided into six groups, and BBN was used to induce urinary bladder cancer. Blood samples were tested for renal functions and complete blood counts, kidney and urinary bladder tissues were harvested for histopathological examination. Total RNAs from urinary bladder tissues was collected, and gene expression of FGFR3, HRAS, P53, and KDM6A was quantified using qRT-PCR. RESULTS: Compared to the induced cancer group, the results revealed that FGFR3 expression levels were down-regulated in the induced cancer group treated by artemisinin only and the induced cancer group pre-treated with artemisinin prior to cisplatin by ~ 0.86-fold and 0.4-folds, respectively, aligning with HRAS down-regulation by ~ 9.54-fold and 9.05-fold, respectively. Whereas, P53 expression levels were up-regulated by ~ 0.68-fold and 0.84-fold, respectively, in parallel with KDM6A expression, which is up-regulated by ~ 0.95-folds and 5.27-folds, respectively. Also, serum creatinine and urea levels decreased significantly in the induced cancer group treated by artemisinin alone and the induced cancer group pre-treated with artemisinin prior to cisplatin, whereas the induced cancer group treated by cisplatin their levels increased significantly. Moreover, Hb, PLT, RBC, and WBC counts improved in both cancer groups treated by artemisinin alone and pre-treated with artemisinin prior to cisplatin. Histologically, in kidney tissues, artemisinin pre-treatment significantly reduced renal injury caused by cisplatin. While Artemisinin treatment for cancer in bladder tissues reverted invasive urothelial carcinoma to moderate urothelial dysplasia. CONCLUSIONS: This study indicates that artemisinin demonstrated a significant effect in reversal of the multi-step carcinogenesis process of high grade urothelial carcinoma and could enhance the effect of cisplatin therapy using artemisinin pre-treatment.
Subject(s)
Artemisinins , Cisplatin , Gene Expression Regulation, Neoplastic , Histone Demethylases , Receptor, Fibroblast Growth Factor, Type 3 , Tumor Suppressor Protein p53 , Urinary Bladder Neoplasms , Animals , Cisplatin/pharmacology , Cisplatin/therapeutic use , Male , Artemisinins/pharmacology , Artemisinins/therapeutic use , Receptor, Fibroblast Growth Factor, Type 3/genetics , Receptor, Fibroblast Growth Factor, Type 3/metabolism , Mice , Urinary Bladder Neoplasms/drug therapy , Urinary Bladder Neoplasms/genetics , Urinary Bladder Neoplasms/pathology , Tumor Suppressor Protein p53/genetics , Tumor Suppressor Protein p53/metabolism , Gene Expression Regulation, Neoplastic/drug effects , Histone Demethylases/metabolism , Histone Demethylases/genetics , Proto-Oncogene Proteins p21(ras)/genetics , Humans , Disease Models, Animal , Antineoplastic Agents/pharmacology , Antineoplastic Agents/therapeutic useABSTRACT
BACKGROUND: Neoadjuvant cisplatin-based chemotherapy (NAC) followed by cystectomy is the standard of care for patients with muscle-invasive bladder cancer (MIBC). Pathologic complete response (pCR) is associated with favorable outcomes, but only 30%-40% of patients achieve that response. The aim of this study is to investigate the role played by the Tumor and Immune Microenvironment (TIME) in association with the clinical outcome of patients with MIBC undergoing NAC. METHODS: Nineteen patients received NAC and were classified as pCR (n = 10) or non-pCR (n = 9). Bulk RNA-seq and immune protein evaluations using Digital Spatial Profiling (DSP) were performed on formalin-fixed paraffin-embedded (FFPE) tumor biopsies collected before NAC (baseline). Immunohistochemistry (IHC) evaluation focused on CD3 and CD20 expression was performed on baseline and end-of-treatment (EOT) FFPEs. Baseline peripheral blood was assessed for lymphocyte and neutrophil counts. Kaplan-Meier analyses and Cox PH regression models were used for survival analyses (OS). RESULTS: In the periphery, pCR patients showed lower neutrophil counts, and neutrophil/ lymphocyte ratio (NLR) when compared to non-pCR patients. In the tumor microenvironment (TME), gene expression analysis and protein evaluations highlighted an abundance of B cells and CD3+ T cells in pCR versus non-pCR patients. On the contrary, increased protein expression of ARG1+ cells, and cells expressing immune checkpoints such as LAG3, ICOS, and STING were observed in the TME of patients with non-pCR. CONCLUSIONS: In the current study, we demonstrated that lower NLR levels and increased CD3+ T cells and B cell infiltration are associated with improved response and long-term outcomes in patients with MIBC receiving NAC. These findings suggest that the impact of immune environment should be considered in determining the clinical outcome of MIBC patients treated with NAC.
Subject(s)
Cisplatin , Neoadjuvant Therapy , Tumor Microenvironment , Urinary Bladder Neoplasms , Humans , Urinary Bladder Neoplasms/drug therapy , Urinary Bladder Neoplasms/immunology , Urinary Bladder Neoplasms/mortality , Urinary Bladder Neoplasms/pathology , Cisplatin/therapeutic use , Male , Female , Neoadjuvant Therapy/methods , Aged , Tumor Microenvironment/immunology , Middle Aged , Neoplasm Invasiveness , Cystectomy , Treatment Outcome , Antineoplastic Combined Chemotherapy Protocols/therapeutic use , Prognosis , Neutrophils/immunology , Neutrophils/metabolismABSTRACT
RATIONALE: Bladder urothelial carcinoma (UC) is a common urinary system tumor that is generally diagnosed by cystoscopy combined with pathological biopsy. However, complete exophytic UC of the bladder is very rare and difficult to diagnose. Early diagnosis and accurate identification of such tumors, followed by aggressive surgical treatment, is essential for the management of these patients. PATIENT CONCERNS: An 84-year-old man was admitted to the hospital with dysuria, a poor diet, and significant weight loss. DIAGNOSIS: Pelvic computed tomography and magnetic resonance imaging revealed an exteriophytic round mass on the right lateral wall of the bladder. Cystoscopy revealed a necrotic mass on the right lateral wall of the bladder cavity, and no tumor cells were found following the biopsy. The tumor was removed via partial cystectomy, and the pathological result indicated high-grade muscle-invasive UC. INTERVENTIONS: The patient refused radical cystectomy and underwent laparoscopic partial cystectomy plus pelvic lymph node dissection followed by cisplatin plus gemcitabine chemotherapy. OUTCOMES: The patient's mental state and appetite were significantly improved after the urinary tube was removed 1 week after surgery. His general state was significantly improved after 1 month of follow-up but died of acute cerebral infarction 3 months after surgery. LESSONS: UC of the bladder may grow completely out of the bladder without symptoms such as gross hematuria; thus, early diagnosis is difficult. For high-risk individuals, regular imaging tests may help to detect tumors early. Partial cystectomy is a reliable surgical modality for bladder preservation in such patients.