Bladder cancer is a prevalent malignancy with high mortality rates worldwide. Hypoxia is a critical factor in the development and progression of cancers. However, whether and how hypoxia-related genes (HRGs) could affect the development and the chemotherapy response of bladder cancer is still largely unexplored. This study comprehensively explored the complex molecular landscape associated with hypoxia in bladder cancer by analyzing 260 hypoxia genes based on transcriptomic and genomic data in 411 samples. Employing the 109 dysregulated hypoxia genes for consensus clustering, we delineated two distinct bladder cancer clusters characterized by disparate survival outcomes and distinct oncogenic roles. We defined a HPscore that was correlated with a variety of clinical features, including TNM stages and pathologic grades. Tumor immune landscape analysis identified three immune clusters and close interactions between hypoxia genes and the various immune cells. Utilizing a network-based method, we defined 129 HRGs exerting influence on apoptotic processes and critical signaling pathways in cancer. Further analysis of chemotherapy drug sensitivity identified potential drug-target HRGs. We developed a Risk Score model that was related to the overall survival of bladder cancer patients based on doxorubicin-target HRGs: ACTG2, MYC, PDGFRB, DHRS2, and KLRD1. This study not only enhanced our understanding of bladder cancer at the molecular level but also provided promising avenues for the development of targeted therapies, representing a significant step toward the identification of effective treatments and addressing the urgent need for advancements in bladder cancer management.

Bladder cancer (BCa), a prevalent malignancy of the urinary tract, is associated with high recurrence and mortality rates. SLC16A7, a member of the solute carrier family 16 (SLC16), encodes monocarboxylate transporters that are involved in the proton-coupled transport of metabolites, including lactate, pyruvate, and ketone bodies, across cell membranes. Evidence suggests that SLC16A7 exhibits variable expression in cancers and may influence tumor development, progression, and immune regulation. This study examined the role of SLC16A7 in cancer prognosis, progression, and immune regulation, focusing on BCa.

A comprehensive analysis was conducted to evaluate the clinical and immunological relevance of SLC16A7 across multiple cancer types using data from 33 tumor datasets from 'The Cancer Genome Atlas (TCGA). ' Associations between SLC16A7 expression and clinicopathological features, prognostic indicators, tumor mutation burden (TMB), microsatellite instability (MSI), immune cell infiltration, and immune-related gene expression were systematically analyzed. Experimental validation was performed to assess SLC16A7 expression in the BCa tissues and cell lines. The prognostic value of SLC16A7 was confirmed using clinical follow-up data from an independent patient cohort. Functional studies included proliferation assays to investigate the effect of SLC16A7. CD8 + T cells were obtained from the peripheral blood of healthy donors and stimulated using CD3 and CD28 antibodies in combination with recombinant IL-2. To investigate the immunological role of SLC16A7, co-culture experiments were performed between BCa cells and activated CD8 + T cells. Additionally, CD8 + T cell chemotaxis assays and ELISA analyses were conducted to evaluate the immune responses mediated by SLC16A7.

SLC16A7 expression was downregulated in 16 cancer types, including BCa, and upregulated in three cancer types. Its expression was significantly associated with tumor stage in four cancers and showed both positive and negative correlations with prognosis, depending on the cancer type. Genomic analyses revealed significant associations between SLC16A7 and TMB in 13 cancer types and MSI in 11 cancer types. Pathway enrichment analyses (Hallmark-GSEA and KEGG-GSEA) indicated strong associations between SLC16A7, immune responses, and tumor progression. Immune infiltration analysis showed a predominantly positive association between SLC16A7 expression and immune cell infiltration, except in low-grade gliomas (LGG). CIBERSORT analysis demonstrated that SLC16A7 expression correlated positively with resting memory CD4 T cells, eosinophils, monocytes, resting mast cells, and memory B cells and negatively with activated memory CD4 T cells, M1 macrophages, follicular helper T cells, M0 macrophages, and CD8 T cells. SLC16A7 expression was also significantly associated with the expression of immune-regulatory molecules. Experimental validation showed reduced SLC16A7 expression in BCa tissues and cell lines compared to that in their normal counterparts. Kaplan-Meier survival analysis indicated that higher SLC16A7 expression was correlated with better overall survival in patients with BCa. Functional assays revealed that SLC16A7 inhibited BCa cell progression and promoted the chemotaxis and tumor-killing ability of CD8 + T cells in the BCa tumor microenvironment (TME).

SLC16A7 exhibits tumor-suppressive properties, with downregulation in most cancers, and is associated with favorable prognosis and enhanced immune responses. SLC16A7 functions as a tumor suppressor in BCa and is associated with improved survival outcomes. These findings suggest that SLC16A7 is a potential biomarker for cancer diagnosis and prognosis.

Bladder cancer (BC) remains a significant global health concern, with substantial sex and racial disparities in incidence, progression, and outcomes. BC is the sixth most common cancer among males and the seventeenth most common among females worldwide. Over 90% of BC cases are urothelial carcinoma (UC) with high degrees of pathological heterogeneity. Molecular subtyping of BC has also revealed distinct luminal, basal, and neuroendocrine subtypes, each with unique genetic and immune signatures. Emerging research uncovers the biasing effects of the sex hormones with androgens increasing BC risk through both tumor cell intrinsic and extrinsic mechanisms. The sex chromosomes, including both the X and Y chromosomes, also contribute to the sex differences in BC. The effect of sex chromosome is both independent from and synergistic with the effects of sex hormones. Loss of the Y chromosome is frequently observed in BC patients, while an extra copy of the X chromosome confers better protection against BC in females than in males. Advent of advanced technologies such as multiomics and artificial intelligence will likely further improve the understanding of sex differences in BC, which may ultimately lead to personalized preventative and treatment strategies depending on the biological sex of patients. This review delves into the impacts of biology of sex on BC, emphasizing the importance of further research into sex-specific biology to improve cancer prevention and care.

Bladder cancer (BC) is a fatal malignancy of the urinary tract with limited effective biomarkers and therapeutic targets. This paper delved into the mechanism of MYH11 and DNMT1 in BC progression.

Differential genes obtained from the GSE3167 dataset were analyzed by the R language limma package. RT-qPCR, Western blot, and immunohistochemistry were carried out to assess MYH11 and DNMT1 expression in BC cell lines and BC tissues. Cell migration, invasion, proliferation, and apoptosis were detected by Transwell assay, CCK-8, and TUNEL after different lentiviral vector treatments. MB49 cells with different infections were administered into mice to monitor tumor growth and immune escape. Flow cytometry detected the rate of CD45+CD4+-positive cells in the tumor tissues and PD-1 and TIM-3 expression in CD4+ T cells. MYH11 methylation was analyzed using the qMSP assay. ChIP and dual-luciferase assay were used for regulatory assays.

MYH11 was lowly expressed in BC. Overexpression of MYH11 inhibited the malignant progression of BC cells, promoted anti-tumor immune responses of CD4+ T cells, and inhibited immune escape and tumor development in mice. DNMT1 inhibited MYH11 expression by elevating MYH11 promoter methylation. DNMT1 inhibition impeded the immune escape of BC cells, which was reversed by silencing MYH11. DNMT1 silencing prevented immune escape via transcriptional activation of MYH11 and hindered tumor growth in mice.

DNMT1 promotes immune escape and malignant progression of BC by methylating the promoter of MYH11.

Despite missense mutation accounts for over 60% of p53 alterations while homozygous deletion (HOM) for only 5% or less in advanced bladder cancer cases, most of the previously reported mouse models are deficient of p53. Accordingly, few studies have addressed the mechanisms of missense mutation occurrence and its functional advantage over HOM in bladder cancer development. Organoids derived from Krt5-expressing mouse urothelium (K5-mUrorganoid) demonstrated the crucial role of Pten loss in driving loss of wild-type allele of Trp53 (Trp53R172H/LOH), which conferred tumorigenic ability to K5-mUrorganoid in athymic mice. These tumors recapitulated the histological and genetic characteristics of the human basal-squamous subtype bladder cancer. Both Trp53R172H/Δ; PtenΔ/Δ and Trp53Δ/Δ; PtenΔ/Δ K5-mUrorganoids formed tumors in athymic mice, whereas only Trp53R172H/Δ; PtenΔ/Δ K5-mUrorganoid formed tumors even when directly inoculated in immunocompetent syngeneic mice. The absence of wild-type Trp53 was associated with upregulation of proliferative signaling, and the presence of a mutant Trp53 allele was associated with immune-excluded microenvironment. This study highlights the functional significance of p53 mutant LOH in bladder carcinogenesis conferring several hallmarks of cancer such as sustaining proliferative signaling and avoiding immune destruction, thus provides a novel immunocompetent mouse model of urothelial carcinoma harboring p53 mutations as a novel tool for cancer immunology research.

Bacterial therapy has emerged as a promising approach for disease treatment due to its environmental sensitivity, immunogenicity, and modifiability. However, the clinical application of engineered bacteria is limited by differences of expression levels in patients and possible off-targeting. Optogenetics, which combines optics and genetics, offers key advantages such as remote controllability, non-invasiveness, and precise spatiotemporal control. By utilizing optogenetic tools, the behavior of engineered bacteria can be finely regulated, enabling on-demand control of the dosage and location of their therapeutic products. In this review, we highlight the latest advancements in the optogenetic engineering of bacteria for light-controlled disease theranostics and therapeutic regulation. By constructing a three-dimensional analytical framework of "sense-produce-apply", we begin by discussing the key components of bacterial optogenetic systems, categorizing them based on their photosensitive protein response to blue, green, and red light. Next, we introduce innovative light-producing tools that extend beyond traditional light sources. Then, special emphasis is placed on the biomedical applications of optogenetically engineered bacteria in treating diseases such as cancer, intestinal inflammation and systemic disease regulation. Finally, we address the challenges and future prospects of bacterial optogenetics, outlining potential directions for enhancing the safety and efficacy of light-controlled bacterial therapies. This review aims to provide insights and strategies for researchers working to advance the application of optogenetically engineered bacteria in drug delivery, precision medicine and therapeutic regulation.

Bladder cancer is a prevalent malignancy associated with significant morbidity and mortality worldwide. Emerging research highlights the critical role of glycosphingolipids (GSLs) in bladder cancer progression. In this review, we examine GSL expression profiles in bladder cancer and explore their contributions to key cancer hallmarks, including invasion and metastasis, immune evasion, and resistance to cell death. We further discuss the potential of GSLs as therapeutic targets and non-invasive biomarkers, with an emphasis on recent advances in GSL-targeting strategies. Additionally, we highlight our recent discovery of a novel, patented biomarker for bladder cancer diagnosis, identified using cutting-edge glyco-analytical technologies.

Rational design of multifunctional nanoplatforms capable of combining therapeutic effects with real-time monitoring of drug distribution and tumor status is emerging as a promising approach in cancer nanomedicine. Here, we introduce pyropheophorbide a-bisaminoquinoline conjugate lipid nanoparticles (PPBC LNPs) as a bimodal system for image-guided phototherapy in bladder cancer treatment. PPBC LNPs not only demonstrate both powerful photodynamic and photothermal effects upon light activation, but also exhibit potent autophagy blockage, effectively inducing bladder cancer cell death. Furthermore, PPBC LNPs possess remarkable photoacoustic (PA) and fluorescence (FL) imaging capabilities, enabling imaging with high-resolution, deep tissue penetration and high sensitivity for tracking drug biodistribution and phototherapy efficacy. Specifically, PA imaging confirms the efficient accumulation of PPBC LNPs within tumor and predicts therapeutic outcomes of photodynamic therapy, while FL imaging confirms their prolonged retention at the tumor site for up to 6 days. PPBC LNPs significantly suppress bladder tumor growth, with several tumors completely ablated following just two doses of the nanoparticles and laser treatment. Additionally, PPBC LNPs were formulated with lipid-based excipients and assembled using microfluidic technology to enhance biocompatibility, stability, and scalability, showing potential for clinical translation. This versatile nanoparticle represents a promising candidate for further development in bladder cancer therapy.

Abnormal regulation of gene expression results in the malignant proliferation of bladder cancer (BC) cells. We previously demonstrated that NPL4 upregulation promotes BC progression; however, its regulatory and functional mechanisms on downstream genes in BC remain unknown. Transcriptome sequencing and reverse transcription-quantitative polymerase chain reaction were used to identify and confirm METTL11A as a downstream gene of NPL4. Protein interactions were detected through co-immunoprecipitation assays. Cell growth and tumor progression were assessed in vitro and in vivo using colony formation and MTS assays as well as xenograft animal models. Chromatin immunoprecipitation and luciferase activity assays were performed to investigate gene transcription regulation. We identified METTL11A as a downstream gene of NPL4, with its upregulation linked to poor outcomes in BC patients. METTL11A facilitates NPL4-regulated BC cell proliferation by promoting cyclin D1 expression. METTL11A enhances MAFG expression and contributes to METTL11A-mediated cell proliferation. Mechanistically, METTL11A interacts with MAFG, preventing its degradation through K6 methylation modification. MAFG and NRF2 bind to the promoter region of NPL4, promoting its transcription. Thus, the METTL11A-MAFG-NPL4 axis forms a positive feedback loop, promoting BC cell proliferation and tumor progression. Targeted inhibition of this regulatory loop could offer a novel therapeutic approach for BC.

Bladder cancer (BC) is characterized by high heterogeneity, with non-muscle-invasive (NMIBC) and muscle-invasive (MIBC) stages differing significantly in clinical behavior and outcomes. The transition from NMIBC to MIBC involves extensive tumor microenvironment (TME) remodeling, particularly in endothelial cells (ECs), which drive angiogenesis and modulate immune and extracellular matrix (ECM) interactions. However, the precise roles of ECs in this progression remain poorly defined.

Public single-cell RNA sequencing (scRNA-seq) datasets from 47 BC patients were analyzed to characterize endothelial cell heterogeneity and functional states across NMIBC and MIBC. Computational tools such as CellChat were applied to reconstruct cell-cell communication networks, focusing on pathways related to angiogenesis, immune crosstalk, and ECM remodeling.

Twelve major cell types were identified, with endothelial cells exhibiting distinct transcriptional profiles between NMIBC and MIBC. NMIBC-associated ECs promoted adhesion and migration through HMGB1 and CXCL12 signaling. In contrast, MIBC was enriched in an ADAM10+ endothelial subset associated with vascular remodeling and activation of Wnt signaling via CTNNB1. Key ligand-receptor interactions highlighted the dynamic roles of ECs in TME modulation during BC progression.

This study reveals stage-specific endothelial cell phenotypes and signaling networks in BC. The identification of an MIBC-specific ADAM10+ endothelial subset underscores its potential role in driving tumor progression and highlights opportunities for stage-adapted vascular-targeted therapies. These findings advance our understanding of BC pathogenesis and provide the foundation for novel therapeutic strategies.

Genitourinary (GU) cancers, including renal cell carcinoma, prostate cancer, bladder cancer, and testicular cancer, represent a significant health burden and are among the leading causes of cancer-related mortality worldwide. Despite advancements in traditional treatment modalities such as chemotherapy, radiotherapy, and surgery, the complex interplay within the tumor microenvironment (TME) poses substantial hurdles to achieving durable remission and cure. The TME, characterized by its dynamic and multifaceted nature, comprises various cell types, signaling molecules, and the extracellular matrix, all of which are instrumental in cancer progression, metastasis, and therapy resistance. Recent breakthroughs in immunotherapy (IO) have opened a new era in the management of GU cancers, offering renewed hope by leveraging the body's immune system to combat cancer more selectively and effectively. This approach, distinct from conventional therapies, aims to disrupt cancer's ability to evade immune detection through mechanisms such as checkpoint inhibition, therapeutic vaccines, and adoptive cell transfer therapies. These strategies highlight the shift towards personalized medicine, emphasizing the importance of understanding the intricate dynamics within the TME for the development of targeted treatments. This article provides an in-depth overview of the current landscape of treatment strategies for GU cancers, with a focus on IO targeting the specific cell types of TME. By exploring the roles of various cell types within the TME and their impact on cancer progression, this review aims to underscore the transformative potential of IO strategies in TME targeting, offering more effective and personalized treatment options for patients with GU cancers, thereby improving outcomes and quality of life.

Exploring the expression of Mitochondrial Permeability Transition Dependent Necrosis lncRNA in bladder cancer and elucidate their precise function within the tumor microenvironment and impact on prognosis.

We employed a comprehensive bioinformatics approach to investigate the function and influence of lncRNA in bladder cancer. Gene expression data, clinical data, and mutation data of bladder cancer are obtained from TCGA database.

We developed a new prognostic model incorporating 6 lncRNAs. The predictive efficacy of this model for bladder cancer prognosis was validated. Furthermore, we investigated the influence of model on the tumor microenvironment and drug sensitivity.

This study presents a novel prognostic framework for bladder cancer that holds great potential for enhancing prognostic prediction accuracy and optimizing treatment strategies for patients with this disease.

Urothelial carcinoma (UC) is the most common malignancy of the urinary tract, with urothelial bladder cancer accounting for approximately 90% of cases. Metastatic UC (mUC) is a particularly aggressive subset that presents significant treatment challenges, especially in patients who are often older than 70 years and have multiple comorbidities. For several decades, cisplatin-based chemotherapy has been the standard first-line treatment for locally advanced (LA) mUC. However, its utility has been limited as many patients are ineligible owing to their health status, and overall survival rates remain suboptimal. Recent advancements, including antibody-drug conjugates and immunotherapies, have begun to reshape the treatment landscape for LA/mUC. The combination of enfortumab vedotin and pembrolizumab has shown promising clinical outcomes. The approval of multiple novel drugs and combination therapies not only provides new opportunities for patient care but also creates the need for physicians to adapt to this evolving therapeutic paradigm. This review explores the latest clinical data on the management of LA/mUC and offers insights into sequencing therapies for patients with LA/mUC.

Bacillus Calmette-Guérin (BCG) is the current standard of care for non-muscle-invasive bladder cancer (NMIBC), but recurrence is common. Additional therapeutic options are a major unmet medical need for treating unresponsive patients. Stimulator of IFN genes (STING) plays a central role in mounting innate and adaptive immune responses to tumor cells, and activation of STING is a promising immunotherapeutic approach. In this study, we developed STING agonist VB-85247 for treating NMIBC by intravesical delivery as a strategy to provide a sustained period of exposure to bladder cancer cells while avoiding potential issues associated with intratumoral injection of STING agonists, which to date have shown only limited clinical efficacy. VB-85247 induced complete response in an orthotopic NMIBC model in contrast to treatment with BCG, which was not efficacious in the model. The efficacious dose was well tolerated and induced an immune response with immunologic memory that protected from rechallenge without further treatment. Activation of the STING pathway via VB-85247 induced upregulation of inflammatory cytokines IFNα/β, TNFα, IL6, and CXCL10, along with maturation and activation of dendritic cells. In addition, VB-85247 provided a therapeutic benefit in combination with immune checkpoint blockade using anti-PD-1 antibody treatment. Together, these preclinical data support the potential utility of VB-85247 for treating BCG-unresponsive patients with NMIBC and for enhancing the clinical benefit of potential of anti-PD-1 in bladder cancer. Based on these data, VB-85247 is being advanced into clinical development. Significance: STING agonist VB-85247 administered by the intravesical route achieves prolonged tumor regression, induces immunologic memory, and provides additive benefits to anti-PD-1 treatment in non-muscle invasive bladder cancer.

Recent years have seen the use of photodynamic technologies concerning the detection and therapy of bladder cancer (BC) due to their rapid development and well-established therapeutic impact. However, a thorough analysis and bibliometric assessment of photodynamic technologies publishing trends in BC has not been completed yet.

Retrieving bibliographies from the Web of Science Core Collection limited the publication date to December 31, 2023, from January 1, 2004. We used VOSviewer (Version 1.6.19) and CiteSpace (Version 6.4 R1) for both statistical and visualization analysis.

We selected a total of 870 documents for analysis. The yearly publication findings show notable upward patterns over the last two decades. The Kochi Medical School in Japan was the most productive school, while the USA was the most productive nation. Japanese researcher Inoue Keiji published the highest number of photodynamic -related articles in BC. The most quoted and prolific journals were the Photodynamic Therapy and Photodiagnosis. According to the keyword analysis, the terms "cystoscopy," "carcinoma in situ," "drug delivery," "follow-up," "hexaminolevulinate," and "impact" are all relatively recent and hot field.

Our investigation produced a bibliometric outcome for the field, potentially opening up new research opportunities. We suggest that future research concentrate on in-situ carcinoma identification, photosensitizer invention, medication delivery enhancement, and photodynamic technology follow-up in BC.

This study aimed to explore the Liquid-liquid phase separation (LLPS)-related genes associated with the prognosis of bladder cancer (BCa) and assess the potential application of LLPS-related prognostic signature for predicting prognosis in BCa patients.

Clinical information and transcriptome data of BCa patients were extracted from the Cancer Genome Atlas-BLCA (TCGA-BLCA) database and the GSE13507 database. Furthermore, 108 BCa patients who received treatment at our institution were subjected to a retrospective analysis. The least absolute shrinkage and selection operator (LASSO) analysis was performed to develop an LLPS-related prognostic signature for BCa. The CCK8, wound healing and Transwell assays were performed.

Based on 62 differentially expressed LLPS-related genes (DELRGs), three DELRGs were screened by LASSO analysis including kallikrein-related peptidase 5 (KLK5), monoacylglycerol O-acyltransferase 2 (MOGAT2) and S100 calcium-binding protein A7 (S100A7). Based on three DELRGs, a novel LLPS-related prognostic signature was constructed for individualized prognosis assessment. Kaplan-Meier curve analyses showed that LLPS-related prognostic signature was significantly correlated with overall survival (OS) of BCa. ROC analyses demonstrated the LLPS-related prognostic signature performed well in predicting the prognosis of BCa patients in the training group (the area under the curve (AUC) = 0.733), which was externally verified in the validation cohort 1 (AUC = 0.794) and validation cohort 2 (AUC = 0.766). Further experiments demonstrated that inhibiting KLK5 could affect the proliferation, migration, and invasion of BCa cells.

In this study, a novel LLPS-related prognostic signature was successfully developed and validated, demonstrating strong performance in predicting the prognosis of BCa patients.

Bladder cancer (BC) is one of the most common malignant tumors of the urinary system, and has a high recurrence rate and treatment resistance. Recent results indicate that mitochondrial metabolism influences the therapeutic outcomes of BC. Mitochondria-targeted photosensitizer (PS) is a promising anticancer therapeutic approach that may overcome the limitations of conventional BC treatments. Herein, two mitochondria-targeted iridium(III) PSs, Ir-Mito1 and Ir-Mito2, have been designed for BC treatment. Mechanically, Ir-Mito2 induced a decrease in mitochondrial membrane potential via white light activation, further triggering a reduction of the B-cell lymphoma 2 protein (Bcl-2)/Bcl-associated X protein (Bax) ratio and increment of cleaved caspase3. Meanwhile, the reduction of glutathione, deactivation of glutathione peroxidase 4 (GPX4), increase of acyl-CoA synthetase long chain family member 4 (ACSL4), and accumulation of lipid peroxide resulted in synergistically activating of ferroptosis and apoptosis. The results demonstrated that Ir-Mito2 exhibited excellent antitumor efficacy with superior biosafety in vivo. This work on light-activated and mitochondrial-targeted PS provides an innovative therapeutic platform for BC.

Despite remarkable advancements in therapeutic strategies, a considerable proportion of patients with bladder cancer (BC) still experience disease progression and unfavorable prognosis. The heterogeneity and biological functions of tumor endothelial cells (ECs) during BC progression remain poorly understood. We collected scRNA-seq data from BC samples and identified two EC subpopulations through hierarchical clustering analysis. The activity of signaling pathways in distinct EC subpopulations was assessed utilizing AUCell analysis. Gene regulatory networks (GRN) were constructed and analyzed for different EC subpopulations using the pySCENIC algorithm. Additionally, we investigated the association between the abundance of EC subpopulations and both clinical prognosis and immune cell infiltration. The biological effects of ESM1 protein on BC cells were further validated through EdU and Transwell assays. We analyzed 7,519 CD45-negative single cells from BC tissues and discerned two distinct EC subpopulations. The two subpopulations were characterized by high expression of ESM1 (S1 ECs) and CXCL2 (S2 ECs), respectively. In S1 ECs, we observed significant activation of signaling pathways involved in tumor promotion, including angiogenesis and cell proliferation. Additionally, our GRN analysis uncovered notable differences in transcription factor activity between S1 and S2 ECs. Moreover, ESM1 protein promoted proliferation and migration of BC cells. Patients with higher abundance of the S1 EC subpopulation exhibited more unfavorable clinical outcomes and increased infiltration of inhibitory immune cells. Our findings elucidate the transcriptional profiles and biological roles of the high ESM1-expression endothelial cell subpopulation in BC. This subpopulation is associated with poor prognosis and immunosuppressive tumor microenvironment. Accordingly, targeting endothelial cells with high ESM1 expression may offer a novel therapeutic strategy for patients with BC.

N6-methyladenosine (m6A) is the most abundant RNA modification in mammalian cells, and has emerged as an important player in tumour development through post-transcriptional gene regulation. In this study, we found that the m6A reader protein IGF2BP3 was the most upregulated m6A modifier in bladder cancer through the proteomic analysis of 17 pairs of human bladder cancer tissues and adjacent normal bladder tissues, for which the expression was also positively correlated with higher tumour stage and poorer prognosis. In vitro and in vivo assays demonstrated the powerful oncogenic function of IGF2BP3 in bladder cancer. Further combined analyses of RNA-sequencing, m6A-sequencing, and RIP (RNA Binding Protein Immunoprecipitation)-sequencing, as well as site-directed mutagenesis assays and RIP-qPCR identified m6A-tagged HSP90AB1 mRNA as a direct target of IGF2BP3. Mechanistically, through in vitro and in vivo assays, as well as clinical sample analysis, we demonstrated that IGF2BP3 modulated the expression of HSP90AB1 in an m6A modification-dependent manner, thus activating the PI3K/AKT-signaling pathway, and promoting the development of bladder cancer. Collectively, our study highlights the critical role of the IGF2BP3-HSP90AB1-signaling axis in bladder cancer progression, which may serve as a promising therapeutic approach for bladder cancer.

The tumor microenvironment is a dynamic and complex three-dimensional network comprising the extracellular matrix and diverse non-cancerous cells, including fibroblasts, adipocytes, endothelial cells and various immune cells (lymphocytes T and B, NK cells, dendritic cells, monocytes/macrophages, myeloid-derived suppressor cells, and innate lymphoid cells). A constantly and rapidly growing number of studies highlight the critical role of these cells in shaping cancer survival, metastatic potential and therapy resistance. This review provides a synthesis of current knowledge on the modulating role of the cellular microenvironment in cancer progression and response to treatment.

Photodynamic therapy (PDT) holds promise for cancer treatment by generating reactive oxygen species via photosensitizers (PSs) activated by specific wavelengths of light. However, the poor water solubility of PSs and the tumor microenvironment, characterized by high glutathione (GSH) levels and hypoxia, limit its efficacy against hypoxic tumors. To overcome these challenges, we developed a novel nano-reactor, Zr(Cu)-MOF@Au@DHA, to augment PDT-ferroptosis therapy. By incorporating Cu2+into the porphyrin ring of PCN-224 and decorating it with gold nanoparticles, we enhanced the photocatalytic efficiency of the metal-organic framework (MOF). Additionally, dihydroartemisinin (DHA) was loaded onto the nano-reactor to boost the ferroptosis sensitivity of bladder cancer cells. Bothin vitroandin vivostudies confirm that under laser irradiation, Zr(Cu)-MOF@Au@DHA significantly elevates oxidative stress, depletes GSH, and triggers DHA release, sensitizing tumor cells to ferroptosis and enhancing PDT-ferroptosis therapy for bladder cancer. This innovative nano-platform integrates near-infrared light-triggered PDT with chemotherapy to induce ferroptosis, addressing critical limitations in bladder cancer treatment.

Bladder cancer (BLCA) is a prevalent and deadly form of urinary cancer, and there is a need for effective therapies, particularly for muscle-invasive bladder cancer (MIBC). Cell cycle inhibitors show promise in restoring control of the cell cycle in BLCA cells, but their clinical prognosis evaluation is limited.

Transcriptome and scRNA-seq data were collected from the Cancer Genome Atlas Program (TCGA)-BLCA and GSE190888 cohort, respectively. R software and the Seurat package were used for data analysis, including cell quality control, dimensionality reduction, and identification of differentially expressed genes. Genes related to the cell cycle were obtained from the genecards website, and a protein-protein interaction network analysis was performed using cytoscape software. Functional enrichment analysis, immune infiltration analysis, drug sensitivity analysis, and molecular docking were conducted using various tools and packages. BLCA cell lines were cultured and transfected for in vitro experimental assays, including RT-qPCR analysis, and CCK-8 cell viability assays.

We identified 32 genes as independent risk or protective factors for BLCA prediction. Functional enrichment analysis revealed their involvement in cell cycle regulation, apoptosis, and various signaling pathways. Using these genes, we developed a nomogram for predicting BLCA survival, which displayed high prognosis stratification efficacy in BLCA patients. Four cell cycle associated key genes identified, including NCAM1, HBB, CKD6, and CTLA4. We also identified the main cell types in BLCA patients and investigated the functional differences between epithelial cells based on their expression levels of key genes. Furthermore, we observed a high positive correlative relationship between the infiltration of cancer-associated fibroblasts and the risk score value. Finally, we conducted in vitro experiments to demonstrate the suppressive role of NCAM1 in BLCA cell proliferation.

These findings suggest that cell cycle associated genes could serve as potential biomarkers for predicting BLCA prognosis and may represent therapeutic targets for the development of more effective therapies. Hopefully, these findings provide valuable insights into the molecular mechanisms and potential therapeutic targets in BLCA from the perspective of cell cycle. Moreover, NCAM1 was a novel cell proliferation suppressor in the BLCA carcinogenesis.

Ferroptosis is an important factor affecting the progression of bladder cancer (BC). Previous studies have confirmed that discoidin domain receptor 1 (DDR1) promotes BC progression. However, the regulatory mechanisms of BC ferroptosis are largely unknown. Therefore, this study aimed to investigate the regulatory effects of DDR1 on BC cell ferroptosis. Ferroptosis-sensitive and -resistant BC cells were screened, and reverse-transcription quantitative PCR and western blotting were used to determine the expression of DDR1 in BC cells. In vitro and in vivo assays were performed to analyse the mechanisms of DDR1 in BC ferroptosis. The ferroptosis inducer erastin inhibited DDR1 expression in TCCSUP cells. The ferroptosis inhibitor ferrostatin-1 inhibited BC cell death caused by DDR1 knockdown. DDR1 increased glutathione, glutathione peroxidase 4 and solute carrier family 7 member 11 expression, while decreasing malondialdehyde and Fe2+ levels and acyl-CoA synthetase long-chain family member 4 levels and inhibiting epithelial mesenchymal transition and neurofibromin 2-yes-associated protein. These effects were abrogated by the knockdown of homeobox A6 (HOXA6). DDR1 targeting of HOXA6 facilitated BC growth and inhibited BC ferroptosis in vivo. DDR1 promotes BC progression by inhibiting ferroptosis and targeting HOXA6. Thus, DDR1 may serve as a potential therapeutic target for BC.

Telomerase demonstrates potential as a non-invasive urinary biomarker for urothelial carcinoma (UC); however, current detection methods are either labor-intensive or exhibit suboptimal performance. There is a need for alternative approaches to enable rapid and early diagnosis of UC. In this study, we propose TE-RPA, which combines telomerase extension (TE) with recombinase polymerase amplification (RPA) for one-tube isothermal amplification. The GC content and length of the telomerase substrate were first considered during the screening process. TE-RPA exponential amplification was initiated by the addition of MgOAc along with a forward primer derived from the products of telomerase-mediated extension and a corresponding reverse primer. The amplification product from TE-RPA was subsequently detected using CRISPR-Cas12a system for trans-cleavage of signal probes on the surface of screen-printed electrode in an electrochemical biosensor, resulting in a current change that reflects the corresponding concentration of telomerase. The TE-RPA/CRISPR-Cas12a/electrochemical sensing platform achieves a limit of detection (LOD) for telomerase activity as low as a single-cell level. In addition, the platform attained an area under the curve (AUC) value of 0.9589 in a clinical evaluation involving urine samples from 43 suspected UC patients. Overall, our proposed platform not only offers an efficient method for telomerase isothermal amplification but also provides a portable and precise diagnostic tool for UC.

Intravesical Bacillus Calmette-Guérin (BCG) therapy is a gold standard for patients with high-risk non-muscle invasive bladder cancer (NMIBC). Although a long-lasting therapeutic response is observed in most patients, BCG failure occurs in 30%-50% of patients and a progression to muscle-invasive disease is found in 10%-15%. Therefore, predicting high-risk patients who might not benefit from BCG treatment is critical. The purpose of this study was to identify, whether the presence of specific oncogenic mutations might be indicative of BCG treatment response.

Nineteen high-grade NMIBC patients who received intravesical BCG were retrospectively enrolled and divided into "responders" and "non-responders" groups. Tissue samples from transurethral resection of bladder cancer were performed before starting therapy and were examined using a multigene sequencing panel.

Mutations in TP53, FGFR3, PIK3CA, KRAS, CTNNB1, ALK and DDR2 genes were detected. TP53 and FGFR3 were found to be the most frequently mutated genes in our cohort (31.6% and 26.3%, respectively), followed by PIK3CA (15.8%). In the BCG-responsive patient group, 90% of samples were found to have mutated genes, with almost 50% of them showing mutations in tyrosine kinase receptors and CTNNB1 genes. On the other hand, in the BCG-unresponsive group, we found mutations in 44.4% of samples, mainly in TP53 gene.

Our findings suggest that a Next-Generation Sequencing (NGS) multigene panel is useful in predicting BCG response in patients with NMIBC.

Bladder cancer (BLCA) is notably associated with advanced age, characterized by its high incidence and mortality among the elderly. Despite promising advancements in models that amalgamate molecular subtypes with treatment and prognostic outcomes, the considerable heterogeneity in BLCA poses challenges to their universal applicability. Consequently, there is an urgent need to develop a new molecular subtyping system focusing on a critical clinical feature of BLCA: senescence.

Utilizing unsupervised clustering on the Cancer Genome Atlas Program (TCGA)-BLCA cohort, we crafted a senescence-associated molecular classification and precision quantification system (Senescore). This method underwent systematic validation against established molecular subtypes, treatment strategies, clinical outcomes, the immune tumor microenvironment (TME), relevance to immune checkpoints, and identification of potential therapeutic targets.

External validations were conducted using the Xiangya cohort, IMvigor210 cohort, and meta-cohort, with multiplex immunofluorescence confirming the correlation between Senescore, immune infiltration, and cellular senescence. Notably, patients categorized within higher Senescore group were predisposed to the basal subtype, showcased augmented immune infiltration, harbored elevated driver gene mutations, and exhibited increased senescence-associated secretory phenotype (SASP) factors expression in the transcriptome. Despite poorer prognoses, these patients revealed greater responsiveness to immunotherapy and neoadjuvant chemotherapy.

Our molecular subtyping and Senescore, informed by age-related clinical features, accurately depict age-associated biological traits and its clinical application potential in BLCA. Moreover, this personalized assessment framework is poised to identify senolysis targets unique to BLCA, furthering the integration of aging research into therapeutic strategies.

Bladder cancer (BC) is the 10th most common type of tumor worldwide, and recently approved immunotherapies and FGFR inhibitors have been shown to improve the prognosis of only a very limited subset of BC patients. Thus, the quest for more effective drugs remains an urgent priority for improving the quality of life of more BC patients. Previously, we demonstrated that a novel biguanide YB-004 has potent antitumor activity. In this study, we found that the novel biguanide YB-004 interrupts the cell cycle by reducing the expression of cyclin D1, causing G0/G1 phase arrest, and suppresses homologous recombination (HR) by inhibiting Rad51, thereby increasing DNA damage and blocking BC cell proliferation. Interestingly, our results further revealed that cell accumulation in the S and G2/M phases is the main reason why HR-proficient BC cells are not sensitive to olaparib, as these phases are conducive to HR activation and DNA repair. Thus, YB-004 increased the sensitivity of BC cells to olaparib by reversing the cell cycle changes and HR activation caused by olaparib. Taken together, these findings suggest that the combination of YB-004 with olaparib has great potential for the clinical treatment of HR-proficient BC.

This meta-analysis aimed to evaluate the association between the Geriatric Nutritional Risk Index (GNRI) and survival outcomes in patients with urological cancer.

Systematic review and meta-analysis of observational studies.

A comprehensive literature search was conducted in Medline, EMBASE, Google Scholar and the Cochrane Library from inception to 7 July 2024.

Studies were included if they examined the correlation between the GNRI and long-term survival outcomes in adult patients (≥18 years old) with urological cancers.

Two researchers independently extracted data and assessed study quality using the Newcastle-Ottawa Scale and certainty of evidence using the Grading of Recommendations, Assessment, Development and Evaluations (GRADE) methodology. Publication bias was evaluated using funnel plots and Egger's test for outcomes with more than 10 studies. Pooled HRs and 95% CIs were calculated using a random-effects model. Subgroup analyses, meta-regression and sensitivity analyses were performed.

17 studies involving 8816 patients were included. Study quality assessment showed that 15 studies had a low risk of bias (scores 7-9) and two had a high risk (scores 5-6). Low GNRI was significantly associated with poor overall survival (OS) (HR: 2.6, 95% CI: 2.0 to 3.38, p<0.00001, I² = 64%, 13 studies), cancer-specific survival (CSS) (HR: 2.65, 95% CI: 1.76 to 3.98, p<0.00001, I² = 75%, 7 studies), recurrence-free survival (RFS) (HR: 1.47, 95% CI: 1.02 to 2.1, p=0.04, I² = 58%, four studies) and progression-free survival (PFS) (HR: 1.86, 95% CI: 1.54 to 2.23, p<0.00001, I² = 0%, five studies). Funnel plot and Egger's test (p=0.948) indicated a low risk of publication bias for OS. GRADE assessment showed low certainty of evidence for OS and PFS, and very low certainty for CSS and RFS. Meta-regression identified follow-up time and sample size as significant sources of heterogeneity.

A low GNRI is significantly associated with poor survival outcomes in patients with urological cancer. The GNRI may serve as a valuable prognostic tool in clinical practice. Further research is needed to validate these findings in diverse populations and to explore the underlying biological mechanisms.

CRD42023476678.

Bladder cancer is a public health concern, with smoking and occupational exposure being major risk factors. However, specific risks in women, particularly hormonal, lifestyle, and environmental factors, are underexplored. This study aimed to assess these risk factors in women, focusing on smoking, occupational exposure, recurrent urinary tract infections (UTIs), body mass index (BMI), menopausal status, and family history of cancer.

This retrospective cohort study included 850 women diagnosed with bladder cancer (2018-2023) and age-matched controls. Data on smoking, occupational exposure, UTIs, BMI, menopausal status, and family history were collected from medical records: multivariate logistic regression and propensity score matching identified independent risk factors. Subgroup analysis explored interactions between menopausal status and other factors.

Smoking (OR = 2.15, p = 0.002), occupational exposure (OR = 1.89, p = 0.007), and recurrent UTIs (OR = 1.72, p = 0.013) were significant risk factors, particularly in post-menopausal women. Menopausal status amplified the effects of smoking and UTIs but was not an independent predictor. BMI and family history showed no significant associations.

Smoking, occupational exposure, and recurrent UTIs are key risk factors for bladder cancer in women, especially post-menopausal women, highlighting the need for targeted prevention strategies.

FGFR3 mutations are among the most frequent genomic alterations in urothelial cancer (UC) being mainly associated with the luminal papillary (LumP) subtype. With the establishment of fibroblast growth factor receptor (FGFR) inhibitors, the treatment of UC is now shifting more and more towards personalized medicine. A systematic review using Medline and scientific meeting records was carried out according to the Preferred Reporting Items for Systematic Review and Meta-analyses guidelines to assess the potential role of FGFR inhibitors in combination with additional therapies for the management of UC. Ongoing trials were identified via a systematic search on ClinicalTrials.gov. A total of eleven full-text papers, ten congress abstracts, and 5 trials on ClinicalTrials.gov were identified. Following the BLC2001 and THOR study, erdafitinib is the only approved FGFR1-4 inhibitor for metastatic UC with susceptible FGFR2/3 alterations following platinum-based chemotherapy. According to the THOR data of cohort 2, erdafitinib should not be recommended in patients who are eligible for and have not received prior immune checkpoint inhibitors (ICIs). One phase 3 trial is currently evaluating the intravesical device system (TAR210) in FGFR-altered intermediate non-muscle invasive bladder cancer (MoonRISe-1). Preclinical evidence suggests that combination-based approaches could be considered to improve the efficacy of FGFR inhibitors in patients with UC. Nine phase 1b/2 trials are focusing on the combination of FGFR inhibitors with ICIs, chemotherapy, or enfortumab vedotin. In metastatic disease, some preliminary analyses have reported promising results from these combinations (e.g. NORSE and FORT-2 trial). However, no phase 3 trial is terminated, so there is currently no level 1 evidence with long-term outcomes to support the combination of FGFR inhibitors with ICIs, chemotherapy, or targeted therapies. A better understanding of the different mechanisms of action to inhibit FGFR signaling pathways, optimal patient selection and treatment approaches is still needed.

Cisplatin-based neoadjuvant chemotherapy is first-line strategy to inhibit progression and metastasis of muscle-invasive bladder cancer (MIBC). However, its clinical efficacy is often limited by drug resistance and severe systemic side effects, highlighting the urgent need for innovative therapeutic approaches. Despite advancements in cisplatin-based regimens, research on intravesical cisplatin delivery systems remains scarce. In this study, we developed an amphiphilic platinum(IV) prodrug micellar platform (Pt (IV)-DI-PEG) capable of efficiently encapsulating sanguinarine (San), which was further coated with fluorinated chitosan (FCS) to construct San@Pt(IV)-DI-PEG@FCS nanoparticles (SPFNPs) for intravesical instillation even targeting MIBC. The resulting SPFNPs demonstrated several advantages: the FCS coating facilitated enhanced trans-epithelial drug delivery by regulating bladder epithelial tight junction proteins, enabling efficient intravesical administration; Second, the glutathione (GSH)-responsive reduction of the Pt(IV) prodrug promoted tumor-targeted release of San and localized accumulation of Pt(II), while simultaneously depleting intracellular GSH. Furthermore, the released San induced reactive oxygen species (ROS) production, oxidative cleavage and inhibit the activation and function of poly (ADP-ribose) polymerase, collectively impairing nucleotide-excision repair and preventing the elimination of Pt-DNA adducts, resulting in persistent DNA damage, cell cycle arrest, and apoptosis in tumor cells. The synergistic effects of San and cisplatin were validated in both orthotopic mouse models and patient-derived orthotopic xenograft, demonstrating robust anti-tumor efficacy. This study underscores the potential of intravesical cisplatin formulations as a promising strategy for MIBC treatment, offering a shift from traditional systemic chemotherapy towards localized, targeted drug delivery systems.

The 5-methylcytosine (m5C) modification is a crucial epigenetic RNA modification, which is involved in the post-transcriptional regulation of genes. It plays an important role in various biological processes, including cell metabolism, growth, apoptosis, and tumorigenesis. By affecting the proliferation, migration, invasion, and drug sensitivity of tumor cells, m5C methylation modification plays a vital part in the initiation and progression of tumors and is closely associated with the poor tumor prognosis. m5C-related proteins are categorized into three functional groups: m5C methyltransferases (m5C writers), m5C demethylases (m5C erasers), and m5C methyl-binding proteins (m5C readers). This paper introduces several common methodologies for detecting m5C methylation; and reviews the molecular structure and biological functions of m5C readers, including ALYREF, YBX1, YBX2, RAD52, YTHDF2, FMRP, and SRSF2. It further summarizes their roles and regulatory mechanisms in tumors, offering novel targets and insights for tumor treatment.

Hedyotis diffusa Willd. (HDW), a traditional Chinese medicinal plant, exhibits a variety of pharmacological effects and has anticancer potential for a wide range of cancer types; Ferroptosis is a non-apoptosis-regulated cell death induced by iron accumulation and subsequent lipid peroxidation; and there is currently an increasing interest in the therapeutic role of ferroptosis in cancer. However, the effects of HDW on bladder cancer and its underlying molecular mechanisms remain largely unknown. In this study, a combination of in vivo and in vitro experiments, network pharmacology and data mining methods were used to investigate the effects of HDW on BLCA. The results showed that HDW exerted its anticancer activity by inducing ferroptosis in bladder cancer cells. Subsequently, we demonstrated for the first time that HDW induced ferroptosis in vitro and in vivo. To further explore the possible targets of HDW-induced ferroptosis in bladder cancer, we performed network pharmacological analyses, transcriptomic analyses, and single-cell analyses; through integrative analyses, we identified three key pivotal genes associated with iron death, CAV1, VEGFA, and JUN.Mechanistically, we showed that CAV1, VEGFA and JUN are key determinants of HDW-induced ferroptosis in BLCA. Knockdown of target genes altered the anticancer effects of HDW in 5637 and T24 cells. In conclusion, our data show for the first time that HDW exerts its anticancer effects on BLCA through CAV1, VEGFA and JUN gene-induced ferroptosis. This is expected to provide a promising compound for bladder cancer therapy.

Background: Bladder cancer (BC) is a heterogeneous malignancy, and predicting response to immune checkpoint inhibitors (ICIs) remains a challenge. Herein, we investigate a high-risk bladder tumor, which developed during anti-BRAF/MEK therapy for a concurrent advanced BRAF-V600E-positive malignant melanoma (MM) and subsequently underwent complete spontaneous necrosis following Nivolumab immunotherapy, only to recur thereafter while still under the same treatment. This unique scenario provided an opportunity to investigate the roles of BRAF gene mutations in BC pathogenesis, respectively, of PD-L1 expression in immunotherapy response prediction. Methods: We retrospectively analyzed BC specimens obtained via transurethral resection at two critical time-points: prior to the complete spontaneous necrosis under Nivolumab (prenecrosis) and after tumor recurrence postnecrosis (postnecrosis). The BRAF gene mutation status was evaluated using quantitative polymerase chain reaction (qPCR). PD-L1 expression was assessed by immunohistochemistry (IHC), quantified using the combined positive score (CPS), and a cutoff of ≥10 for positivity. Results: Neither pre- nor postnecrosis BC samples harbored BRAF gene mutations. Prenecrosis PD-L1 expression (CPS = 5) indicated a minimal likelihood of response to immunotherapy. However, complete spontaneous necrosis occurred under Nivolumab, followed by recurrence with further reduced PD-L1 expression (CPS = 1). Conclusions: The complete BC regression challenges the conventional role of PD-L1 as a sole predictive biomarker for immunotherapy. This study also highlights the potential role of BRAF/MEK inhibitors in BC oncogenesis and underscores the need for alternative biomarkers, such as tumor mutation burden (TMB) and circulating tumor DNA (ctDNA), to guide treatment selection in BC better.

Disulfidptosis, which was recently identified, has shown promise as a potential cancer treatment. Nonetheless, the precise role of long non-coding RNAs (lncRNAs) in this phenomenon is currently unclear. To elucidate their significance in bladder cancer (BLCA), a signature of disulfidptosis-related lncRNAs (DRlncRNAs) was developed and their potential prognostic significance was explored. BLCA sample data were sourced from The Cancer Genome Atlas. A predictive signature comprising DRlncRNAs was formulated and subsequently validated. The combination of this signature with clinical characteristics facilitated the development of a nomogram with practical clinical utility. Additionally, enrichment analysis was conducted, the tumor microenvironment (TME) was assessed, the tumor mutational burden (TMB) was analyzed, and drug sensitivity was explored. Reverse transcription-quantitative PCR (RT-qPCR) was utilized to quantify lncRNA expression. The results revealed an eight-gene signature based on DRlncRNAs was established, and the predictive accuracy of the nomogram that incorporated the risk score [area under the curve (AUC)=0.733] outperformed the nomogram without it (AUC=0.703). High-risk groups were associated with pathways such as WNT signaling, focal adhesion and cell cycle pathways. The TME study revealed that high-risk patients had increased immune infiltration, whereas the TMB and tumor immune dysfunction and exclusion scores in low-risk patients indicated a potentially robust immune response. Drug sensitivity analysis identified appropriate antitumor drugs for each group. RT-qPCR experiments validated significant differences in DRlncRNAs expression between normal and BLCA cell lines. In conclusion, the prognostic risk signature, which includes the eight identified DRlncRNAs, demonstrates promise for predicting prognosis of patients with BLCA and guiding the selection of suitable immunotherapy and chemotherapy strategies.