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Identification of the Targets to Overcome Clinical Problems in Bladder...
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Identification of the Targets to Overcome Clinical Problems in Bladder Cancer

A special issue of Cancers (ISSN 2072-6694). This special issue belongs to the section "Clinical Research of Cancer".

Deadline for manuscript submissions: closed (15 May 2024) | Viewed by 12435

Special Issue Editor

Dr. Hiroki Ide

E-Mail Website
Guest Editor
Department of Urology, Keio University School of Medicine, Tokyo 160-8582, Japan
Interests: urology; bladder cancer

Special Issue Information

Dear Colleagues,

Bladder cancer has been reported to be the 10th most common cancer worldwide, and in 2020, there were more than 573,000 new cases worldwide. In 2022, it is estimated that it will cause 17,100 deaths in the USA. Nevertheless, effective diagnostic and prognostic markers of bladder cancer have yet to be identified.

Recent evidence has suggested that the signaling of steroid hormonal receptors, including the androgen, estrogen and glucocorticoid receptors, was strongly linked with carcinogenesis and progression in bladder cancer. Moreover, the modification of these signaling receptors has the potential to enhance the sensitivity of conventional treatments such as chemotherapy, BCG and radiotherapy.

More recently, it has been shown that there are three molecular subtypes in muscle invasive bladder cancer according to their gene expressions (basal, luminal and p53-like luminal).

Considering clinical challenges such as a lack of effective markers and potent second-line treatments in bladder cancer, a key target in the diagnosis and prognosis of bladder cancer needs to be identified. Therefore, we believe that by exploring potential targets and summarizing and evaluating recent evidence in this Special Issue, we will contribute to prognostic improvement in bladder cancer patients. 

Dr. Hiroki Ide
Guest Editor

Manuscript Submission Information

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Keywords

  • bladder cancer
  • urothelial carcinoma
  • diagnostic marker
  • prognostic marker
  • chemotherapy
  • immunotherapy
  • radiotherapy

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Published Papers (6 papers)

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Research

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12 pages, 2181 KiB  
Article
C-Reactive Protein Is a Potential Prognostic Marker in Patient with Advanced or Metastatic Urothelial Carcinoma Treated with Enfortumab Vedotin: A Multi-Center Retrospective Study
by Toshiharu Morikawa, Taku Naiki, Yosuke Sugiyama, Aya Naiki-Ito, Takashi Nagai, Toshiki Etani, Keitaro Iida, Teruki Isobe, Yusuke Noda, Nobuhiko Shimizu, Maria Aoki, Masakazu Gonda, Rika Banno, Hiroki Kubota, Ryosuke Ando, Yukihiro Umemoto, Noriyasu Kawai and Takahiro Yasui
Cancers 2024, 16(9), 1725; https://doi.org/10.3390/cancers16091725 - 28 Apr 2024
Viewed by 1632
Abstract
Background: In the EV-301 trial, enfortumab vedotin prolonged survival in patients with locally advanced or metastatic urothelial carcinoma previously treated with platinum-based therapy and programmed cell death 1/programmed death-ligand 1 inhibitor. However, real-world Asian data are limited, and potential prognostic markers are non-existent. [...] Read more.
Background: In the EV-301 trial, enfortumab vedotin prolonged survival in patients with locally advanced or metastatic urothelial carcinoma previously treated with platinum-based therapy and programmed cell death 1/programmed death-ligand 1 inhibitor. However, real-world Asian data are limited, and potential prognostic markers are non-existent. We aimed to investigate potential prognostic markers for enfortumab vedotin therapy in Asian patients. Methods: We retrospectively enrolled 61 Japanese patients treated with enfortumab vedotin therapy at our hospital and affiliated hospitals between January 2019 and September 2023. Results: Enrolled patients (38 men, 23 women; median age 74 [IQR: 68–79] years) had bladder cancer (26 patients) or upper-tract urothelial carcinoma (35 patients). Fifty-four patients reported adverse events (grade >3 in 12). Skin disorders, pruritus, and neuropathy were common adverse effects. The median overall survival was 17.1 months (95% confidence interval: 10.0–not applicable). In multivariate analysis, the C-reactive protein level was an independent marker predicting favorable overall survival with enfortumab vedotin. Patient characteristics did not differ between C-reactive protein-high and -low groups. Conclusions: Our study provides real-world data showing that enfortumab vedotin prolonged survival in Asian patients similar to the EV-301 trial. Additionally, the C-reactive protein level might be considered a prognostic marker of enfortumab vedotin therapy in such patients. Full article
(This article belongs to the Special Issue Identification of the Targets to Overcome Clinical Problems in Bladder Cancer)
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14 pages, 4135 KiB  
Article
Immuno-Transcriptomic Profiling of Blood and Tumor Tissue Identifies Gene Signatures Associated with Immunotherapy Response in Metastatic Bladder Cancer
by Emma Desponds, Davide Croci, Victoria Wosika, Noushin Hadadi, Sara S. Fonseca Costa, Laura Ciarloni, Marco Ongaro, Hana Zdimerova, Marine M. Leblond, Sahar Hosseinian Ehrensberger, Pedro Romero and Grégory Verdeil
Cancers 2024, 16(2), 433; https://doi.org/10.3390/cancers16020433 - 19 Jan 2024
Cited by 1 | Viewed by 1690
Abstract
Blood-based biomarkers represent ideal candidates for the development of non-invasive immuno-oncology-based assays. However, to date, no blood biomarker has been validated to predict clinical responses to immunotherapy. In this study, we used next-generation sequencing (RNAseq) on bulk RNA extracted from whole blood and [...] Read more.
Blood-based biomarkers represent ideal candidates for the development of non-invasive immuno-oncology-based assays. However, to date, no blood biomarker has been validated to predict clinical responses to immunotherapy. In this study, we used next-generation sequencing (RNAseq) on bulk RNA extracted from whole blood and tumor samples in a pre-clinical MIBC mouse model. We aimed to identify biomarkers associated with immunotherapy response and assess the potential application of simple non-invasive blood biomarkers as a therapeutic decision-making assay compared to tissue-based biomarkers. We established that circulating immune cells and the tumor microenvironment (TME) display highly organ-specific transcriptional responses to ICIs. Interestingly, in both, a common lymphocytic activation signature can be identified associated with the efficient response to immunotherapy, including a blood-specific CD8+ T cell activation/proliferation signature which predicts the immunotherapy response. Full article
(This article belongs to the Special Issue Identification of the Targets to Overcome Clinical Problems in Bladder Cancer)
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20 pages, 3049 KiB  
Article
Mechanism of cis-Nerolidol-Induced Bladder Carcinoma Cell Death
by Mateo Glumac, Vedrana Čikeš Čulić, Ivana Marinović-Terzić and Mila Radan
Cancers 2023, 15(3), 981; https://doi.org/10.3390/cancers15030981 - 3 Feb 2023
Cited by 6 | Viewed by 2366
Abstract
Nerolidol is a naturally occurring sesquiterpene alcohol with multiple properties, including antioxidant, antibacterial, and antiparasitic activities. A few studies investigating the antitumor properties of nerolidol have shown positive results in both cell culture and mouse models. In this study, we investigated the antitumor [...] Read more.
Nerolidol is a naturally occurring sesquiterpene alcohol with multiple properties, including antioxidant, antibacterial, and antiparasitic activities. A few studies investigating the antitumor properties of nerolidol have shown positive results in both cell culture and mouse models. In this study, we investigated the antitumor mechanism of cis-nerolidol in bladder carcinoma cell lines. The results of our experiments on two bladder carcinoma cell lines revealed that nerolidol inhibited cell proliferation and induced two distinct cell death pathways. We confirmed that cis-nerolidol induces DNA damage and ER stress. A mechanistic study identified a common cAMP, Ca2+, and MAPK axis involved in signal propagation and amplification, leading to ER stress. Inhibition of any part of this signaling cascade prevented both cell death pathways. The two cell death mechanisms can be distinguished by the involvement of caspases. The early occurring cell death pathway is characterized by membrane blebbing and cell swelling followed by membrane rupture, which can be prevented by the inhibition of caspase activation. In the late cell death pathway, which was found to be caspase-independent, cytoplasmic vacuolization and changes in cell shape were observed. cis-Nerolidol shows promising antitumor activity through an unorthodox mechanism of action that could help target resistant forms of malignancies, such as bladder cancer. Full article
(This article belongs to the Special Issue Identification of the Targets to Overcome Clinical Problems in Bladder Cancer)
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17 pages, 5737 KiB  
Article
Sulfatase 2 Affects Polarization of M2 Macrophages through the IL-8/JAK2/STAT3 Pathway in Bladder Cancer
by Wentao Zhang, Fuhan Yang, Zongtai Zheng, Cheng Li, Shiyu Mao, Yuan Wu, Ruiliang Wang, Junfeng Zhang, Yue Zhang, Hong Wang, Wei Li, Jianhua Huang and Xudong Yao
Cancers 2023, 15(1), 131; https://doi.org/10.3390/cancers15010131 - 26 Dec 2022
Cited by 10 | Viewed by 2087
Abstract
Sulfatase 2 (SULF2) affects the occurrence and development of cancer by regulating HSPG-binding factors. However, the mechanism of SULF2 in bladder cancer (BCa) is unknown. To determine this, we analyzed the RNA sequencing of 90 patients with BCa. The results showed that the [...] Read more.
Sulfatase 2 (SULF2) affects the occurrence and development of cancer by regulating HSPG-binding factors. However, the mechanism of SULF2 in bladder cancer (BCa) is unknown. To determine this, we analyzed the RNA sequencing of 90 patients with BCa. The results showed that the expression of SULF2 was closely related to the prognosis of BCa. Moreover, in vivo and in vitro experiments revealed that SULF2 promotes tumor proliferation and invasion. Furthermore, using a mouse orthotopic BCa model and flow cytometric analysis, we identified that SULF2 affects the polarization of macrophages. Mechanism studies clarified that SULF2 promoted the release of HSPG-binding factors, such as IL-8, in the microenvironment through β-catenin. Meanwhile, IL-8 activated the JAK2/STAT3 pathway of macrophages to promote the expression of CD163 and CD206, thereby regulating the polarization of macrophages to the M2-type. Conclusively, these results indicate that SULF2 plays an important role in regulating the microenvironment of BCa and promotes the polarization of macrophages to the M2-type by secreting IL-8, which further deepens the malignant progression of BCa. Full article
(This article belongs to the Special Issue Identification of the Targets to Overcome Clinical Problems in Bladder Cancer)
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18 pages, 3519 KiB  
Article
DNMT3A/miR-129-2-5p/Rac1 Is an Effector Pathway for SNHG1 to Drive Stem-Cell-like and Invasive Behaviors of Advanced Bladder Cancer Cells
by Jiheng Xu, Rui Yang, Jingxia Li, Lidong Wang, Mitchell Cohen, Diane M. Simeone, Max Costa and Xue-Ru Wu
Cancers 2022, 14(17), 4159; https://doi.org/10.3390/cancers14174159 - 27 Aug 2022
Cited by 5 | Viewed by 1929
Abstract
The stem-cell-like behavior of cancer cells plays a central role in tumor heterogeneity and invasion and correlates closely with drug resistance and unfavorable clinical outcomes. However, the molecular underpinnings of cancer cell stemness remain incompletely defined. Here, we show that SNHG1, a [...] Read more.
The stem-cell-like behavior of cancer cells plays a central role in tumor heterogeneity and invasion and correlates closely with drug resistance and unfavorable clinical outcomes. However, the molecular underpinnings of cancer cell stemness remain incompletely defined. Here, we show that SNHG1, a long non-coding RNA that is over-expressed in ~95% of human muscle-invasive bladder cancers (MIBCs), induces stem-cell-like sphere formation and the invasion of cultured bladder cancer cells by upregulating Rho GTPase, Rac1. We further show that SNHG1 binds to DNA methylation transferase 3A protein (DNMT3A), and tethers DNMT3A to the promoter of miR-129-2, thus hyper-methylating and repressing miR-129-2-5p transcription. The reduced binding of miR-129-2 to the 3′-UTR of Rac1 mRNA leads to the stabilization of Rac1 mRNA and increased levels of Rac1 protein, which then stimulates MIBC cell sphere formation and invasion. Analysis of the Human Protein Atlas shows that a high expression of Rac1 is strongly associated with poor survival in patients with MIBC. Our data strongly suggest that the SNHG1/DNMT3A/miR-129-2-5p/Rac1 effector pathway drives stem-cell-like and invasive behaviors in MIBC, a deadly form of bladder cancer. Targeting this pathway, alone or in combination with platinum-based therapy, may reduce chemoresistance and improve longer-term outcomes in MIBC patients. Full article
(This article belongs to the Special Issue Identification of the Targets to Overcome Clinical Problems in Bladder Cancer)
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Review

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14 pages, 750 KiB  
Review
Carcinoma In Situ (CIS): Is There a Difference in Efficacy between Various BCG Strains? A Comprehensive Review of the Literature
by Andres Llano, Amy Chan, Cynthia Kuk, Wassim Kassouf and Alexandre R. Zlotta
Cancers 2024, 16(2), 245; https://doi.org/10.3390/cancers16020245 - 5 Jan 2024
Cited by 2 | Viewed by 1822
Abstract
Introduction: Intravesical Bacillus Calmette-Guérin (BCG) immunotherapy is the standard of care for high-risk and intermediate-risk non-muscle-invasive bladder cancer (NMIBC) as well as for Carcinoma in situ (CIS). Evidence supports that the different BCG strains, despite genetic variability, are equally effective clinically for preventing [...] Read more.
Introduction: Intravesical Bacillus Calmette-Guérin (BCG) immunotherapy is the standard of care for high-risk and intermediate-risk non-muscle-invasive bladder cancer (NMIBC) as well as for Carcinoma in situ (CIS). Evidence supports that the different BCG strains, despite genetic variability, are equally effective clinically for preventing the recurrence and progression of papillary NMIBC. The available evidence regarding possible differences in clinical efficacy between various BCG strains in CIS is lacking. Methods: We reviewed the literature on the efficacy of different BCG strains in patients with CIS (whether primary, secondary, concomitant, or unifocal/multifocal), including randomized clinical trials (RCTs), phase II/prospective trials, and retrospective studies with complete response rates (CRR), recurrence-free survival (RFS), or progression-free survival (PFS) as endpoints. Results: In most studies, being RCTs, phase II prospective trials, or retrospective studies, genetic differences between BCG strains did not translate into meaningful differences in clinical efficacy against CIS, regardless of the CIS subset (primary, secondary, or concurrent) or CIS focality (unifocal or multifocal). CRR, RFS, and PFS were not statistically different between various BCG strains. None of these trials were designed as head-to-head comparisons between BCG strains focusing specifically on CIS. Limitations include the small sample size of many studies and most comparisons between strains being indirect rather than head-to-head. Conclusions: This review suggests that the clinical efficacy of the various BCG strains appears similar, irrespective of CIS characteristics. However, based on the weak level of evidence available and underpowered studies, randomized studies in this space should be encouraged as no definitive conclusion can be drawn at this stage. Full article
(This article belongs to the Special Issue Identification of the Targets to Overcome Clinical Problems in Bladder Cancer)
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