scholarly journals ATF2 promotes urothelial cancer outgrowth via cooperation with androgen receptor signaling

2018 ◽  
Vol 7 (12) ◽  
pp. 1397-1408 ◽  
Author(s):  
Satoshi Inoue ◽  
Taichi Mizushima ◽  
Hiroki Ide ◽  
Guiyang Jiang ◽  
Takuro Goto ◽  
...  
Keyword(s):  
Bladder Cancer ◽  
Androgen Receptor ◽  
Urothelial Cancer ◽  
Nuclear Translocation ◽  
Significant Inhibition ◽  
Migration And Invasion ◽  
Cycle Phase ◽  
Low Grade ◽  
Urothelial Cells ◽  
Muscle Invasive

We investigated the functional role of ATF2, a transcription factor normally activated via its phosphorylation in response to phospho-ERK/MAPK signals, in the outgrowth of urothelial cancer. In both neoplastic and non-neoplastic urothelial cells, the expression levels of androgen receptor (AR) correlated with those of phospho-ATF2. Dihydrotestosterone treatment in AR-positive bladder cancer cells also induced the expression of phospho-ATF2 and phospho-ERK as well as nuclear translocation and transcriptional activity of ATF2. Meanwhile, ATF2 knockdown via shRNA resulted in significant decreases in cell viability, migration and invasion of AR-positive bladder cancer lines, but not AR-negative lines, as well as significant increases and decreases in apoptosis or G0/G1 cell cycle phase and S or G2/M phase, respectively. Additionally, the growth of AR-positive tumors expressing ATF2-shRNA in xenograft-bearing mice was retarded, compared with that of control tumors. ATF2 knockdown also resulted in significant inhibition of neoplastic transformation induced by a chemical carcinogen 3-methylcholanthrene, as well as the expression of Bcl-2/cyclin-A2/cyclin-D1/JUN/MMP-2, in immortalized human normal urothelial SVHUC cells stably expressing AR, but not AR-negative SVHUC cells. Finally, immunohistochemistry in surgical specimens demonstrated significant elevation of ATF2/phospho-ATF2/phospho-ERK expression in bladder tumors, compared with non-neoplastic urothelial tissues. Multivariate analysis further showed that moderate/strong ATF2 expression and phospho-ATF2 positivity were independent predictors for recurrence of low-grade tumors (hazard ratio (HR) = 2.956, P = 0.045) and cancer-specific mortality of muscle-invasive tumors (HR = 5.317, P = 0.012), respectively. Thus, ATF2 appears to be activated in urothelial cells through the AR pathway and promotes the development and progression of urothelial cancer.

scholarly journals Combined cytotoxic effect of UV-irradiation and TiO2microbeads in normal urothelial cells, low-grade and high-grade urothelial cancer cells

2015 ◽  
Vol 14 (3) ◽  
pp. 583-590 ◽  
Author(s):  
Roghayeh Imani ◽  
Peter Veranič ◽  
Aleš Iglič ◽  
Mateja Erdani Kreft ◽  
Meysam Pazoki ◽  
...  
Keyword(s):  
Bladder Cancer ◽  
Cancer Cells ◽  
Uv Irradiation ◽  
Cytotoxic Effect ◽  
Urothelial Cancer ◽  
Low Grade ◽  
High Grade ◽  
Urothelial Cells ◽  
Efficient Approach

Paper shows that internalization of the TiO2microbeads followed by the UV-irradiation is an efficient approach for killing cancer urothelial cells. Additionally, differentiation dependent differences in the sensitivity of the cells to the UV-irradiation are shown, and a model of photocatalytic treatment of thein vivobladder cancer is presented.

FOXO1 as a tumor suppressor inactivated via AR/ERβ signals in urothelial cells

2020 ◽  
Vol 27 (4) ◽  
pp. 231-244 ◽  
Author(s):  
Hiroki Ide ◽  
Taichi Mizushima ◽  
Guiyang Jiang ◽  
Takuro Goto ◽  
Yujiro Nagata ◽  
...  
Keyword(s):  
Bladder Cancer ◽  
Tumor Suppressor ◽  
Cancer Cells ◽  
Urothelial Cancer ◽  
Neoplastic Transformation ◽  
Migration And Invasion ◽  
Urothelial Cells ◽  
Estradiol Treatment ◽  
Downstream Target ◽  
Bladder Cancer Cells

Androgen receptor (AR) and estrogen receptor-β (ERβ) have been implicated in urothelial tumor outgrowth as promoters, while underlying mechanisms remain poorly understood. Our transcription factor profiling previously performed identified FOXO1 as a potential downstream target of AR in bladder cancer cells. We here investigated the functional role of FOXO1 in the development and progression of urothelial cancer in relation to AR and ERβ signals. In non-neoplastic urothelial SVHUC cells or bladder cancer lines, AR/ERβ expression or dihydrotestosterone/estradiol treatment reduced the expression levels of FOXO1 gene and induced those of a phosphorylated inactive form of FOXO1 (p-FOXO1). In chemical carcinogen-induced models, FOXO1 knockdown via shRNA or inhibitor treatment resulted in considerable induction of the neoplastic transformation of urothelial cells or bladder cancer development in mice. Similarly, FOXO1 inhibition considerably induced the viability, migration, and invasion of bladder cancer cells. Importantly, in FOXO1 knockdown sublines, an anti-androgen hydroxyflutamide or an anti-estrogen tamoxifen did not significantly inhibit the neoplastic transformation of urothelial cells, while dihydrotestosterone or estradiol did not significantly promote the proliferation or migration of urothelial cancer cells. In addition, immunohistochemistry in surgical specimens showed that FOXO1 and p-FOXO1 expression was down-regulated and up-regulated, respectively, in bladder tumor tissues, which was further associated with worse patient outcomes. AR or ERβ activation is thus found to correlate with inactivation of FOXO1 which appears to be their key downstream effector. Moreover, FOXO1, as a tumor suppressor, is likely inactivated in bladder cancer, which contributes in turn to inducing urothelial carcinogenesis and cancer growth.

scholarly journals A urine-based DNA methylation assay to facilitate early detection and risk stratification of bladder cancer

2021 ◽  
Vol 13 (1) ◽  
Author(s):  
Weimei Ruan ◽  
Xu Chen ◽  
Ming Huang ◽  
Hong Wang ◽  
Jiaxin Chen ◽  
...  
Keyword(s):  
Dna Methylation ◽  
Bladder Cancer ◽  
Risk Stratification ◽  
Early Stage ◽  
Operative Risk ◽  
Low Grade ◽  
Single Center ◽  
Detection Model ◽  
Methylation Assay ◽  
Muscle Invasive

Abstract Background Current non-invasive tests have limited sensitivities and lack capabilities of pre-operative risk stratification for bladder cancer (BC) diagnosis. We aimed to develop and validate a urine-based DNA methylation assay as a clinically feasible test for improving BC detection and enabling pre-operative risk stratifications. Methods A urine-based DNA methylation assay was developed and validated by retrospective single-center studies in patients of suspected BC in Cohort 1 (n = 192) and Cohort 2 (n = 98), respectively. In addition, a prospective single-center study in hematuria patient group (Cohort 3, n = 174) was used as a second validation of the model. Results The assay with a dual-marker detection model showed 88.1% and 91.2% sensitivities, 89.7% and 85.7% specificities in validation Cohort 2 (patients of suspected BC) and Cohort 3 (patients of hematuria), respectively. Furthermore, this assay showed improved sensitivities over cytology and FISH on detecting low-grade tumor (66.7–77.8% vs. 0.0–22.2%, 0.0–22.2%), Ta tumor (83.3% vs. 22.2–41.2%, 44.4–52.9%) and non-muscle invasive BC (NMIBC) (80.0–89.7% vs. 51.5–52.0%, 59.4–72.0%) in both cohorts. The assay also had higher accuracies (88.9–95.8%) in diagnosing cases with concurrent genitourinary disorders as compared to cytology (55.6–70.8%) and FISH (72.2–77.8%). Meanwhile, the assay with a five-marker stratification model identified high-risk NMIBC and muscle invasive BC with 90.5% sensitivity and 86.8% specificity in Cohort 2. Conclusions The urine-based DNA methylation assay represents a highly sensitive and specific approach for BC early-stage detection and risk stratification. It has a potential to be used as a routine test to improve diagnosis and prognosis of BC in clinic.

scholarly journals Sex Hormone Receptor Signaling in Bladder Cancer: A Potential Target for Enhancing the Efficacy of Conventional Non-Surgical Therapy

Cells ◽  
2021 ◽  
Vol 10 (5) ◽  
pp. 1169
Author(s):  
Hiroki Ide ◽  
Hiroshi Miyamoto
Keyword(s):  
Bladder Cancer ◽  
Estrogen Receptor ◽  
Androgen Receptor ◽  
Surgical Therapy ◽  
Urothelial Cancer ◽  
Hormone Receptors ◽  
Estrogen Receptor Α ◽  
Vital Role ◽  
Sex Hormone ◽  
Sex Steroid Hormone

There have been critical problems in the non-surgical treatment for bladder cancer, especially residence to intravesical pharmacotherapy, including BCG immunotherapy, cisplatin-based chemotherapy, and radiotherapy. Recent preclinical and clinical evidence has suggested a vital role of sex steroid hormone-mediated signaling in the progression of urothelial cancer. Moreover, activation of the androgen receptor and estrogen receptor pathways has been implicated in modulating sensitivity to conventional non-surgical therapy for bladder cancer. This may indicate the possibility of anti-androgenic and anti-estrogenic drugs, apart from their direct anti-tumor activity, to function as sensitizers of such conventional treatment. This article summarizes available data suggesting the involvement of sex hormone receptors, such as androgen receptor, estrogen receptor-α, and estrogen receptor-β, in the progression of urothelial cancer, focusing on their modulation for the efficacy of conventional therapy, and discusses their potential of overcoming therapeutic resistance.

scholarly journals Imaging of Bladder Cancer: Standard Applications and Future Trends

Medicina ◽  
2021 ◽  
Vol 57 (3) ◽  
pp. 220
Author(s):  
Rasha Taha Abouelkheir ◽  
Abdalla Abdelhamid ◽  
Mohamed Abou El-Ghar ◽  
Tarek El-Diasty
Keyword(s):  
Bladder Cancer ◽  
Malignant Tumors ◽  
Cancer Staging ◽  
Low Grade ◽  
Diagnostic Modality ◽  
Positron Emission ◽  
Standard Application ◽  
Muscle Invasive ◽  
Muscle Invasion ◽  
Low Sensitivity

The evolution in imaging has had an increasing role in the diagnosis, staging and follow up of bladder cancer. Conventional cystoscopy is crucial in the diagnosis of bladder cancer. However, a cystoscopic procedure cannot always depict carcinoma in situ (CIS) or differentiate benign from malignant tumors prior to biopsy. This review will discuss the standard application, novel imaging modalities and their additive role in patients with bladder cancer. Staging can be performed with CT, but distinguishing between T1 and T2 BCa (bladder cancer) cannot be assessed. MRI can distinguish muscle-invasive from non-muscle-invasive tumors with accurate local staging. Vesical Imaging-Reporting and Data System (VI-RADS) score is a new diagnostic modality used for the prediction of tumor aggressiveness and therapeutic response. Bone scintigraphy is recommended in patients with muscle-invasive BCa with suspected bony metastases. CT shows low sensitivity for nodal staging; however, PET (Positron Emission Tomography)/CT is superior and highly recommended for restaging and determining therapeutic effect. PET/MRI is a new imaging technique in bladder cancer imaging and its role is promising. Texture analysis has shown significant steps in discriminating low-grade from high-grade bladder cancer. Radiomics could be a reliable method for quantitative assessment of the muscle invasion of bladder cancer.

scholarly journals MicroRNAs Which Can Prognosticate Aggressiveness of Bladder Cancer

Cancers ◽  
2019 ◽  
Vol 11 (10) ◽  
pp. 1551 ◽  
Author(s):  
Edyta Marta Borkowska ◽  
Tomasz Konecki ◽  
Michał Pietrusiński ◽  
Maciej Borowiec ◽  
Zbigniew Jabłonowski
Keyword(s):  
Bladder Cancer ◽  
Area Under The Curve ◽  
Roc Curves ◽  
Control Group ◽  
Low Grade ◽  
Operating Characteristics ◽  
High Death Rate ◽  
Biological Potential ◽  
High Death ◽  
Muscle Invasive

Bladder cancer (BC) is still characterized by a very high death rate in patients with this disease. One of the reasons for this is the lack of adequate markers which could help determine the biological potential of the tumor to develop into its invasive stage. It has been found that some microRNAs (miRNAs) correlate with disease progression. The purpose of this study was to identify which miRNAs can accurately predict the presence of BC and can differentiate low grade (LG) tumors from high grade (HG) tumors. The study included 55 patients with diagnosed bladder cancer and 30 persons belonging to the control group. The expression of seven selected miRNAs was estimated with the real-time PCR technique according to miR-103-5p (for the normalization of the results). Receiver operating characteristics (ROC) curves and the area under the curve (AUC) were used to evaluate the feasibility of using selected markers as biomarkers for detecting BC and discriminating non-muscle invasive BC (NMIBC) from muscle invasive BC (MIBC). For HG tumors, the relevant classifiers are miR-205-5p and miR-20a-5p, whereas miR-205-5p and miR-182-5p are for LG (AUC = 0.964 and AUC = 0.992, respectively). NMIBC patients with LG disease are characterized by significantly higher miR-130b-3p expression values compared to patients in HG tumors.

scholarly journals Biomarkers in Bladder Cancer Surveillance

2021 ◽  
Vol 8 ◽  
Author(s):  
Sukumar S. Sugeeta ◽  
Anand Sharma ◽  
Kenrick Ng ◽  
Arvind Nayak ◽  
Nikhil Vasdev
Keyword(s):  
Bladder Cancer ◽  
Clinical Trials ◽  
Prospective Studies ◽  
Urine Cytology ◽  
Cancer Surveillance ◽  
Invasive Bladder Cancer ◽  
Low Grade ◽  
Protein Biomarkers ◽  
Muscle Invasive Bladder Cancer ◽  
Muscle Invasive

Aim: This is a narrative review with an aim to summarise and describe urinary biomarkers in the surveillance of non-muscle-invasive bladder cancer (NMIBC). It provides a summary of FDA-approved protein biomarkers along with emerging ones which utilise genetic, epigenetic and exosomal markers. We discuss the current limitations of the available assays.Background: Current guidelines advice a combination of cystoscopy, imaging,and urine cytology in diagnosis and surveillance. Although cytology has a high specificity, it is limited by low sensitivity particularly in low grade tumours. There are six FDA-approved urinary assays for diagnosis and surveillance of bladder cancer. They have shown to improve sensitivity and specificity to be used alongside cytology and cystoscopy but have a lower specificity in comparison to cytology and false positives often occur in benign conditions. Recent developments in laboratory techniques has allowed for use of markers which are RNA-, DNA-based as well as extracellular vesicles in the past decade.Methods: Using the PubMed/Medline search engines as well as Google Scholar, we performed an online search using the terms “bladder cancer,” “non-muscle invasive bladder cancer,” and “urine biomarkers” with filter for articles in English published up to May 2021. Systematic reviews and original data of clinical trials or observational studies which contributed to the development of the biomarkers were collated.Results: Biomarkers identified were divided into FDA-approved molecular biomarkers, protein biomarkers and gene-related biomarker with a table summarising the findings of each marker with the most relevant studies. The studies conducted were mainly retrospective. Due to the early stages of development, only a few prospective studies have been done for more recently developed biomarkers and limited meta-analyses are available.Therefore a detailed evaluation of these markers are still required to decide on their clinical use.Conclusion: Advancements of analytical methods in BC has driven the research towards non-invasive liquid-based biomarkers in adjunct to urine cytology. Further large prospective studies are required to determine its feasibility in a clinical setting as they are not effective when used in isolation as they have their limitation. With the ongoing pandemic, other than reduction in costs and increased accuracy, the need for biomarkers to cope with delay in cystoscopies in diagnosis and surveillance is crucial. Thus clinical trials with direct comparison is required to improve patient care.

Neoadjuvant or adjuvant immunotherapy in bladder cancer: biological opportunity or clinical utility?

2021 ◽  
pp. 030089162110616
Author(s):  
Fausto Petrelli ◽  
Gianluca Perego ◽  
Ivano Vavassori ◽  
Andrea Luciani
Keyword(s):  
Bladder Cancer ◽  
Immune Checkpoint ◽  
Immune Checkpoint Inhibitors ◽  
Urothelial Cancer ◽  
Checkpoint Inhibitors ◽  
Phase Iii ◽  
Invasive Bladder Cancer ◽  
Muscle Invasive Bladder Cancer ◽  
Cancer Of The Bladder ◽  
Muscle Invasive

In urothelial cancer of the bladder, the introduction of immunotherapy with immune checkpoint inhibitors represents progress in the management of the disease’s early and advanced stages. In particular, recent studies have implemented these drugs in the neoadjuvant and adjuvant phases to treat muscle-invasive bladder cancer. In some studies, patients received neoadjuvant immune checkpoint inhibitors alone (PURE and ABACUS) to treat muscle invasive bladder cancer, whereas other studies provided this therapy to cisplatin-ineligible patients. Furthermore, a large Phase III study (CheckMate 247) compared placebo with adjuvant nivolumab therapy in patients with high-risk urothelial cancer after neoadjuvant chemotherapy and surgery or surgery alone. Despite some uncertain niches (nonbladder, PD-L1-negative tumors, and node-negative resected cancers), certain biological opportunities (exploring new targets, evaluating in vivo pathologic response, focusing on biomarkers for response) and clinical uses (avoiding chemotherapy at all or in frail patients, attaining similar pathologic complete response rates as in cisplatin-based chemotherapy) are valid reasons for incorporating these agents into the therapeutic armamentarium of medical uro-oncologists.

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