Extracellular Vesicles as Biomarkers Carriers in Bladder Cancer: Diagnosis, Surveillance, and Treatment

Exosomes are extracellular vesicles, enriched in biomolecular cargo consisting of nucleic acids, proteins, and lipids, which take part in intercellular communication and play a crucial role in both physiologic functions and oncogenesis. Bladder cancer is the most common urinary malignancy and its incidence is steadily rising in developed countries. Despite the high five-year survival in patients diagnosed at early disease stage, survival substantially drops in patients with muscle-invasive or metastatic disease. Therefore, early detection of primary disease as well as recurrence is of paramount importance. The role that exosomal biomarkers could play in bladder cancer patient diagnosis and surveillance, as well as their potential therapeutic applications, has not been extensively studied in this malignancy. In the present review, we summarize all relevant data obtained so far from cell lines, animal models, and patient biofluids and tissues. Current literature suggests that urine is a rich source of extracellular vesicle-derived biomarkers, compared with blood and bladder tissue samples, with potential applications in bladder cancer management. Further studies improving sample collection procedures and optimizing purification and analytical methods should augment bladder cancer diagnostic, prognostic, and therapeutic input of extracellular vesicles biomarkers in the future.

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Spotlight on PSMA as a new theranostic biomarker for bladder cancer

Scientific Reports ◽

10.1038/s41598-021-89160-0 ◽

2021 ◽

Vol 11 (1) ◽

Author(s):

Maria Maddalena Tumedei ◽

Sara Ravaioli ◽

Federica Matteucci ◽

Monica Celli ◽

Ugo De Giorgi ◽

...

Keyword(s):

Bladder Cancer ◽

Diagnostic Tests ◽

Radionuclide Therapy ◽

Tumor Type ◽

Prostate Specific Membrane Antigen ◽

Bladder Tissue ◽

Tissue Samples ◽

Specific Membrane ◽

Psma Expression ◽

Degree Of Extension

AbstractBladder cancer (BCa) patients are diagnosed by cytology and cystoscopy. However, these diagnostic tests bear some limitations. We sought for reliable biomarkers to better determine BCa extension. Prostate-specific membrane antigen (PSMA) appears to fulfill this requirement in prostate cancer but its role in BCa has not been established yet. We then analyzed 87 bladder tissue samples from 74 patients assessing PSMA expression by immunohistochemistry. The median PSMA expression, exclusively found in tumor neovasculature, in terms of H-score significantly differed between non-tumor samples and tumor samples (p = 0.00288) showing a higher neovasculature-related PSMA expression. No differences were observed in relation to tumor type, grade and stage. BCa neovasculature-related PSMA overexpression may be useful in defining the degree of extension of the neoplasm. In addition, testing PSMA expression by immunohistochemistry may hold theranostic implications both considering anti-angiogenesis agents and radio-labelled PSMA ligands for intracavitary radionuclide therapy. In our opinion, BCa neovasculature-related PSMA overexpression may be considered an apt target for anti-angiogenesis and radionuclide treatment in BCa, once the evaluation of tumor-retention time for the appropriateness of long half-life therapeutic PSMA ligands as radionuclide treatment will be performed.

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Co-Delivery of Cisplatin and Gemcitabine via Viscous Nanoemulsion for Potential Synergistic Intravesical Chemotherapy

Pharmaceutics ◽

10.3390/pharmaceutics12100949 ◽

2020 ◽

Vol 12 (10) ◽

pp. 949

Author(s):

Ting-Yu Chen ◽

Ming-Jun Tsai ◽

Li-Ching Chang ◽

Pao-Chu Wu

Keyword(s):

Drug Delivery ◽

Bladder Cancer ◽

Combined Chemotherapy ◽

Chemotherapeutic Drugs ◽

Intravesical Administration ◽

Bladder Tissue ◽

Tissue Samples ◽

Chemotherapy Agents

Combined chemotherapy is an effective and safe treatment for cancers. Co-administration of cisplatin and gemcitabine produces a synergistic effect for bladder cancer treatment, so viscous microemulsions were developed for co-delivery of cisplatin and gemcitabine to extend the retention time and improve the permeability of chemotherapeutic drugs into the urothelium by intravesical administration. Results showed that the deposition amounts of cisplatin and gemcitabine significantly increased in in vitro and in vivo study. The penetration depth in bladder tissue samples increased from 60 to 120 μm. The dual-loaded formulation also showed thermodynamic and chemical stability, demonstrating that these gel-based microemulsions are promising drug delivery carriers for chemotherapy agents by intravesical administration.

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Urinary extracellular vesicles: a rising star in bladder cancer management

Translational Andrology and Urology ◽

10.21037/tau-20-1039 ◽

2021 ◽

Vol 10 (4) ◽

pp. 1878-1889

Author(s):

Fumihiko Urabe ◽

Takahiro Kimura ◽

Kagenori Ito ◽

Yusuke Yamamoto ◽

Shunsuke Tsuzuki ◽

...

Keyword(s):

Bladder Cancer ◽

Extracellular Vesicles ◽

Cancer Management

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Pan-tumor analyses of kinase fusions detected in circulating tumor DNA (ctDNA) and concordance with paired tissue.

Journal of Clinical Oncology ◽

10.1200/jco.2020.38.15_suppl.3517 ◽

2020 ◽

Vol 38 (15_suppl) ◽

pp. 3517-3517

Author(s):

Jessica Kim Lee ◽

Daniel Lieber ◽

Russell Madison ◽

Jon Chung ◽

Alexa Betzig Schrock ◽

...

Keyword(s):

Bladder Cancer ◽

Median Time ◽

Liquid Biopsy ◽

Clinical Care ◽

Driver Mutations ◽

Gene Fusions ◽

Sample Collection ◽

Liquid Biopsies ◽

Kinase Gene ◽

Tissue Samples

3517 Background: Oncogenic kinase gene fusions are targetable with approved and investigational therapies and can also emerge as acquired resistance (AR) to targeted therapy. To understand the clinical validity of liquid biopsy comprehensive genomic profiling (CGP) to detect kinase fusions, we compared patient-matched plasma and tissue-based CGP. Methods: Hybrid capture-based CGP was performed on 28,743 plasma and 325,131 tumor tissue samples in the course of clinical care. Complete exonic regions of 13 kinases involved in oncogenic fusions plus select introns in ALK, EGFR, FGFR2/3, PDGFRA, RET, and ROS1 were sequenced to capture fusions with well characterized breakpoints. ctDNA fraction was estimated by maximum somatic allele frequency (MSAF). Results: 86% of cases had detectable ctDNA in plasma (MSAF > 0). Kinase fusions were detected in 2.1% of ctDNA cases (478/23,294) and were most prevalent in patients (pts) with bladder cancer (4.5%), non-small cell lung cancer (NSCLC) (4.3%), and cholangiocarcinoma (3.9%). The most commonly rearranged kinases were ALK (60%, 162/271) and RET (19%, 51/271) in NSCLC, FGFR2 (85%, 11/13) in cholangiocarcinoma, and FGFR3 (88%, 7/8) in bladder cancer. ALK fusions were detected in 26% (54/207) of fusion+ non-NSCLC cases. Paired tissue and ctDNA samples where ≥1 sample harbored a kinase fusion were available for 147 pts; median time between sample collection was 150 days (interquartile range: 444 days). Positive percent agreement (PPA) to tissue and liquid biopsies was 76% and 80%. Median MSAF in concordant and discordant ctDNA samples was 2.3% and 0.41% (p = 0.04) and median time between specimen collection for concordant and discordant pairs was 110 and 344 days (p = 0.04). PPA to tissue and liquid was 86% and 88% for pairs collected < 60 days apart (n = 53), versus 70% and 74% for pairs collected > 60 days apart. 6 pts with paired samples all collected > 196 days apart (median 593 days) had initial tissue samples with EGFR driver mutations and had an acquired kinase fusion (4 ALK, 1 FGFR2, 1 FGFR3) in the 2nd ctDNA sample, likely representing AR. Conclusions: Kinase gene fusions identified by tissue-based CGP were detected by liquid biopsy CGP in 85% of temporally-matched plasma samples. Kinase fusion detection by liquid biopsy CGP is feasible and had high PPA to tissue-based CGP. Subsequent sampling by liquid biopsy identified acquired fusions in EGFR driver positive cases consistent with known mechanisms of resistance to EGFR inhibitors suggesting utility of liquid biopsy at progression to identify targetable mechanisms of AR.

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Segmentation of the Urothelium in Optical Coherence Tomography Images with Dynamic Contrast

10.1101/2021.02.26.433072 ◽

2021 ◽

Author(s):

Hui Wang ◽

Zhuo Xu ◽

Hui Zhu

Keyword(s):

Bladder Cancer ◽

Optical Coherence Tomography ◽

Autocorrelation Function ◽

Layer Structure ◽

Optical Coherence ◽

Urothelial Cells ◽

Bladder Tumors ◽

Bladder Tissue ◽

Tissue Samples ◽

Cancerous Cells

Significance: Speckle variations induced by intracellular motion (IM) in the urothelium was observed in optical coherence tomography (OCT) images. It is feasible to use the IM as a dynamic contrast to segment the urothelium with only two sequential OCT images. This new method opens the possibility of tracking the distribution of the urothelial cells to identify the microinvasion of bladder tumors. Approach: With fresh porcine bladder tissue, IM was analyzed by tracking speckle variations using autocorrelation function, then quantified with CONTINE algorism to identify the decorrelation time (DT) of the speckle variations. Variance analysis is conducted to show IM amplitude and distribution in the urothelium. The segmentation of the urothelium is demonstrated using tissue samples with and without significantly stretching. Results: Significant speckle variations induced by IM exists in the urothelium. However, the distribution of the IM is heterogeneous. The DTs are majorly distributed between 1ms to 30ms. Using the IM as a dynamic contrast, the urothelium can be accurately and exclusively segmented, even the layer structure of the bladder is invisible. Conclusions: With fresh porcine bladders, we show that IM can be used as a dynamic contrast to exclusively segment the urothelium. This contrast may provide a new mechanism for OCT to diagnosis the invasion of urothelial cancerous cells for the better staging of bladder cancer.

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KIF5A Promotes Bladder Cancer Proliferation In Vitro and In Vivo

Disease Markers ◽

10.1155/2019/4824902 ◽

2019 ◽

Vol 2019 ◽

pp. 1-9

Author(s):

Da-Wei Tian ◽

Zhou-Liang Wu ◽

Li-Ming Jiang ◽

Jie Gao ◽

Chang-Li Wu ◽

...

Keyword(s):

Cell Proliferation ◽

Bladder Cancer ◽

Regulatory Networks ◽

Migration And Invasion ◽

Bladder Tissue ◽

Tissue Samples ◽

Normal Bladder ◽

Tumor Tissues

Background. Bladder cancer is a common malignancy with uncontrolled and rapid growth. Although lots of the important regulatory networks in bladder cancer have been found, the cancer-relevant genes remain to be further identified. Methods. We examined the KIF5A expression levels in bladder cancer and normal bladder tissue samples via immunohistochemistry and observed the effect of KIF5A on bladder tumor cell proliferation in vitro and in vivo. Additionally, a coexpression between KIF5A and KIF20B in tumor tissues was explored. Results. KIF5A expression level was higher in the bladder cancer tissues than in the adjacent nontumor tissues. Patients with higher KIF5A expression displayed advanced clinical features and shorter survival time than those with lower KIF5A expression. Moreover, KIF5A knockdown inhibited bladder cancer cell proliferation, migration, and invasion demonstrated in vivo and in vitro. In addition, coexpression was found between KIF5A and KIF20B in tumor tissues. Conclusion. The results demonstrated that KIF5A is a critical regulator in bladder cancer development and progression, as well as a potential target in the treatment of bladder cancer.

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Advances in Breast Cancer Management and Extracellular Vesicle Research, a Bibliometric Analysis

Current Oncology ◽

10.3390/curroncol28060382 ◽

2021 ◽

Vol 28 (6) ◽

pp. 4504-4520

Author(s):

Ramon Handerson Gomes Teles ◽

Rafael Sussumu Yano ◽

Nicolas Jones Villarinho ◽

Ana Sayuri Yamagata ◽

Ruy Gastaldoni Jaeger ◽

...

Keyword(s):

Breast Cancer ◽

Drug Delivery ◽

Extracellular Vesicles ◽

Cell Communication ◽

Extracellular Vesicle ◽

Liquid Biopsies ◽

Research Production ◽

Cancer Management ◽

Breast Cancer Management

Extracellular vesicles transport variable content and have crucial functions in cell–cell communication. The role of extracellular vesicles in cancer is a current hot topic, and no bibliometric study has ever analyzed research production regarding their role in breast cancer and indicated the trends in the field. In this way, we aimed to investigate the trends in breast cancer management involved with extracellular vesicle research. Articles were retrieved from Scopus, including all the documents published concerning breast cancer and extracellular vesicles. We analyzed authors, journals, citations, affiliations, and keywords, besides other bibliometric analyses, using R Studio version 3.6.2. and VOSviewer version 1.6.0. A total of 1151 articles were retrieved, and as the main result, our analysis revealed trending topics on biomarkers of liquid biopsy, drug delivery, chemotherapy, autophagy, and microRNA. Additionally, research related to extracellular vesicles in breast cancer has been focused on diagnosis, treatment, and mechanisms of action of breast tumor-derived vesicles. Future studies are expected to explore the role of extracellular vesicles on autophagy and microRNA, besides investigating the application of extracellular vesicles from liquid biopsies for biomarkers and drug delivery, enabling the development and validation of therapeutic strategies for specific cancers.

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Small Extracellular Vesicles: A Novel Avenue for Cancer Management

Frontiers in Oncology ◽

10.3389/fonc.2021.638357 ◽

2021 ◽

Vol 11 ◽

Author(s):

Yanan Gao ◽

You Qin ◽

Chao Wan ◽

Yajie Sun ◽

Jingshu Meng ◽

...

Keyword(s):

Clinical Trials ◽

Extracellular Vesicles ◽

Anticancer Agents ◽

Early Stage ◽

Cell Types ◽

The United States ◽

Extracellular Vesicle ◽

Cancer Therapies ◽

Clinical Implementation ◽

Cancer Management

Extracellular vesicles are small membrane particles derived from various cell types. EVs are broadly classified as ectosomes or small extracellular vesicles, depending on their biogenesis and cargoes. Numerous studies have shown that EVs regulate multiple physiological and pathophysiological processes. The roles of small extracellular vesicles in cancer growth and metastasis remain to be fully elucidated. As endogenous products, small extracellular vesicles are an ideal drug delivery platform for anticancer agents. However, several aspects of small extracellular vesicle biology remain unclear, hindering the clinical implementation of small extracellular vesicles as biomarkers or anticancer agents. In this review, we summarize the utility of cancer-related small extracellular vesicles as biomarkers to detect early-stage cancers and predict treatment outcomes. We also review findings from preclinical and clinical studies of small extracellular vesicle-based cancer therapies and summarize interventional clinical trials registered in the United States Food and Drug Administration and the Chinese Clinical Trials Registry. Finally, we discuss the main challenges limiting the clinical implementation of small extracellular vesicles and recommend possible approaches to address these challenges.

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Signatures containing miR-133a identified by large scale miRNA profiling in bladder cancer

10.21203/rs.2.10628/v2 ◽

2019 ◽

Author(s):

Shuai Jiang ◽

Miaojun Zhu ◽

Zhuoyi Xiang ◽

Fengwu Zhang ◽

Jun Hou ◽

...

Keyword(s):

Bladder Cancer ◽

Mirna Expression ◽

Large Scale ◽

Training Group ◽

Support Vector ◽

Bladder Tissue ◽

Tissue Samples ◽

Mirna Profiling ◽

Normal Bladder ◽

Testing Group

Abstract Background: Identifying bladder cancer-specific miRNA expression signatures by large scale miRNA profiling Methods：30 bladder cancer (BC) tissue samples and matched adjacent normal bladder tissue samples from patients with BC were collected and were divided into two groups； a training group and a blind testing group. Expressions of 1900 miRNAs and controls were detected in a BC miRNA pool and in a normal miRNAs pool, respectively. 380 differential expressed miRNAs between the BC miRNA pool and the normal miRNA pool were selected. The primers for detecting the 380 selected miRNAs and controls were used to generate one 384-well panel. This panel was used to profile miRNA expression of each individual sample in the training group and in the blind testing group. Data analysis was performed using a machine learning approach of a support vector machine classifier with a Student's t-test feature selection procedure. Results： We identified signatures consisting of three or four miRNAs that could distinguish BC from normal controls with an accuracy of 100% in the training model and an accuracy of over 95% in the blind test. All identified signatures contain hsa-miR-133a. We also revealed that the miRNA183-96 cluster and the miR200 cluster are both significantly up-regulated in BC. Conclusions：The identified signatures containing hsa-miR-133a could be used as biomarkers in the diagnosis and prognosis of BC.

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