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Cell Biology in Urothelial Cancer
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Cell Biology in Urothelial Cancer

A special issue of Cells (ISSN 2073-4409). This special issue belongs to the section "Cellular Pathology".

Deadline for manuscript submissions: closed (31 January 2022) | Viewed by 18899

Special Issue Editor

Dr. Marcello Tucci

E-Mail Website
Guest Editor
Division of Medical Oncology, Cardinal Massaia Hospital, Department of Oncology, University of Turin, Corso Dante Alighieri 202, 14100 Asti, Italy
Interests: kidney; urothelial
Special Issues, Collections and Topics in MDPI journals

Special Issue Information

Dear Colleagues,

Recently a revolution in our understanding of heterogeneity, disease pathogenesis, and molecular features of urothelial carcinoma provides new opportunities for disease monitoring and personalized therapy. A so-called ‘two-pathway’ model has evolved. Urothelial carcinoma of the bladder comprises two disease entities with different clinical outcomes and molecular features: low-grade, non-muscle-invasive tumors that rarely progress to muscle-invasive disease and muscle-invasive tumors that frequently metastasize. The treatment landscape of bladder carcinoma remained unchanged until the approval of immune checkpoint inhibitors in metastatic disease. Unfortunately, a significant percentage of patients do not benefit from approved therapies. For this reason, there is a need to find biomarkers that may better select patients able to respond to a specific therapy. Recent genome sequencing studies identified genetic pathways that are key drivers of urothelial cancer and revealed a complex landscape with multiple molecular subclasses. Multiple studies reported molecular classifications of bladder cancers. These classifications have improved our knowledge of bladder cancer biology. Specific genomic alterations are enriched in specific molecular subtypes, including mutations in genes involved in receptor tyrosine kinase signaling, cell cycle regulation, chromatin remodeling. Several works have highlighted the clinical significance of molecular stratification of muscle-invasive bladder carcinoma, suggesting that responses to chemotherapy and immunotherapy are enriched in specific molecular subtypes and identifying specific targets that can be druggable with specific treatments. This Special Issue is focused on new horizons in the molecular evaluation of urothelial cancer.

We look forward to your contributions.

Dr. Marcello Tucci
Guest Editor

Manuscript Submission Information

Manuscripts should be submitted online at www.mdpi.com by registering and logging in to this website. Once you are registered, click here to go to the submission form. Manuscripts can be submitted until the deadline. All submissions that pass pre-check are peer-reviewed. Accepted papers will be published continuously in the journal (as soon as accepted) and will be listed together on the special issue website. Research articles, review articles as well as short communications are invited. For planned papers, a title and short abstract (about 100 words) can be sent to the Editorial Office for announcement on this website.

Submitted manuscripts should not have been published previously, nor be under consideration for publication elsewhere (except conference proceedings papers). All manuscripts are thoroughly refereed through a single-blind peer-review process. A guide for authors and other relevant information for submission of manuscripts is available on the Instructions for Authors page. Cells is an international peer-reviewed open access semimonthly journal published by MDPI.

Please visit the Instructions for Authors page before submitting a manuscript. The Article Processing Charge (APC) for publication in this open access journal is 2700 CHF (Swiss Francs). Submitted papers should be well formatted and use good English. Authors may use MDPI's English editing service prior to publication or during author revisions.

Published Papers (6 papers)

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Editorial

Jump to: Research, Review

9 pages, 280 KiB  
Editorial
Metastatic Urothelial Carcinoma: Have We Take the Road to the Personalized Medicine?
by Marco Audisio, Consuelo Buttigliero, Fabio Turco, Marco Donatello Delcuratolo, Chiara Pisano, Elena Parlagreco, Rosario Francesco Di Stefano, Lavinia Di Prima, Veronica Crespi, Giovanni Farinea, Massimiliano Cani and Marcello Tucci
Cells 2022, 11(10), 1614; https://doi.org/10.3390/cells11101614 - 11 May 2022
Cited by 2 | Viewed by 1806
Abstract
Urothelial cancer is a lethal malignancy characterized by a wide diffusion in Western countries due to a larger exposure to known risk factors, such as aromatic amines, tobacco smoke and benzene [...] Full article
(This article belongs to the Special Issue Cell Biology in Urothelial Cancer)

Research

Jump to: Editorial, Review

20 pages, 4698 KiB  
Article
Loss of Proximal Tubular Sirtuin 6 Aggravates Unilateral Ureteral Obstruction-Induced Tubulointerstitial Inflammation and Fibrosis by Regulation of β-Catenin Acetylation
by Jixiu Jin, Wenjia Li, Tian Wang, Byung-Hyun Park, Sung Kwang Park and Kyung Pyo Kang
Cells 2022, 11(9), 1477; https://doi.org/10.3390/cells11091477 - 27 Apr 2022
Cited by 14 | Viewed by 2650
Abstract
Renal fibrosis is a significant pathologic change associated with progressive kidney disease. Sirt6 is an NAD+-dependent deacetylase and mono-ADP ribosyltransferase known to play diverse roles in the processes attendant to aging, metabolism, and carcinogenesis. However, the role of proximal tubule-specific Sirt6 [...] Read more.
Renal fibrosis is a significant pathologic change associated with progressive kidney disease. Sirt6 is an NAD+-dependent deacetylase and mono-ADP ribosyltransferase known to play diverse roles in the processes attendant to aging, metabolism, and carcinogenesis. However, the role of proximal tubule-specific Sirt6 in renal fibrosis remains elusive. This study investigates the effect of proximal tubule-specific Sirt6 knockdown on unilateral ureteral obstruction (UUO)-induced renal tubulointerstitial inflammation and fibrosis. Renal fibrosis in wild type and PT-Sirt6KO (Sirt6flox/flox; Ggt1-Cre+) mice was induced by UUO surgery. After seven days, histologic examination and Western blot analysis were performed to examine extracellular matrix (ECM) protein expression. We evaluated inflammatory cytokine and cell adhesion molecule expression after ureteral obstruction. The therapeutic effect of Sirt6 activator MDL-800 on UUO-induced tubulointerstitial inflammation and fibrosis was assessed. The loss of Sirt6 in the proximal tubules aggravated UUO-induced tubular injury, ECM deposition, F4/80 positive macrophage infiltration, and proinflammatory cytokine and chemokine expression. Sirt6 activator MDL-800 mitigated UUO-induced renal tubulointerstitial inflammation and fibrosis. In an in vitro experiment, MDL-800 decreases the transforming growth factor (TGF)-β1-induced activation of myofibroblast and ECM production by regulating Sirt6-dependent β-catenin acetylation and the TGF-β1/Smad signaling pathway. In conclusion, proximal tubule Sirt6 may play an essential role in UUO-induced tubulointerstitial inflammation and fibrosis by regulating Sirt6-dependent β-catenin acetylation and ECM protein promoter transcription. Full article
(This article belongs to the Special Issue Cell Biology in Urothelial Cancer)
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22 pages, 4218 KiB  
Article
Determination of WWOX Function in Modulating Cellular Pathways Activated by AP-2α and AP-2γ Transcription Factors in Bladder Cancer
by Damian Kołat, Żaneta Kałuzińska, Andrzej K. Bednarek and Elżbieta Płuciennik
Cells 2022, 11(9), 1382; https://doi.org/10.3390/cells11091382 - 19 Apr 2022
Cited by 2 | Viewed by 2334
Abstract
Following the invention of high-throughput sequencing, cancer research focused on investigating disease-related alterations, often inadvertently omitting tumor heterogeneity. This research was intended to limit the impact of heterogeneity on conclusions related to WWOX/AP-2α/AP-2γ in bladder cancer which differently influenced carcinogenesis. The study examined [...] Read more.
Following the invention of high-throughput sequencing, cancer research focused on investigating disease-related alterations, often inadvertently omitting tumor heterogeneity. This research was intended to limit the impact of heterogeneity on conclusions related to WWOX/AP-2α/AP-2γ in bladder cancer which differently influenced carcinogenesis. The study examined the signaling pathways regulated by WWOX-dependent AP-2 targets in cell lines as biological replicates using high-throughput sequencing. RT-112, HT-1376 and CAL-29 cell lines were subjected to two stable lentiviral transductions. Following CAGE-seq and differential expression analysis, the most important genes were identified and functionally annotated. Western blot was performed to validate the selected observations. The role of genes in biological processes was assessed and networks were visualized. Ultimately, principal component analysis was performed. The studied genes were found to be implicated in MAPK, Wnt, Ras, PI3K-Akt or Rap1 signaling. Data from pathways were collected, explaining the differences/similarities between phenotypes. FGFR3, STAT6, EFNA1, GSK3B, PIK3CB and SOS1 were successfully validated at the protein level. Afterwards, a definitive network was built using 173 genes. Principal component analysis revealed that the various expression of these genes explains the phenotypes. In conclusion, the current study certified that the signaling pathways regulated by WWOX and AP-2α have more in common than that regulated by AP-2γ. This is because WWOX acts as an EMT inhibitor, AP-2γ as an EMT enhancer while AP-2α as a MET inducer. Therefore, the relevance of AP-2γ in targeted therapy is now more evident. Some of the differently regulated genes can find application in bladder cancer treatment. Full article
(This article belongs to the Special Issue Cell Biology in Urothelial Cancer)
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17 pages, 2570 KiB  
Article
Angiogenesis Driven by the CEBPD–hsa-miR-429–VEGFA Signaling Axis Promotes Urothelial Carcinoma Progression
by Ti-Chun Chan, Chung-Hsi Hsing, Yow-Ling Shiue, Steven K. Huang, Kun-Lin Hsieh, Yu-Hsuan Kuo and Chien-Feng Li
Cells 2022, 11(4), 638; https://doi.org/10.3390/cells11040638 - 11 Feb 2022
Cited by 10 | Viewed by 1830
Abstract
Background and Purpose: This research aimed to excavate the alternative mechanism of CEBPD on tumor growth and explore the biological significance of the CEBPD/hsa-miR-429/VEGFA axis on angiogenesis in urothelial carcinoma (UC). Methods: Quantitative RT-PCR, immunoblotting assay and tube formation examined the effect of [...] Read more.
Background and Purpose: This research aimed to excavate the alternative mechanism of CEBPD on tumor growth and explore the biological significance of the CEBPD/hsa-miR-429/VEGFA axis on angiogenesis in urothelial carcinoma (UC). Methods: Quantitative RT-PCR, immunoblotting assay and tube formation examined the effect of hsa-miR-429 mimic or/and inhibitor on VEGFA expression and angiogenesis in CEBPD-overexpressing UC-derived cells. The association between CEBPD, hsa-miR-429, VEGFA and microvascular density (MVD) and clinical outcome were evaluated in 296 patients with UBUC and 340 patients with UTUC, respectively. Results: The increase in the transcript and protein of VEGFA as well as HUVECs tube formation was diminished upon the treatment of hsa-miR-429 mimic in CEBPD-overexpressing BFTC909 and TCCSUP. Nevertheless, the inhibited regulation of hsa-miR-429 mimic on the expression of VEGFA and ability of HUVECs tube formation was rescued by the combined incubation with hsa-miR-429 inhibitor in these two UC-derived cell lines. Furthermore, the clinical correlations showed that the higher level of VEGFA or MVD has a positive correlation with the expression of CEBPD and a negative relation to hsa-miR-429 and leads to tumor aggressiveness with worse disease-specific, metastasis-free survival in UBUC and UTUC cohorts. Conclusions: We decipher the oncogenic mechanism of CEBPD on angiogenesis through the hsa-miR-429 inhibition to stabilize the expression of VEGFA in UC. The novel research unveiled the modulation of the CEBPD/hsa-miR-429/VEGFA axis on the progression of UC and could be accessible to theranostic biomarkers. Full article
(This article belongs to the Special Issue Cell Biology in Urothelial Cancer)
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Review

Jump to: Editorial, Research

20 pages, 1080 KiB  
Review
Antibody-Drug Conjugates in Urothelial Carcinoma: A New Therapeutic Opportunity Moves from Bench to Bedside
by Antonio Ungaro, Marcello Tucci, Alessandro Audisio, Lavinia Di Prima, Chiara Pisano, Fabio Turco, Marco Donatello Delcuratolo, Massimo Di Maio, Giorgio Vittorio Scagliotti and Consuelo Buttigliero
Cells 2022, 11(5), 803; https://doi.org/10.3390/cells11050803 - 25 Feb 2022
Cited by 19 | Viewed by 5714
Abstract
Significant progress has been achieved over the last decades in understanding the biology and mechanisms of tumor progression in urothelial carcinoma (UC). Although the therapeutic landscape has dramatically changed in recent years with the introduction of immune checkpoint inhibitors, advanced UC is still [...] Read more.
Significant progress has been achieved over the last decades in understanding the biology and mechanisms of tumor progression in urothelial carcinoma (UC). Although the therapeutic landscape has dramatically changed in recent years with the introduction of immune checkpoint inhibitors, advanced UC is still associated with rapidly progressing disease and poor survival. The increasing knowledge of the pathogenesis and molecular pathways underlying cancer development and progression is leading the introduction of target therapies, such as the recently approved FGFR inhibitor Erdafitinib, or the anti-nectin 4 antibody drug-conjugate Enfortumab vedotin. Antibody drug conjugates represent an innovative therapeutic approach that allows the combination of a tar get-specific monoclonal antibody covalently conjugated via a linker to a cytotoxic agent (payload). UC is a perfect candidate for this therapeutic approach since it is particularly enriched in antigen expression on its surface and each specific antigen can represent a potential therapeutic target. In this review we summarize the mechanism of action of ADCs, their applications in localized and metastatic UC, the main mechanisms of resistance, and future perspectives for their use in clinical practice. Full article
(This article belongs to the Special Issue Cell Biology in Urothelial Cancer)
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16 pages, 963 KiB  
Review
New Perspectives in the Medical Treatment of Non-Muscle-Invasive Bladder Cancer: Immune Checkpoint Inhibitors and Beyond
by Alessandro Audisio, Consuelo Buttigliero, Marco Donatello Delcuratolo, Elena Parlagreco, Marco Audisio, Antonio Ungaro, Rosario Francesco Di Stefano, Lavinia Di Prima, Fabio Turco and Marcello Tucci
Cells 2022, 11(3), 357; https://doi.org/10.3390/cells11030357 - 21 Jan 2022
Cited by 16 | Viewed by 3909
Abstract
Non-muscle-invasive bladder cancer (NMIBC) is characterized by a high rate of cure, but also by a non-negligible probability of recurrence and risk progression to muscle-invasive disease. NMIBC management requires a proper local resection and staging, followed by a risk-based treatment with intravesical agents. [...] Read more.
Non-muscle-invasive bladder cancer (NMIBC) is characterized by a high rate of cure, but also by a non-negligible probability of recurrence and risk progression to muscle-invasive disease. NMIBC management requires a proper local resection and staging, followed by a risk-based treatment with intravesical agents. For many years, the current gold standard treatment for patients with intermediate or high-risk disease is transurethral resection of the bladder (TURB) followed by intravesical bacillus Calmette–Guérin (BCG) instillations. Unfortunately, in about half of high-risk patients, intravesical BCG treatment fails and NMIBC persists or recurs early. While radical cystectomy remains the gold standard for these patients, new therapeutic targets are being individuated and studied. Radical cystectomy in fact can provide an excellent long-term disease control, but can deeply interfere with quality of life. In particular, the enhanced immune checkpoints expression shown in BCG-unresponsive patients and the activity of immune checkpoints inhibitors (ICIs) in advanced bladder cancer provided the rationale for testing ICIs in NMIBC. Recently, pembrolizumab has shown promising activity in BCG-unresponsive NMIBC patients, obtaining FDA approval. Meanwhile multiple novel drugs with alternative mechanisms of action have proven to be safe and effective in NMIBC treatment and others are under investigation. The aim of this review is to analyse and describe the clinical activity of new emerging drugs in BCG-unresponsive NMIBC focusing on immunotherapy results. Full article
(This article belongs to the Special Issue Cell Biology in Urothelial Cancer)
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