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Biomarker-Oriented Treatment of Urogenital Cancers

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A special issue of International Journal of Molecular Sciences (ISSN 1422-0067). This special issue belongs to the section "Molecular Pathology, Diagnostics, and Therapeutics".

Deadline for manuscript submissions: closed (30 June 2021) | Viewed by 23729

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Dr. Francesca Sanguedolce

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Department of Pathology, University Hospital, Viale Pinto 1, 71121 Foggia, Italy
Interests: genitourinary pathology; diagnostic biomarkers; prognostic/predictive biomarkers; digital pathology; emolymphopathology; bladder cancer; prostate cancer
Special Issues, Collections and Topics in MDPI journals

Prof. Dr. Luigi Cormio

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Urology and Andrology Unit, Andria Teaching Hospital, University of Foggia, Foggia, Italy
Interests: urology; urogenital diseases; surgery
Special Issues, Collections and Topics in MDPI journals

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Dear Colleagues,

Tumors of the kidney, bladder, and prostate are a major health concern. In recent decades, great effort has been done to identify biomarkers that may increase our diagnostic ability at the early stage of disease or that can provide a better risk stratification, thus allowing to predict response to currently available treatment options.

This issue aims to provide readers with currently available and possible novel information on: (1) biomarkers that have shown to predict response to available treatment options; (2) predictive models based on biomarkers or integrating biomarkers with standard clinical and pathological factors; and (3) biomarkers that may represent novel therapeutic targets.

All the above-mentioned subjects contribute to the implementation of the so-called precision medicine approach, which is what patients affected by such diseases are really looking for.

Prof. Dr. Francesca Sanguedolce
Prof. Dr. Luigi Cormio
Guest Editors

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. International Journal of Molecular Sciences is an international peer-reviewed open access semimonthly journal published by MDPI.

Please visit the Instructions for Authors page before submitting a manuscript. There is an Article Processing Charge (APC) for publication in this open access journal. For details about the APC please see here. 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.

Keywords

Bladder cancer
Prostate cancer
Kidney cancer
Biomarker
Target therapy

Published Papers (6 papers)

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Research

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12 pages, 3649 KiB

Open AccessArticle

High Stroma T-Cell Infiltration is Associated with Better Survival in Stage pT1 Bladder Cancer

by Sabine Hülsen, Eleonora Lippolis, Fulvia Ferrazzi, Wolfgang Otto, Luitpold Distel, Rainer Fietkau, Stefan Denzinger, Johannes Breyer, Maximilian Burger, Simone Bertz, Markus Eckstein, Annette Ebner, Arndt Hartmann and Carol-I. Geppert

Int. J. Mol. Sci. 2020, 21(21), 8407; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms21218407 - 09 Nov 2020

Cited by 14 | Viewed by 2283

Abstract

Stage pT1 bladder cancer (BC) shows highly diverse outcomes. Predictive markers are required to stratify patients for personalized treatment. The present study aimed to validate immune response quantification as a prognostic marker. Patients with pT1 BC (n = 167) treated by transurethral resection of the bladder (TURB) were enrolled. Formaldehyde-fixed paraffin-embedded material was stained for CD3 and CD8. Corresponding T cells were counted in three regions with the highest immune response. Numbers of tertiary lymphoid structures (TLS) and lymphocyte aggregates (LA) were quantified. High CD3⁺ stroma T-cell infiltration was associated with improved survival (p = 0.045), especially in the G3 subgroup (p = 0.01). Cluster with higher immune response showed less recurrence (p = 0.034) and favorable overall survival (OS) (p = 0.019). In contrast, higher CD3⁺ and CD8⁺ tumor T-cell infiltration seemed to have a negative impact on prognosis. TLS and LA were more frequently observed in G3 tumors, indicating an increased anti-tumoral immune response. We proved the role of immune cell infiltration and showed that higher infiltration numbers of CD3⁺ (not CD8⁺) lymphocytes in the stroma are associated with favorable outcome. Immune cell quantification could be used as a marker to help stratify patients’ risk and therefore, to optimize patients’ management and follow-up examination as well as possible therapies. Full article

(This article belongs to the Special Issue Biomarker-Oriented Treatment of Urogenital Cancers)

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13 pages, 1740 KiB

Open AccessArticle

Expression of Nectin-4 and PD-L1 in Upper Tract Urothelial Carcinoma

by Eisuke Tomiyama, Kazutoshi Fujita, Maria Del Carmen Rodriguez Pena, Diana Taheri, Eri Banno, Taigo Kato, Koji Hatano, Atsunari Kawashima, Takeshi Ujike, Motohide Uemura, Tetsuya Takao, Seiji Yamaguchi, Hiroaki Fushimi, Kazuhiro Yoshimura, Hirotsugu Uemura, George J. Netto and Norio Nonomura

Int. J. Mol. Sci. 2020, 21(15), 5390; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms21155390 - 29 Jul 2020

Cited by 48 | Viewed by 3963

Abstract

Enfortumab vedotin is a novel antibody–drug conjugate targeting Nectin-4, which is highly expressed in urothelial carcinoma. However, the expression status of Nectin-4 in upper tract urothelial carcinoma (UTUC) remains unclear. The relationship between Nectin-4 and Programmed Death Ligand 1 (PD-L1) in UTUC is also ambiguous. We performed immunohistochemical analysis of 99 UTUC tissue microarray to assess the expression of Nectin-4 and PD-L1 in UTUC. Nectin-4-positivity was detected in 65 (65.7%) samples, and PD-L1 was detected in 24 (24.2%) samples. There was no correlation between the expression of Nectin-4 and PD-L1. Patients with strong Nectin-4-expressing tumors had a significantly higher risk of progression (p = 0.031) and cancer-specific mortality (p = 0.036). Strong Nectin-4 expression was also an independent predictor of disease progression in the high-risk group (pT3 ≤ or presence of lymphovascular invasion or lymph node metastasis) (Hazard ratio, 3.32 [95% confidence interval, 1.20–7.98; p = 0.027]). In conclusion, we demonstrated that Nectin-4 expression rate in UTUC was 65.7% and independent of PD-L1 expression. Strong Nectin-4 expression was associated with worse progression-free survival in high-risk UTUC. These findings suggested that enfortumab vedotin may be effective in a broad range of patients with UTUC, regardless of PD-L1 expression. Full article

(This article belongs to the Special Issue Biomarker-Oriented Treatment of Urogenital Cancers)

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Review

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32 pages, 2711 KiB

Open AccessReview

What Do We Have to Know about PD-L1 Expression in Prostate Cancer? A Systematic Literature Review. Part 3: PD-L1, Intracellular Signaling Pathways and Tumor Microenvironment

by Andrea Palicelli, Stefania Croci, Alessandra Bisagni, Eleonora Zanetti, Dario De Biase, Beatrice Melli, Francesca Sanguedolce, Moira Ragazzi, Magda Zanelli, Alcides Chaux, Sofia Cañete-Portillo, Maria Paola Bonasoni, Alessandra Soriano, Stefano Ascani, Maurizio Zizzo, Carolina Castro Ruiz, Antonio De Leo, Guido Giordano, Matteo Landriscina, Giuseppe Carrieri, Luigi Cormio, Daniel M. Berney, Jatin Gandhi, Valerio Copelli, Giuditta Bernardelli, Giacomo Santandrea and Martina Bonacini Show full author list Hide full author list

Int. J. Mol. Sci. 2021, 22(22), 12330; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms222212330 - 15 Nov 2021

Cited by 17 | Viewed by 5449

Abstract

The tumor microenvironment (TME) includes immune (T, B, NK, dendritic), stromal, mesenchymal, endothelial, adipocytic cells, extracellular matrix, and cytokines/chemokines/soluble factors regulating various intracellular signaling pathways (ISP) in tumor cells. TME influences the survival/progression of prostate cancer (PC), enabling tumor cell immune-evasion also through the activation of the PD-1/PD-L1 axis. We have performed a systematic literature review according to the PRISMA guidelines, to investigate how the PD-1/PD-L1 pathway is influenced by TME and ISPs. Tumor immune-escape mechanisms include suppression/exhaustion of tumor infiltrating cytotoxic T lymphocytes, inhibition of tumor suppressive NK cells, increase in immune-suppressive immune cells (regulatory T, M2 macrophagic, myeloid-derived suppressor, dendritic, stromal, and adipocytic cells). IFN-γ (the most investigated factor), TGF-β, TNF-α, IL-6, IL-17, IL-15, IL-27, complement factor C5a, and other soluble molecules secreted by TME components (and sometimes increased in patients’ serum), as well as and hypoxia, influenced the regulation of PD-L1. Experimental studies using human and mouse PC cell lines (derived from either androgen-sensitive or androgen-resistant tumors) revealed that the intracellular ERK/MEK, Akt-mTOR, NF-kB, WNT and JAK/STAT pathways were involved in PD-L1 upregulation in PC. Blocking the PD-1/PD-L1 signaling by using immunotherapy drugs can prevent tumor immune-escape, increasing the anti-tumor activity of immune cells. Full article

(This article belongs to the Special Issue Biomarker-Oriented Treatment of Urogenital Cancers)

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25 pages, 586 KiB

Open AccessReview

What Do We Have to Know about PD-L1 Expression in Prostate Cancer? A Systematic Literature Review. Part 5: Epigenetic Regulation of PD-L1

by Andrea Palicelli, Stefania Croci, Alessandra Bisagni, Eleonora Zanetti, Dario De Biase, Beatrice Melli, Francesca Sanguedolce, Moira Ragazzi, Magda Zanelli, Alcides Chaux, Sofia Cañete-Portillo, Maria Paola Bonasoni, Alessandra Soriano, Stefano Ascani, Maurizio Zizzo, Carolina Castro Ruiz, Antonio De Leo, Guido Giordano, Matteo Landriscina, Giuseppe Carrieri, Luigi Cormio, Daniel M. Berney, Jatin Gandhi, Davide Nicoli, Enrico Farnetti, Giacomo Santandrea and Martina Bonacini Show full author list Hide full author list

Int. J. Mol. Sci. 2021, 22(22), 12314; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms222212314 - 15 Nov 2021

Cited by 8 | Viewed by 3234

Abstract

Epigenetic alterations (including DNA methylation or miRNAs) influence oncogene/oncosuppressor gene expression without changing the DNA sequence. Prostate cancer (PC) displays a complex genetic and epigenetic regulation of cell-growth pathways and tumor progression. We performed a systematic literature review (following PRISMA guidelines) focused on the epigenetic regulation of PD-L1 expression in PC. In PC cell lines, CpG island methylation of the CD274 promoter negatively regulated PD-L1 expression. Histone modifiers also influence the PD-L1 transcription rate: the deletion or silencing of the histone modifiers MLL3/MML1 can positively regulate PD-L1 expression. Epigenetic drugs (EDs) may be promising in reprogramming tumor cells, reversing epigenetic modifications, and cancer immune evasion. EDs promoting a chromatin-inactive transcriptional state (such as bromodomain or p300/CBP inhibitors) downregulated PD-L1, while EDs favoring a chromatin-active state (i.e., histone deacetylase inhibitors) increased PD-L1 expression. miRNAs can regulate PD-L1 at a post-transcriptional level. miR-195/miR-16 were negatively associated with PD-L1 expression and positively correlated to longer biochemical recurrence-free survival; they also enhanced the radiotherapy efficacy in PC cell lines. miR-197 and miR-200a-c positively correlated to PD-L1 mRNA levels and inversely correlated to the methylation of PD-L1 promoter in a large series. miR-570, miR-34a and miR-513 may also be involved in epigenetic regulation. Full article

(This article belongs to the Special Issue Biomarker-Oriented Treatment of Urogenital Cancers)

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31 pages, 2356 KiB

Open AccessReview

What Do We Have to Know about PD-L1 Expression in Prostate Cancer? A Systematic Literature Review. Part 4: Experimental Treatments in Pre-Clinical Studies (Cell Lines and Mouse Models)

by Andrea Palicelli, Stefania Croci, Alessandra Bisagni, Eleonora Zanetti, Dario De Biase, Beatrice Melli, Francesca Sanguedolce, Moira Ragazzi, Magda Zanelli, Alcides Chaux, Sofia Cañete-Portillo, Maria Paola Bonasoni, Alessandra Soriano, Stefano Ascani, Maurizio Zizzo, Carolina Castro Ruiz, Antonio De Leo, Guido Giordano, Matteo Landriscina, Giuseppe Carrieri, Luigi Cormio, Daniel M. Berney, Jatin Gandhi, Giacomo Santandrea and Martina Bonacini Show full author list Hide full author list

Int. J. Mol. Sci. 2021, 22(22), 12297; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms222212297 - 14 Nov 2021

Cited by 8 | Viewed by 4173

Abstract

In prostate cancer (PC), the PD-1/PD-L1 axis regulates various signaling pathways and it is influenced by extracellular factors. Pre-clinical experimental studies investigating the effects of various treatments (alone or combined) may discover how to overcome the immunotherapy-resistance in PC-patients. We performed a systematic literature review (PRISMA guidelines) to delineate the landscape of pre-clinical studies (including cell lines and mouse models) that tested treatments with effects on PD-L1 signaling in PC. NF-kB, MEK, JAK, or STAT inhibitors on human/mouse, primary/metastatic PC-cell lines variably down-modulated PD-L1-expression, reducing chemoresistance and tumor cell migration. If PC-cells were co-cultured with NK, CD8+ T-cells or CAR-T cells, the immune cell cytotoxicity increased when PD-L1 was downregulated (opposite effects for PD-L1 upregulation). In mouse models, radiotherapy, CDK4/6-inhibitors, and RB deletion induced PD-L1-upregulation, causing PC-immune-evasion. Epigenetic drugs may reduce PD-L1 expression. In some PC experimental models, blocking only the PD-1/PD-L1 pathway had limited efficacy in reducing the tumor growth. Anti-tumor effects could be increased by combining the PD-1/PD-L1 blockade with other approaches (inhibitors of tyrosine kinase, PI3K/mTOR or JAK/STAT3 pathways, p300/CBP; anti-RANKL and/or anti-CTLA-4 antibodies; cytokines; nitroxoline; DNA/cell vaccines; radiotherapy/Radium-223). Full article

(This article belongs to the Special Issue Biomarker-Oriented Treatment of Urogenital Cancers)

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18 pages, 350 KiB

Open AccessReview

Biomarker-Oriented Therapy in Bladder and Renal Cancer

by Mathijs P. Scholtes, Arnout R. Alberts, Iris G. Iflé, Paul C. M. S. Verhagen, Astrid A. M. van der Veldt and Tahlita C. M. Zuiverloon

Int. J. Mol. Sci. 2021, 22(6), 2832; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms22062832 - 11 Mar 2021

Cited by 20 | Viewed by 3858

Abstract

Treatment of patients with urothelial carcinoma (UC) of the bladder or renal cancer has changed significantly during recent years and efforts towards biomarker-directed therapy are being investigated. Immune checkpoint inhibition (ICI) or fibroblast growth factor receptor (FGFR) directed therapy are being evaluated for non-muscle invasive bladder cancer (NMIBC) patients, as well as muscle-invasive bladder cancer (MIBC) patients. Meanwhile, efforts to predict tumor response to neoadjuvant chemotherapy (NAC) are still ongoing, and genomic biomarkers are being evaluated in prospective clinical trials. Currently, patients with metastatic UC (mUC) are usually treated with second-line ICI, while cisplatin-ineligible patients with programmed death-ligand 1 (PD-L1) positive tumors can benefit from first-line ICI. Platinum-relapsed UC patients harboring FGFR2/3 mutations can be treated with erdafitinib, while enfortumab vedotin has emerged as a novel third-line treatment option for mUC. In metastatic (clear cell) renal cell carcinoma (RCC), ICI was first introduced as second-line treatment after vascular endothelial growth factor receptor—tyrosine kinase inhibition (VEGFR-TKI). Currently, ICIs have also been introduced as first-line treatment in metastatic RCC. Although there is no evidence up to now for beneficial adjuvant treatment after surgery with VEGFR-TKIs in high-risk non-metastatic RCC, several trials are underway investigating the potential beneficial effect of ICIs in this setting. Full article

(This article belongs to the Special Issue Biomarker-Oriented Treatment of Urogenital Cancers)

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