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Molecular Mechanisms of Tumor Progression and New Therapeutic Strategies for Urological Cancers, 2nd Edition

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A special issue of International Journal of Molecular Sciences (ISSN 1422-0067). This special issue belongs to the section "Molecular Oncology".

Deadline for manuscript submissions: closed (20 April 2025) | Viewed by 11540

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Special Issue Editors

Dr. Vicenç Ruiz de Porras

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Guest Editor

1. Catalan Institute of Oncology, Badalona Applied Research Group in Oncology (B·ARGO), Ctra. Can Ruti-Camí de les Escoles s/n, 08916 Badalona, Spain
2. Germans Trias i Pujol Research Institute (IGTP), Ctra. Can Ruti-Camí de les escoles s/n, 08916 Badalona, Spain
Interests: metastatic prostate cancer; bladder cancer; therapy resistance; chemotherapy; predictive biomarkers
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Dr. Albert Font

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Guest Editor

Badalona–Badalona Applied Research Group in Oncology (B·ARGO), Catalan Institute of Oncology, 08916 Badalona, Spain
Interests: genitourinary tumors
Special Issues, Collections and Topics in MDPI journals

Special Issue Information

Dear Colleagues,

Urological tumors comprise bladder, prostate, renal, upper urinary tract, and germ-cell tumors, among others. The incidence of urological tumors has increased significantly over the past 40 years. In fact, all of them rank in the top ten list of human cancers and account for up to 33% of malignancies affecting the male population. Their different pathogenetic mechanisms and their varied diagnostic and therapeutic approaches represent a challenge in clinical practice. Thus, treatment for urologic cancers depends on several factors, such as the tumor’s grade and stage. Common options include surgery, chemotherapy, and radiation therapy.

However, although the therapeutic landscape of urological tumors has significantly improved in recent years with the incorporation of new treatment options such as immunotherapy and target therapies, understanding the molecular mechanisms of tumor progression and therapy resistance will help us to develop novel treatment strategies and predict drug response toward precision medicine.

This Special Issue of the International Journal of Molecular Sciences therefore encompasses original and review articles on the molecular mechanisms leading to tumor progression and resistance to current treatment options, new therapeutic strategies, as well as new prognostic and predictive biomarkers for urological tumors.

More published papers could be found in the closed Special Issue: Molecular Mechanisms of Tumor Progression and New Therapeutic Strategies for Urological Cancers.

Dr. Vicenç Ruiz de Porras
Dr. Albert Font Pous
Guest Editors

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Keywords

prostate cancer
bladder cancer
renal cell carcinoma
upper urinary tract tumors
testicular cancer
predictive and prognostic biomarkers
tumor progression
novel treatment strategies
chemotherapy
immunotherapy
target therapies
drug resistance mechanisms
tumor microenvironment
precision medicine

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Published Papers (7 papers)

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Research

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19 pages, 2526 KiB

Open AccessArticle

Cellular and Molecular Evidence of the Synergistic Antitumour Effects of Hydroxytyrosol and Metformin in Prostate Cancer

by Francisco Porcel-Pastrana, Antonio J. Montero-Hidalgo, Miguel E. G-García, Ignacio Gil-Duque, Antonio Prats-Escribano, Manuel D. Gahete, André Sarmento-Cabral, Raúl M. Luque and Antonio J. León-González

Int. J. Mol. Sci. 2025, 26(3), 1341; https://doi.org/10.3390/ijms26031341 - 5 Feb 2025

Cited by 1 | Viewed by 856

Abstract

Prostate cancer (PCa) is the tumour pathology with the second highest incidence among men worldwide. PCa is strongly influenced by obesity (OB), which increases its aggressiveness. Hence, some metabolic drugs like metformin have emerged as potential anti-tumour agents against several endocrine-related cancers. Likewise, a high adherence to the Mediterranean diet has been associated with lower rates of OB and a reduction in PCa aggressiveness since this diet contains phenolic bioactive compounds such as hydroxytyrosol (HT) that is mainly present in extra virgin olive oil. Thus, we decided to analyse the therapeutic potential of the combination of HT + metformin in different PCa cell models. Specifically, combinations of different doses of HT and metformin were evaluated by analysing the proliferation rate of LNCaP, 22Rv1, DU-145, and PC−3 cells using the SynergicFinder method. The results revealed a synergistic effect of HT + metformin in significantly reducing proliferation, especially in LNCaP cells. This anti-tumour effect of HT + metformin was also confirmed in migration and tumoursphere formation assays in LNCaP. The effects on the cell cycle and apoptosis were also assessed by flow-cytometry, and a cycle arrest in the G1 phase and an increase in late apoptosis were observed with the combination of HT + metformin. The phosphorylation levels of critical components of different oncogenic pathways were measured which revealed that the combination of HT + metformin significantly reduced the activity of multiple components of the MAPK, AKT, and TGF-β pathways. Overall, the combination of HT + metformin might represent a new therapeutic avenue for the management of PCa patients, an observation that certainly warrants further investigation through a well-designed clinical trial. Full article

(This article belongs to the Special Issue Molecular Mechanisms of Tumor Progression and New Therapeutic Strategies for Urological Cancers, 2nd Edition)

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11 pages, 1349 KiB

Open AccessArticle

MMP-14 Exhibits Greater Expression, Content and Activity Compared to MMP-15 in Human Renal Carcinoma

by Grzegorz Młynarczyk, Anna Tokarzewicz, Monika Gudowska-Sawczuk, Barbara Mroczko, Vojtěch Novák, Adam Novák, Przemysław Mitura and Lech Romanowicz

Int. J. Mol. Sci. 2024, 25(15), 8107; https://doi.org/10.3390/ijms25158107 - 25 Jul 2024

Cited by 2 | Viewed by 1136

Abstract

Membrane-type metalloproteinases (including MMP-14 and MMP-15) are enzymes involved in the degradation of extracellular matrix components. In cancer, they are involved in processes such as cellular invasion, angiogenesis and metastasis. Therefore, the aim of this study was to evaluate the expression, content and activity of MMP-14 and MMP-15 in human renal cell carcinoma. Samples of healthy kidney tissue (n = 20) and tissue from clear-cell kidney cancer (n = 20) were examined. The presence and contents of the MMPs were assessed using Western blot and ELISA techniques, respectively. Their activity—both actual and specific—was evaluated using fluorimetric analysis. Both control and cancer human kidney tissues contain MMP-14 and MMP-15 enzymes in the form of high-molecular-weight complexes. Moreover, these enzymes occur in both active and latent forms. Their content in cancer tissues is very similar, but with a noteworthy decrease in content with an increase in the kidney cancer grade for both membrane-type metalloproteinases. Even more notable is the highest content of the investigated enzymes represented by MMP-14 in the control tissues. Considering the actual and specific activity outcomes, MMP-14 dominates over MMP-15 in all of the investigated tissues. Nevertheless, we also noted a significant enhancement of the activity of both metalloproteinases with an increase in the grade of renal cancer. The expression and activity of both enzymes were detected in all examined renal cancer tissues. However, our findings suggest that transmembrane metalloproteinase 14 (MMP-14) plays a much more significant and essential role than MMP-15 in the studied renal carcinoma tissues. Therefore, it seems that MMP-14 could be a promising target in the diagnosis, prognosis and therapy of renal cell carcinoma. Full article

(This article belongs to the Special Issue Molecular Mechanisms of Tumor Progression and New Therapeutic Strategies for Urological Cancers, 2nd Edition)

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13 pages, 2432 KiB

Open AccessArticle

Interleukin-1β/Interleukin (IL)-1-Receptor-Antagonist (IL1-RA) Axis in Invasive Bladder Cancer—An Exploratory Analysis of Clinical and Tumor Biological Significance

by Marko Vukovic, Jorge M. Chamlati, Jörg Hennenlotter, Tilman Todenhöfer, Thomas Lütfrenk, Sebastian Jersinovic, Igor Tsaur, Arnulf Stenzl and Steffen Rausch

Int. J. Mol. Sci. 2024, 25(4), 2447; https://doi.org/10.3390/ijms25042447 - 19 Feb 2024

Cited by 1 | Viewed by 2185

Abstract

Previous data indicate a role of IL-1 and IL-1RA imbalance in bladder carcinoma (BC); the inhibition of IL-1 signaling might be considered a treatment option. Objective: To assess expression patterns and the prognostic role of IL-1β and IL-1RA in invasive BC and to evaluate their interaction with AKT signaling and proliferation. The study included two independent cohorts of n = 92 and n = 102 patients who underwent a radical cystectomy for BC. Specimen from BC and benign urothelium (n = 22 and n = 39) were processed to a tissue microarray and immunohistochemically stained for IL-1β, IL-1RA, AKT, and Ki-67. Expression scores were correlated to clinical variables and Ki-67 and AKT expression. An association with outcome was assessed using Wilcoxon Kruskal–Wallis tests, Chi-square tests or linear regression, dependent on the variable’s category. Kaplan–Meier and Cox proportional hazard analyses were used to estimate recurrence-free (RFS), cancer-specific (CSS) and overall survival (OS). Both IL-1β and IL-1RA were significantly overexpressed in invasive BC compared to benign urothelium in both cohorts (p < 0.005). IL-1β was associated with vascular invasion (210 vs. 183, p < 0.02), lymphatic invasion (210 vs. 180, <0.05) and G3 cancer (192 vs. 188, <0.04). The survival analysis revealed favorable RFS, CSS, and OS in the case of high IL-1β expression (p < 0.02, <0.03, and <0.006, respectively). Multivariate analyses revealed an independent impact of (low) IL1β expression on RFS, CSS, and OS. The IL-1β and IL-1β/IL-1RA ratios were positively correlated to the AKT expression (p < 0.05 and <0.01, respectively). Additionally, the high expression of Ki-67 (>15%) correlated with higher levels of IL-1β (p = 0.01). The overexpression of IL-1β and IL-1RA is frequently found in BC, with a prognostic significance observed for the IL-1β protein expression. The observed link between the IL-1β/IL-1RA axis and AKT signaling may indicate possible autophagy activation processes besides the known tumor-promoting effects of AKT. Full article

(This article belongs to the Special Issue Molecular Mechanisms of Tumor Progression and New Therapeutic Strategies for Urological Cancers, 2nd Edition)

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10 pages, 915 KiB

Open AccessCommunication

Tumor-Agnostic Circulating Tumor DNA Testing for Monitoring Muscle-Invasive Bladder Cancer

by Raquel Carrasco, Mercedes Ingelmo-Torres, Ramón Trullas, Fiorella L. Roldán, Leonardo Rodríguez-Carunchio, Lourdes Juez, Joan Sureda, Antonio Alcaraz, Lourdes Mengual and Laura Izquierdo

Int. J. Mol. Sci. 2023, 24(23), 16578; https://doi.org/10.3390/ijms242316578 - 21 Nov 2023

Cited by 10 | Viewed by 1974

Abstract

Circulating tumor DNA (ctDNA) has recently emerged as a real-time prognostic and predictive biomarker for monitoring cancer patients. Here, we aimed to ascertain whether tumor-agnostic ctDNA testing would be a feasible strategy to monitor disease progression and therapeutic response in muscle-invasive bladder cancer (MIBC) patients after radical cystectomy (RC). Forty-two MIBC patients who underwent RC were prospectively included. Blood samples from these patients were collected at different follow-up time points. Two specific mutations (TERT c.1-124C>T and ATM c.1236-2A>T) were analyzed in the patients’ plasma samples by droplet digital PCR to determine their ctDNA status. During a median follow-up of 21 months, 24% of patients progressed in a median of six months. ctDNA status was identified as a prognostic biomarker of tumor progression before RC and 4 and 12 months later (HR 6.774, HR 3.673, and HR 30.865, respectively; p < 0.05). Lastly, dynamic changes in ctDNA status between baseline and four months later were significantly associated with patient outcomes (p = 0.045). In conclusion, longitudinal ctDNA analysis using a tumor-agnostic approach is a potential tool for monitoring MIBC patients after RC. The implementation of this testing in a clinical setting could improve disease management and patients’ outcomes. Full article

(This article belongs to the Special Issue Molecular Mechanisms of Tumor Progression and New Therapeutic Strategies for Urological Cancers, 2nd Edition)

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12 pages, 2879 KiB

Open AccessArticle

GABBR2 as a Downstream Effector of the Androgen Receptor Induces Cisplatin Resistance in Bladder Cancer

by Mohammad Amin Elahi Najafi, Masato Yasui, Yuki Teramoto, Tomoyuki Tatenuma, Guiyang Jiang and Hiroshi Miyamoto

Int. J. Mol. Sci. 2023, 24(18), 13733; https://doi.org/10.3390/ijms241813733 - 6 Sep 2023

Cited by 5 | Viewed by 1834

Abstract

The precise molecular mechanisms responsible for resistance to cisplatin-based chemotherapy in patients with bladder cancer remain elusive, while we have indicated that androgen receptor (AR) activity in urothelial cancer is associated with its sensitivity. Our DNA microarray analysis in control vs. AR-knockdown bladder cancer sublines suggested that the expression of a GABA B receptor GABBR2 and AR was correlated. The present study aimed to determine the functional role of GABBR2 in modulating cisplatin sensitivity in bladder cancer. AR knockdown and dihydrotestosterone treatment considerably reduced and induced, respectively, GABBR2 expression, and the effect of dihydrotestosterone was at least partially restored by an antiandrogen hydroxyflutamide. A chromatin immunoprecipitation assay further revealed the binding of AR to the promoter region of GABBR2 in bladder cancer cells. Meanwhile, GABBR2 expression was significantly elevated in a cisplatin-resistant bladder cancer subline, compared with control cells. In AR-positive bladder cancer cells, knockdown of GABBR2 or treatment with a selective GABA B receptor antagonist, CGP46381, considerably enhanced the cytotoxic activity of cisplatin. However, no additional effect of CGP46381 on cisplatin-induced growth suppression was seen in GABBR2-knockdown cells. Moreover, in the absence of cisplatin, CGP46381 treatment and GABBR2 knockdown showed no significant changes in cell proliferation or migration. These findings suggest that GABBR2 represents a key downstream effector of AR signaling in inducing resistance to cisplatin treatment. Accordingly, inhibition of GABBR2 has the potential of being a means of chemosensitization, especially in patients with AR/GABBR2-positive bladder cancer. Full article

(This article belongs to the Special Issue Molecular Mechanisms of Tumor Progression and New Therapeutic Strategies for Urological Cancers, 2nd Edition)

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Review

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20 pages, 1765 KiB

Open AccessReview

Tumor-Educated Platelets in Urological Tumors: A Novel Biosource in Liquid Biopsy

by Mariona Figols, Sviatoslav Chekhun, Maria Fernández-Saorin, Ignacio Pérez-Criado, Ana Bautista, Albert Font and Vicenç Ruiz de Porras

Int. J. Mol. Sci. 2025, 26(8), 3595; https://doi.org/10.3390/ijms26083595 - 11 Apr 2025

Viewed by 369

Abstract

Platelets, traditionally recognized for their role in hemostasis, have emerged as pivotal players in cancer biology. They actively contribute to tumor proliferation, angiogenesis, immune evasion, and metastasis and thus play a significant role in cancer progression. Tumor-educated platelets (TEPs) acquire protumorigenic phenotypes through RNA, protein, and receptor profile alterations driven by interactions with tumors and their microenvironment. These modifications enable TEPs to enhance tumor growth and dissemination and to play a critical role throughout the metastatic process. Moreover, TEPs are promising biomarkers that can easily be analyzed in liquid biopsies. Since they dynamically mirror tumor activity through transcriptomic and proteomic changes, their analysis offers a non-invasive method for determining cancer detection and diagnosis, patient prognosis, therapy monitoring, and personalization of treatment. Their demonstrated accuracy in identifying cancer types and predicting treatment responses underscores their ability to provide real-time insights into tumor biology, including in urological malignancies. Their diagnostic potential and their accessibility as blood-sourced biomarkers position TEPs as transformative tools in advancing personalized oncology. Here, we focus on the role of TEPs in urological tumors, exploring their applications in early cancer detection, disease monitoring, and the design of tailored therapeutic strategies. Full article

(This article belongs to the Special Issue Molecular Mechanisms of Tumor Progression and New Therapeutic Strategies for Urological Cancers, 2nd Edition)

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Other

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8 pages, 1848 KiB

Open AccessCase Report

Metastatic Penile Squamous Cell Carcinoma Responsive to Enfortumab Vedotin

by Catherine C. Fahey, Caroline A. Nebhan, Sally York, Nancy B. Davis, Paula J. Hurley, Jennifer B. Gordetsky and Kerry R. Schaffer

Int. J. Mol. Sci. 2023, 24(22), 16109; https://doi.org/10.3390/ijms242216109 - 9 Nov 2023

Cited by 8 | Viewed by 2330

Abstract

Penile squamous cell carcinoma is a rare disease with very limited data to guide treatment decisions. In particular, there is minimal evidence for effective therapies in the metastatic setting. Here, we present a case of metastatic penile squamous cell carcinoma with response to the Nectin-4 inhibitor enfortumab-vedotin-ejfv (EV). EV was selected due to the evidence of the high expression of Nectin-4 in squamous cell carcinomas, including penile carcinoma. The patient had both radiographic and symptomatic improvement after two cycles of treatment, despite having been treated with multiple prior lines of traditional chemotherapy. This case provides support for the use of antibody–drug conjugates (ADC), including EV, in this disease with few other options in the advanced setting. Further studies examining Nectin-4 and ADCs in penile squamous cell carcinoma should be completed, as high-quality evidence is needed to guide treatment after initial progression for these patients. Full article

(This article belongs to the Special Issue Molecular Mechanisms of Tumor Progression and New Therapeutic Strategies for Urological Cancers, 2nd Edition)

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