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Pathology of Urogenital Cancers

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A special issue of Cancers (ISSN 2072-6694). This special issue belongs to the section "Cancer Pathophysiology".

Deadline for manuscript submissions: closed (31 January 2024) | Viewed by 20106

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Prof. Roberta Mazzucchelli

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Section of Pathological Anatomy, United Hospitals, School of Medicine, Polytechnic University of the Marche Region, Via Conca 71, 60126 Ancona, Italy
Interests: prostate cancer; bladder cancer; renal cell carcinoma; carcinogenesis; diagnosis; upper urinary tract tumors; treatment

Dr. Giovanni Tossetta

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Department of Experimental and Clinical Medicine, Polytechnic University of Marche, Via Tronto, 60126 Ancona, Italy
Interests: pregnancy complications; preeclampsia; preterm birth; ovarian cancer; early marker of pregnancy complications; oxidative stress; chemoresistance
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Special Issue Information

Dear Colleagues,

We are pleased to invite you to submit a manuscript to the Special Issue “Pathology of Urologic Cancers”. The incidence of urological malignancies has increased significantly over the past 50 years. Despite advances in medical tumor therapy, the occurrence of chemoresistance and metastatic disease is a common cause of death in patients with urological malignancies. Thus, it is necessary to develop new therapeutic approaches that can improve diagnosis and treatment outcomes. To this aim, we need a better understanding of the molecular changes occurring in urological tumors and the development of molecular biomarkers able to predict tumor behavior and risk of disease recurrence and chemoresistance.

This Special Issue of Cancers, therefore, welcomes original research articles and reviews related to urological malignancies. Communications, mini-reviews, systematic reviews and meta-analyses are also welcome.

We look forward to receiving your contributions.

Prof. Roberta Mazzucchelli
Dr. Giovanni Tossetta
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. Cancers 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 2900 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.

Keywords

prostate cancer
bladder cancer
renal cell carcinoma
testicular cancer
carcinogenesis
biomarker
early diagnosis
upper urinary tract tumors
diagnosis
treatment

Published Papers (10 papers)

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Editorial

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3 pages, 201 KiB

Open AccessEditorial

Pathology of Urologic Cancers

by Giovanni Tossetta and Roberta Mazzucchelli

Cancers 2022, 14(15), 3751; https://doi.org/10.3390/cancers14153751 - 01 Aug 2022

Viewed by 1102

Abstract

We are pleased to present this Special Issue of Cancers, entitled “Pathology of Urologic Cancers” [...] Full article

(This article belongs to the Special Issue Pathology of Urogenital Cancers)

Research

Jump to: Editorial, Review

13 pages, 2238 KiB

Open AccessArticle

Higher Content but No Specific Activity in Gelatinase B (MMP-9) Compared with Gelatinase A (MMP-2) in Human Renal Carcinoma

by Grzegorz Młynarczyk, Monika Gudowska-Sawczuk, Barbara Mroczko, Marta Bruczko-Goralewska, Lech Romanowicz and Anna Tokarzewicz

Cancers 2023, 15(22), 5475; https://doi.org/10.3390/cancers15225475 - 20 Nov 2023

Cited by 1 | Viewed by 806

Abstract

Gelatinases belong to a group of enzymes known as matrix metalloproteinases (MMPs). Gelatinases A and B (MMP-2 and MMP-9, respectively) are the enzymes with the highest ability to destroy collagen, primarily type IV collagen, which is an essential component of the base membrane. Hence, it can be assumed that they are involved, among other things, with the metastasis process of cancer. As a result, the objective of this study was to assess the presence, activity, and expression of selected gelatinases in human renal cancer. Healthy (n = 20) and clear-cell kidney cancer tissue samples (G2 n = 10, G3 n = 10) were analyzed. The presence and content of MMPs were measured using the Western blot and ELISA methods, respectively. The activity (actual and specific) was analyzed with a fluorimetric method. The presence of both investigated enzymes was demonstrated in the representative zymogram. MMP-9 showed the most intensive saturation. It has been observed that both gelatinases occur primarily in high molecular complexes in the human kidney, regardless of whether it is a control or tumor tissue. Both gelatinases were present in comparable amounts in healthy tissues of the kidney. MMP-9 showed a higher content than MMP-2 in both renal cancer grades, but we observed the enhanced activity of both gelatinases with an increase in the grade of renal cancer. A higher MMP-9 content and, on the other hand, lower specific activity in the cancer tissue suggest that MMP-9 is predominantly present in an inactive form in renal cancer. The higher activity of MMP-9 demonstrated using the zymography method may be a cause of different values of activity that depend on the phase of the carcinogenic process. The present study revealed changes in the tested gelatinases in healthy and cancerous tissues of renal cell carcinoma. Therefore, it can be concluded that matrix metalloproteinases 2 and 9 are enzymes directly involved in carcinogenesis, and hence, it seems that MMPs may have potential in the diagnosis and treatment of renal carcinoma. Full article

(This article belongs to the Special Issue Pathology of Urogenital Cancers)

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18 pages, 7836 KiB

Open AccessArticle

CXCR3 Expression Is Associated with Advanced Tumor Stage and Grade Influencing Survival after Surgery of Localised Renal Cell Carcinoma

by Andrea Katharina Lindner, Agnieszka Martowicz, Gerold Untergasser, Johannes Haybaeck, Eva Compérat, Florian Kocher, Andreas Seeber, Martin Thurnher and Renate Pichler

Cancers 2023, 15(4), 1001; https://doi.org/10.3390/cancers15041001 - 04 Feb 2023

Cited by 1 | Viewed by 1755

Abstract

Background: Surgery is the standard treatment in localized renal cell carcinoma (RCC). Pembrolizumab is now approved for adjuvant therapy in high-risk patients. However, inhomogeneity of studies gives ambiguity which patient benefit most from adjuvant therapy. A high infiltration of CD8⁺ T cells is known to be linked with poor prognosis in RCC. CXCR3 is a key player of CD8⁺ T cell differentiation and infiltration. We aimed to evaluate CXCR3 as a potential marker for predicting recurrence. Methods: CXCR3 and immune cell subsets (CD4, CD8, CD68 and FoXP3) were measured on RCC samples by multiplex immunofluorescence (mIF) staining. Cellular localization of CXCR3 was evaluated using single-cell RNA analysis on a publicly available dataset. Results: Tumor samples of 42 RCC patients were analyzed, from which 59.5% were classified as clear-cell RCC and of which 20 had recurrence. Single-cell RNA analysis revealed that CXCR3 was predominantly expressed in intratumoral T cells and dendritic cells. CXCR3 expression was higher in advanced tumors stages (p = 0.0044) and grade (p = 0.0518), correlating significantly with a higher CD8⁺ T cell expression (p < 0.001). Patients with CXCR3^high RCCs had also a significant shorter RFS compared to CXCR3^low (median: 78 vs. 147 months, p = 0.0213). In addition, also tumor stage pT3/4 (p < 0.0001) as well as grade G3/4 (p = 0.0008) negatively influenced RFS. Conclusion: CXCR3^high cell density was associated with high T cell infiltration and advanced tumor stage, worsening RFS in surgically resected RCC patients. Beside its prognostic value, CXCR3 might be a predictive biomarker to guide therapy decision for adjuvant therapy in localized RCC. Full article

(This article belongs to the Special Issue Pathology of Urogenital Cancers)

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10 pages, 1564 KiB

Open AccessArticle

Survival of Testicular Pure Teratoma vs. Mixed Germ Cell Tumor Patients in Primary Tumor Specimens across All Stages

by Cristina Cano Garcia, Francesco Barletta, Reha-Baris Incesu, Mattia Luca Piccinelli, Stefano Tappero, Andrea Panunzio, Zhe Tian, Fred Saad, Shahrokh F. Shariat, Alessandro Antonelli, Carlo Terrone, Ottavio De Cobelli, Markus Graefen, Derya Tilki, Alberto Briganti, Mike Wenzel, Severine Banek, Luis A. Kluth, Felix K. H. Chun and Pierre I. Karakiewicz

Cancers 2023, 15(3), 694; https://doi.org/10.3390/cancers15030694 - 23 Jan 2023

Cited by 2 | Viewed by 1650

Abstract

We aimed to test for survival differences between testicular pure teratoma vs. mixed germ cell tumor (GCT) patients in a stage-specific fashion. Pure teratoma and mixed GCT in primary tumor specimens were identified within the Surveillance, Epidemiology, and End Results database (2004–2019). Kaplan–Meier curves depicted five-year overall survival (OS) and subsequently, cumulative incidence plots depicted cancer-specific mortality (CSM) and other-cause mortality (OCM) in a stage-specific fashion. Multivariable competing risks regression (CRR) models were used. Of 9049 patients, 299 (3%) had pure teratoma. In stage I, II and III, five-year OS rates differed between pure teratoma and mixed GCT (stage I: 91.6 vs. 97.2%, p < 0.001; stage II: 100 vs. 95.9%, p < 0.001; stage III: 66.8 vs. 77.8%, p = 0.021). In stage I, survival differences originated from higher OCM (6.4 vs. 1.2%; p < 0.001). Conversely in stage III, survival differences originated from higher CSM (29.4 vs. 19.0%; p = 0.03). In multivariable CRR models, pure teratoma was associated with higher OCM in stage I (Hazard Ratio (HR): 4.83; p < 0.01). Conversely, in stage III, in multivariable CRR models, pure teratoma was associated with higher CSM (HR: 1.92; p = 0.04). In pure teratoma, survival disadvantage in stage I patients relates to OCM. Survival disadvantage in stage III pure teratoma originates from higher CSM. Full article

(This article belongs to the Special Issue Pathology of Urogenital Cancers)

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16 pages, 3173 KiB

Open AccessArticle

Spatial Profiling of the Prostate Cancer Tumor Microenvironment Reveals Multiple Differences in Gene Expression and Correlation with Recurrence Risk

by Vinay Kumar, Pavneet Randhawa, Robert Bilodeau, Dan Mercola, Michael McClelland, Anshu Agrawal, James Nguyen, Patricia Castro, Michael M. Ittmann and Farah Rahmatpanah

Cancers 2022, 14(19), 4923; https://doi.org/10.3390/cancers14194923 - 08 Oct 2022

Cited by 2 | Viewed by 3563

Abstract

The tumor microenvironment plays a crucial role in both the development and progression of prostate cancer. Furthermore, identifying protein and gene expression differences between different regions is valuable for treatment development. We applied Digital Spatial Profiling multiplex analysis to formalin-fixed paraffin embedded prostatectomy tissue blocks to investigate protein and transcriptome differences between tumor, tumor-adjacent stroma (TAS), CD45+ tumor, and CD45+ TAS tissue. Differential expression of an immunology/oncology protein panel (n = 58) was measured. OX40L and CTLA4 were expressed at higher levels while 22 other proteins, including CD11c, were expressed at lower levels (FDR < 0.2 and p-value < 0.05) in TAS as compared to tumor epithelia. A tissue microarray analysis of 97 patients with 1547 cores found positive correlations between high expression of CD11c and increased time to recurrence in tumor and TAS, and inverse relationships for CTLA4 and OX40L, where higher expression in tumor correlated with lower time to recurrence, but higher time to recurrence in TAS. Spatial transcriptomic analysis using a Cancer Transcriptome Atlas panel (n = 1825 genes) identified 162 genes downregulated and 69 upregulated in TAS versus tumor, 26 downregulated and 6 upregulated in CD45+ TAS versus CD45+ tumor. We utilized CIBERSORTx to estimate the relative immune cell fractions using CD45+ gene expression and found higher average fractions for memory B, naïve B, and T cells in TAS. In summary, the combination of protein expression differences, immune cell fractions, and correlations of protein expression with time to recurrence suggest that closely examining the tumor microenvironment provides valuable data that can improve prognostication and treatment techniques. Full article

(This article belongs to the Special Issue Pathology of Urogenital Cancers)

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Review

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14 pages, 1826 KiB

Open AccessReview

Renal Cell Carcinoma in End-Stage Kidney Disease and the Role of Transplantation

by Samuel Robinson, Alena Nag, Benjamin Peticca, Tomas Prudencio, Antonio Di Carlo and Sunil Karhadkar

Cancers 2024, 16(1), 3; https://doi.org/10.3390/cancers16010003 - 19 Dec 2023

Viewed by 1218

Abstract

Kidney transplant patients have a higher risk of renal cell carcinoma (RCC) compared to non-transplanted end-stage kidney disease (ESKD) patients. This increased risk has largely been associated with the use of immunosuppression; however, recent genetic research highlights the significance of tissue specificity in cancer driver genes. The implication of tissue specificity becomes more obscure when addressing transplant patients, as two distinct metabolic environments are present within one individual. The oncogenic potential of donor renal tissue is largely unknown but assumed to pose minimal risk to the kidney transplant recipient (KTR). Our review challenges this notion by examining how donor and recipient microenvironments impact a transplant recipient’s associated risk of renal cell carcinoma. In doing so, we attempt to encapsulate how ESKD-RCC and KTR-RCC differ in their incidence, pathogenesis, outcome, and approach to management. Full article

(This article belongs to the Special Issue Pathology of Urogenital Cancers)

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24 pages, 666 KiB

Open AccessReview

Recent Advances in the Management of Clear Cell Renal Cell Carcinoma: Novel Biomarkers and Targeted Therapies

by Valentina Schiavoni, Roberto Campagna, Valentina Pozzi, Monia Cecati, Giulio Milanese, Davide Sartini, Eleonora Salvolini, Andrea Benedetto Galosi and Monica Emanuelli

Cancers 2023, 15(12), 3207; https://doi.org/10.3390/cancers15123207 - 16 Jun 2023

Cited by 4 | Viewed by 2000

Abstract

Renal cell carcinoma (RCC) belongs to a heterogenous cancer group arising from renal tubular epithelial cells. Among RCC subtypes, clear cell renal cell carcinoma (ccRCC) is the most common variant, characterized by high aggressiveness, invasiveness and metastatic potential, features that lead to poor prognosis and high mortality rate. In addition, diagnosis of kidney cancer is incidental in the majority of cases, and this results in a late diagnosis, when the stage of the disease is advanced and the tumor has already metastasized. Furthermore, ccRCC treatment is complicated by its strong resistance to chemo- and radiotherapy. Therefore, there is active ongoing research focused on identifying novel biomarkers which could be useful for assessing a better prognosis, as well as new molecules which could be used for targeted therapy. In this light, several novel targeted therapies have been shown to be effective in prolonging the overall survival of ccRCC patients. Thus, the aim of this review is to analyze the actual state-of-the-art on ccRCC diagnosis, prognosis and therapeutic options, while also reporting the recent advances in novel biomarker discoveries, which could be exploited for a better prognosis or for targeted therapy. Full article

(This article belongs to the Special Issue Pathology of Urogenital Cancers)

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22 pages, 1060 KiB

Open AccessReview

Role of Natural and Synthetic Compounds in Modulating NRF2/KEAP1 Signaling Pathway in Prostate Cancer

by Giovanni Tossetta, Sonia Fantone, Daniela Marzioni and Roberta Mazzucchelli

Cancers 2023, 15(11), 3037; https://doi.org/10.3390/cancers15113037 - 02 Jun 2023

Cited by 13 | Viewed by 1780

Abstract

Prostate cancer is the second most common cancer in men worldwide. Prostate cancer can be treated by surgery or active surveillance when early diagnosed but, when diagnosed at an advanced or metastatic stage, radiation therapy or androgen-deprivation therapy is needed to reduce cancer progression. However, both of these therapies can cause prostate cancer resistance to treatment. Several studies demonstrated that oxidative stress is involved in cancer occurrence, development, progression and treatment resistance. The nuclear factor erythroid 2-related factor 2 (NRF2)/KEAP1 (Kelch-Like ECH-Associated Protein 1) pathway plays an important role in protecting cells against oxidative damage. Reactive oxygen species (ROS) levels and NRF2 activation can determine cell fate. In particular, toxic levels of ROS lead physiological cell death and cell tumor suppression, while lower ROS levels are associated with carcinogenesis and cancer progression. On the contrary, a high level of NRF2 promotes cell survival related to cancer progression activating an adaptive antioxidant response. In this review, we analyzed the current literature regarding the role of natural and synthetic compounds in modulating NRF2/KEAP1 signaling pathway in prostate cancer. Full article

(This article belongs to the Special Issue Pathology of Urogenital Cancers)

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14 pages, 295 KiB

Open AccessReview

Precision Medicine in the Treatment of Locally Advanced or Metastatic Urothelial Cancer: New Molecular Targets and Pharmacological Therapies

by Antonio Vitiello, Francesco Ferrara, Ruggero Lasala and Andrea Zovi

Cancers 2022, 14(20), 5167; https://doi.org/10.3390/cancers14205167 - 21 Oct 2022

Cited by 7 | Viewed by 2061

Abstract

Many variants of urothelial cancer present diagnostic challenges and carry clinical implications that influence prognosis and treatment decisions. The critical issues of treatment-resistant clones are a crucial barrier to care in individuals affected by urothelial carcinoma. Laying the foundations for the resistance evolution, a wide mutational heterogeneity characterizes urothelial carcinoma, noticeable also in patients affected by a early stage disease. In recent years the growing knowledge of the pathogenesis and molecular paths underlying the onset and progression of urothelial cancer are leading to the development of new therapies based on immune checkpoints. Chemotherapy and immunotherapy both operate selectively by shaping the developmental trajectory of urothelial carcinoma in the course of the illness. To date, a promising new therapeutic treatment is represented by antibody-drug conjugates, therapeutic tools that exploit the targeted ability of an antibody to administer cytotoxic drugs directly to the tumor. Indeed, nowadays in the clinical setting there are several treatments available for the treatment of locally advanced or metastatic urothelial cancer, from classic chemotherapeutics such as Gemcitabine, Cisplatin and Carboplatin, Paclitaxel and Docetaxel, to Programmed cell death protein 1 (PD-1) or Programmed death-ligand 1 (PD-L1) inhibitors such as Atezolizumab, Avelumab, Nivolumab, Pembrolizumab, up to anti-nectin 4 Enfortumab Vedotin and Sacituzumab govitecan, which binds Tumor-associated calcium signal transducer 2 (Trop-2) and activates as a topoisomerase inhibitor. The aim of this work is to describe the molecular mechanisms underlying the onset of the urothelial cancer and provide an overview of the immunotherapies that can be used in the clinical setting to counteract it, deepening the efficacy and safety results of the pivotal studies and the place in therapy of these treatments. Full article

(This article belongs to the Special Issue Pathology of Urogenital Cancers)

15 pages, 303 KiB

Open AccessReview

The Impact of Meat Intake on Bladder Cancer Incidence: Is It Really a Relevant Risk?

by Achille Aveta, Crescenzo Cacciapuoti, Biagio Barone, Erika Di Zazzo, Francesco Del Giudice, Martina Maggi, Matteo Ferro, Daniela Terracciano, Gian Maria Busetto, Giuseppe Lucarelli, Octavian Sabin Tataru, Emanuele Montanari, Benito Fabio Mirto, Alfonso Falcone, Gaetano Giampaglia, Enrico Sicignano, Federico Capone, Gianluca Villano, Pasquale Angellotto, Celeste Manfredi, Luigi Napolitano, Ciro Imbimbo, Savio Domenico Pandolfo and Felice Crocetto Show full author list Hide full author list

Cancers 2022, 14(19), 4775; https://doi.org/10.3390/cancers14194775 - 29 Sep 2022

Cited by 23 | Viewed by 2986

Abstract

Bladder cancer (BC) represents the second most common genitourinary malignancy. The major risk factors for BC include age, gender, smoking, occupational exposure, and infections. The BC etiology and pathogenesis have not been fully defined yet. Since catabolites are excreted through the urinary tract, the diet may play a pivotal role in bladder carcinogenesis. Meat, conventionally classified as “red”, “white” or “processed”, represents a significant risk factor for chronic diseases like cardiovascular disease, obesity, type 2 diabetes, and cancer. In particular, red and processed meat consumption seems to increase the risk of BC onset. The most accepted mechanism proposed for explaining the correlation between meat intake and BC involves the generation of carcinogens, such as heterocyclic amines and polycyclic aromatic hydrocarbons by high-temperature cooking. This evidence claims the consumption limitation of meat. We reviewed the current literature on potential biological mechanisms underlying the impact of meat (red, white, and processed) intake on the increased risk of BC development and progression. Toward this purpose, we performed an online search on PubMed using the term “bladder cancer” in combination with “meat”, “red meat”, “white meat” or “processed meat”. Although some studies did not report any association between BC and meat intake, several reports highlighted a positive correlation between red or processed meat intake, especially salami, pastrami, corned beef and bacon, and BC risk. We speculate that a reduction or rather a weighting of the consumption of red and processed meat can reduce the risk of developing BC. Obviously, this remark claims future indications regarding food education (type of meat to be preferred, quantity of red meat to be eaten and how to cook it) to reduce the risk of developing BC. Further well-designed prospective studies are needed to corroborate these findings. Full article

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