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Bladder Cancer: Molecular Advances in Pathology, Diagnostics, and Therapeutics

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

Deadline for manuscript submissions: closed (31 August 2022) | Viewed by 22563

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Prof. Dr. Wilhelm K. Aicher

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Department of Urology, University of Tuebingen Hospital, Waldhoernlestr 22, D-72072 Tubingen, Germany
Interests: cell therapy; mesenchymal stromal cells; organoids; preclinical animal models in urology; bladder cancer
Special Issues, Collections and Topics in MDPI journals

Special Issue Information

Dear Colleagues,

Bladder cancer ranks among the most frequent malignancies disturbing wellbeing and health of patients affected. According to the WHO-associated international agency for research on cancer Cancer Today°, approximately 550,000 new cases are diagnosed each year. In regions with a very high human development index, the incidence rate is higher, associated with the overall aging of these populations. Occupational and environmental aspects as well as lifestyle-associated factors contribute to the individual risk of suffering from bladder cancer.

Despite intensive basic and clinical research, the five-year survival rates of bladder cancer patients have not improved significantly in the last twenty to thirty years. However, detailed knowledge of genes and mutants contributing to bladder cancer initiation as well as its propagation, data on expression of cancer-associated cell surface molecules in combination with drugs controlling intracellular pathways, and better understanding of the role of a distracted immune system in bladder cancer hold great promise for a breakthrough in future cancer therapy.

Progress has also been noted in basic research: The advent of organoid cultures derived from urothelial carcinoma explants has facilitated advanced in vitro studies which investigate cancer etiology and screening for hopeful therapeutics. Modern imaging in combination with deep learning algorithms is improving the power of histology and cancer diagnosis significantly. Future cancer surgery will also be aided by minimally invasive sensors discriminating normal and healthy bladder tissue from mutant and malignant tissue. We therefore look forward to reviews and original articles on different aspects of current methods to diagnose and treat urothelial carcinoma to improve survival rates. In this Special Issue of the IJMS on Bladder Cancer, we will publish papers on the following topics:

Clinical relevance of molecular subtyping of bladder cancer;
Pathology and diagnosis of bladder cancer;
Evolution of bladder cancer markers on tumor organoids;
Simplified procedures to generate tumor organoids from urine samples;
Impedance-based discrimination of bladder cancer.

Other manuscripts will complement the above-listed articles.

Prof. Dr. Wilhelm K. Aicher
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. International Journal of Molecular Sciences is an international peer-reviewed open access semimonthly journal published by MDPI.

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Published Papers (9 papers)

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Research

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16 pages, 8612 KiB

Open AccessArticle

Genetic Interference of FGFR3 Impedes Invasion of Upper Tract Urothelial Carcinoma Cells by Alleviating RAS/MAPK Signal Activity

by Gong-Kai Huang, Chao-Cheng Huang, Chih-Hsiung Kang, Yuan-Tso Cheng, Po-Ching Tsai, Ying-Hsien Kao and Yueh-Hua Chung

Int. J. Mol. Sci. 2023, 24(2), 1776; https://doi.org/10.3390/ijms24021776 - 16 Jan 2023

Cited by 4 | Viewed by 2616

Abstract

Upper tract urothelial cancer (UTUC) is a less common disease in Western countries but has a high level of prevalence in Asian populations. Compared to bladder cancer, unique etiologic and genomic factors are involved in UTUC. Fibroblast growth factor receptor 3 (FGFR3) up-regulation has been proposed as a promising target for bladder cancer therapy. In this study, we aimed to profile the expression of FGFR3 in Asian and Caucasian UTUC tissues and to evaluate the in vitro therapeutic efficacy of small interference RNA (siRNA)-mediated FGFR3 silencing in UTUC treatment. The FGFR3 expression levels in renal pelvis tissues and microarray sections from Asian and Caucasian patients with UTUC, respectively, were measured via immunohistochemistry. The BFTC-909 and UM-UC-14 UTUC cell lines were used to examine the effects of FGFR3 silencing on proliferation, migration, epithelial–mesenchymal transition (EMT) marker expression, and signaling machinery. FGFR3 expression increased as the TNM stage increased in both Asian and Caucasian UTUC tumors, and no statistical difference was identified between the two groups. In vitro studies demonstrated that FGFR3 siRNA delivery significantly inhibited proliferation and migration and suppressed the expression of EMT markers and transcription factors in UTUC cells. Mechanistically, FGFR3 silencing alleviated the constitutive expression of RAS and the phosphorylation of MAPK signaling mediators, including ERK1/2 and JNK1/2. FGFR3 silencing elicited an apoptosis-inducing effect similar to that of FGFR inhibition. Conclusion: siRNA-targeted FGFR3 expression may impede the expansion and invasion of UTUC cells by alleviating the RAS/MAPK signaling pathway. The genetic interference of FGFR3 expression via siRNA in UTUC cells may constitute a useful therapeutic strategy. Full article

(This article belongs to the Special Issue Bladder Cancer: Molecular Advances in Pathology, Diagnostics, and Therapeutics)

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14 pages, 1530 KiB

Open AccessArticle

Multiparametric Classification of Non-Muscle Invasive Papillary Urothelial Neoplasms: Combining Morphological, Phenotypical, and Molecular Features for Improved Risk Stratification

by Ivonne A. Montes-Mojarro, Saki Hassas, Sina Staehle, Philip Sander, Niklas Harland, Lina Maria Serna-Higuita, Irina Bonzheim, Hans Bösmüller, Arnulf Stenzl and Falko Fend

Int. J. Mol. Sci. 2022, 23(15), 8133; https://doi.org/10.3390/ijms23158133 - 23 Jul 2022

Cited by 5 | Viewed by 2085

Abstract

Diagnosis and grading of non-invasive papillary urothelial tumors according to the current WHO classification poses some challenges for pathologists. The diagnostic reproducibility of separating low-grade and high-grade lesions is low, which impacts their clinical management. Whereas papillary urothelial neoplasms with low malignant potential (PUN-LMP) and low-grade papillary non-invasive carcinoma (LG-PUC) are comparable and show frequent local recurrence but rarely metastasize, high-grade papillary non-invasive carcinoma (HG-PUC) has a poor prognosis. The main objective of this work is to develop a multiparametric classification to unambiguously distinguish low-grade and high-grade tumors, considering immunohistochemical stains for p53, FGFR3, CK20, MIB-1, p16, p21 and p-HH3, and pathogenic mutations in TP53, FGFR3, TP53, ERCC2, PIK3CA, PTEN and STAG2. We reviewed and analyzed the clinical and histological data of 45 patients with a consensus diagnosis of PUN-LMP (n = 8), non-invasive LG-PUC (n = 23), and HG-PUC (n = 14). The proliferation index and mitotic count assessed with MIB-1 and P-HH3 staining, respectively correlated with grading and clinical behavior. Targeted sequencing confirmed frequent FGFR3 mutations in non-invasive papillary tumors and identified mutations in TP53 as high-risk. Cluster analysis of the different immunohistochemical and molecular parameters allowed a clear separation in two different clusters: cluster 1 corresponding to PUN-LMP and LG-PUC (low MIB-1 and mitotic count/FGFR3 and STAG2 mutations) and cluster 2, HG-PUC (high MIB-1 and mitosis count/CK20 +++ expression, FGFR3 WT and TP53 mutation). Further analysis is required to validate and analyze the reproducibility of these clusters and their biological and clinical implication. Full article

(This article belongs to the Special Issue Bladder Cancer: Molecular Advances in Pathology, Diagnostics, and Therapeutics)

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21 pages, 6766 KiB

Open AccessArticle

Data-Driven Identification of Biomarkers for In Situ Monitoring of Drug Treatment in Bladder Cancer Organoids

by Lucas Becker, Felix Fischer, Julia L. Fleck, Niklas Harland, Alois Herkommer, Arnulf Stenzl, Wilhelm K. Aicher, Katja Schenke-Layland and Julia Marzi

Int. J. Mol. Sci. 2022, 23(13), 6956; https://doi.org/10.3390/ijms23136956 - 23 Jun 2022

Cited by 10 | Viewed by 2939

Abstract

Three-dimensional (3D) organoid culture recapitulating patient-specific histopathological and molecular diversity offers great promise for precision medicine in cancer. In this study, we established label-free imaging procedures, including Raman microspectroscopy (RMS) and fluorescence lifetime imaging microscopy (FLIM), for in situ cellular analysis and metabolic monitoring of drug treatment efficacy. Primary tumor and urine specimens were utilized to generate bladder cancer organoids, which were further treated with various concentrations of pharmaceutical agents relevant for the treatment of bladder cancer (i.e., cisplatin, venetoclax). Direct cellular response upon drug treatment was monitored by RMS. Raman spectra of treated and untreated bladder cancer organoids were compared using multivariate data analysis to monitor the impact of drugs on subcellular structures such as nuclei and mitochondria based on shifts and intensity changes of specific molecular vibrations. The effects of different drugs on cell metabolism were assessed by the local autofluorophore environment of NADH and FAD, determined by multiexponential fitting of lifetime decays. Data-driven neural network and data validation analyses (k-means clustering) were performed to retrieve additional and non-biased biomarkers for the classification of drug-specific responsiveness. Together, FLIM and RMS allowed for non-invasive and molecular-sensitive monitoring of tumor-drug interactions, providing the potential to determine and optimize patient-specific treatment efficacy. Full article

(This article belongs to the Special Issue Bladder Cancer: Molecular Advances in Pathology, Diagnostics, and Therapeutics)

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21 pages, 3158 KiB

Open AccessArticle

Urinary Tract Tumor Organoids Reveal Eminent Differences in Drug Sensitivities When Compared to 2-Dimensional Culture Systems

by Yi Wei, Bastian Amend, Tilman Todenhöfer, Nizar Lipke, Wilhelm K. Aicher, Falko Fend, Arnulf Stenzl and Niklas Harland

Int. J. Mol. Sci. 2022, 23(11), 6305; https://doi.org/10.3390/ijms23116305 - 4 Jun 2022

Cited by 8 | Viewed by 2205

Abstract

Generation of organoids from urinary tract tumor samples was pioneered a few years ago. We generated organoids from two upper tract urothelial carcinomas and from one bladder cancer sample, and confirmed the expression of cytokeratins as urothelial antigens, vimentin as a mesenchymal marker, and fibroblast growth factor receptor 3 by immunohistochemistry. We investigated the dose response curves of two novel components, venetoclax versus S63845, in comparison to the clinical standard cisplatin in organoids in comparison to the corresponding two-dimensional cultures. Normal urothelial cells and tumor lines RT4 and HT1197 served as controls. We report that upper tract urothelial carcinoma cells and bladder cancer cells in two-dimensional cultures yielded clearly different sensitivities towards venetoclax, S63845, and cisplatin. Two-dimensional cultures were more sensitive at low drug concentrations, while organoids yielded higher drug efficacies at higher doses. In some two-dimensional cell viability experiments, colorimetric assays yielded different IC₅₀ toxicity levels when compared to chemiluminescence assays. Organoids exhibited distinct sensitivities towards cisplatin and to a somewhat lesser extent towards venetoclax or S63845, respectively, and significantly different sensitivities towards the three drugs investigated when compared to the corresponding two-dimensional cultures. We conclude that organoids maintained inter-individual sensitivities towards venetoclax, S63845, and cisplatin. The preclinical models and test systems employed may bias the results of cytotoxicity studies. Full article

(This article belongs to the Special Issue Bladder Cancer: Molecular Advances in Pathology, Diagnostics, and Therapeutics)

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21 pages, 2365 KiB

Open AccessArticle

CD24: A Marker for an Extended Expansion Potential of Urothelial Cancer Cell Organoids In Vitro?

by Ruizhi Geng, Niklas Harland, Ivonne A. Montes-Mojarro, Falko Fend, Wilhelm K. Aicher, Arnulf Stenzl and Bastian Amend

Int. J. Mol. Sci. 2022, 23(10), 5453; https://doi.org/10.3390/ijms23105453 - 13 May 2022

Cited by 7 | Viewed by 2515

Abstract

Background: Bladder cancer is the most cost-intensive cancer due to high recurrence rates and long follow-up times. Bladder cancer organoids were considered interesting tools for investigating better methods for the detection and treatment of this cancer. Methods: Organoids were generated from urothelial carcinoma tissue samples, then expanded and characterized; the expression of immune modulatory antigens and tumor stem cells markers CD24 and CD44 was explored in early (P ≤ 3) and later (P ≥ 5) passages (P) by immunofluorescence and by quantitative PCR of cDNA. The expression of these factors was investigated in the corresponding cancer tissue samples by immunohistochemistry. Results: The expression of the PD-L1 was detected on some but not all organoids. CD276 and CD47 were observed on organoids in all passages investigated. Organoids growing beyond passage 8 expressed both CD24 and CD44 at elevated levels in early and late cultures. Organoids proliferating to the eighth passage initially expressed both CD24 and CD44, but lost CD24 expression over time, while CD44 remained. Organoids growing only up to the 6th passage failed to express CD24 but expressed CD44. Conclusions: The data indicate that the expression of CD24 in urothelial cancer cell organoids may serve as an indicator for the prolonged proliferation potential of the cells. Full article

(This article belongs to the Special Issue Bladder Cancer: Molecular Advances in Pathology, Diagnostics, and Therapeutics)

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18 pages, 31356 KiB

Open AccessArticle

Profiling the Biological Characteristics and Transitions through Upper Tract Tumor Origin, Bladder Recurrence, and Muscle-Invasive Bladder Progression in Upper Tract Urothelial Carcinoma

by Keisuke Shigeta, Kazuhiro Matsumoto, Nobuyuki Tanaka, Shuji Mikami, Takeo Kosaka, Yota Yasumizu, Toshikazu Takeda, Ryuichi Mizuno, Eiji Kikuchi and Mototsugu Oya

Int. J. Mol. Sci. 2022, 23(9), 5154; https://doi.org/10.3390/ijms23095154 - 5 May 2022

Cited by 4 | Viewed by 1947

Abstract

To evaluate biological characteristics and transitions of upper tract urothelial carcinoma (UTUC) through metachronous bladder tumors after radical nephroureterectomy (RNU), we conducted immunohistochemical (IHC) staining of tumor specimens of UTUC tumor origin, non-muscle-invasive bladder cancer (NMIBC) and MIBC progressed after intravesical recurrence (IVR), and bladder primary MIBC. Fibroblast growth factor receptor 3 (FGFR3), p53, cytokeratin 5/6 (CK5/6), and CK20 were stained to examine expression rates. After expression assessment with heatmap clustering, the overexpression of four biomarkers from UTUC origin to metachronous MIBC progression was analyzed with clinicopathological variables. We found that high CK20 and low CK5/6 expression were both observed in UTUC tumor origin and subsequent NMIBC after RNU. By investigating molecular expression in the IVR specimen, we observed that low pT stage bladder recurrence occupied the majority of CK20 high CK5/6 low expression, but would change to CK20 low CK5/6 high expression as it progressed to MIBC. UTUC metachronous MIBC has different characteristics compared with bladder primary MIBC, which comprises favorable biological features such as high FGFR3 expression, and follows favorable prognosis compared to those without FGFR3 expression. The present study demonstrated that the biological characteristics of UTUC tumor origin shifts from luminal to basal-like features with progression to MIBC, but FGFR3 expression taken over from UTUC origin may comprise a favorable entity compared to primary MIBC. Full article

(This article belongs to the Special Issue Bladder Cancer: Molecular Advances in Pathology, Diagnostics, and Therapeutics)

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19 pages, 4784 KiB

Open AccessArticle

Elevated Expression of the Immune Checkpoint Ligand CD276 (B7-H3) in Urothelial Carcinoma Cell Lines Correlates Negatively with the Cell Proliferation

by Niklas Harland, Florian B. Maurer, Tanja Abruzzese, Cornelia Bock, Ivonne A. Montes-Mojarro, Falko Fend, Wilhelm K. Aicher, Arnulf Stenzl and Bastian Amend

Int. J. Mol. Sci. 2022, 23(9), 4969; https://doi.org/10.3390/ijms23094969 - 29 Apr 2022

Cited by 5 | Viewed by 2074

Abstract

The cell surface molecule CD276 (B7-H3) is an immune checkpoint antigen. The elevated expression of CD276 on tumors contributes to the suppression of anti-tumor T-cell responses and correlates with poor prognosis. Methods: The expression of CD276 was explored in vitro on eight urothelial carcinoma cell lines (UM-UC) in comparison to eight normal urothelial cells (NUCs) by RT-qPCR, Western blotting, and flow cytometry. Cell proliferation was enumerated over consecutive passages. The expression of cancer stem cell markers CD24 and CD44, cytokeratins, and vimentin was investigated by immunofluorescence. The expression of CD276 in bladder tumor samples and metastases was explored by immunohistochemistry. Results: Expression of CD276 on cell surfaces was elevated on UM-UCs when compared to NUCs. In UM-UCs, CD276 transcripts correlated moderately positive with CD276 protein expression (ρ = 0.660) and strongly positive with CD276 surface-expression (ρ = 0.810). CD276 mRNA expression (ρ = −0.475) and CD276 protein expression (ρ = −0.417) had a significant negative correlation with proliferation, while a significant correlation between proliferation and cell surface expression was not observed in UM-UCs. Conclusion: The expression of CD276 on UM-UC bladder tumor cell surfaces is elevated. Slow proliferating UM-UC cells express more CD276 mRNA and protein than fast proliferating cells. In patients, slow proliferating CD276^high tumor (stem) cells may evade immune surveillance. However, cancer therapy targeting CD276 may be effective in the treatment of slow proliferating tumor cells. Full article

(This article belongs to the Special Issue Bladder Cancer: Molecular Advances in Pathology, Diagnostics, and Therapeutics)

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15 pages, 2728 KiB

Open AccessArticle

Bladder Cancer Extracellular Vesicles Elicit a CD8 T Cell-Mediated Antitumor Immunity

by Carlos J. Ortiz-Bonilla, Taylor P. Uccello, Scott A. Gerber, Edith M. Lord, Edward M. Messing and Yi-Fen Lee

Int. J. Mol. Sci. 2022, 23(6), 2904; https://doi.org/10.3390/ijms23062904 - 8 Mar 2022

Cited by 7 | Viewed by 2480

Abstract

Tumor-derived extracellular vesicles (TEVs) play crucial roles in mediating immune responses, as they carry and present functional MHC-peptide complexes that enable them to modulate antigen-specific CD8⁺ T-cell responses. However, the therapeutic potential and immunogenicity of TEV-based therapies against bladder cancer (BC) have not yet been tested. Here, we demonstrated that priming with immunogenic Extracellular Vesicles (EVs) derived from murine MB49 BC cells was sufficient to prevent MB49 tumor growth in mice. Importantly, antibody-mediated CD8⁺ T-cell depletion diminished the protective effect of MB49 EVs, suggesting that MB49 EVs elicit cytotoxic CD8⁺ T-cell-mediated protection against MB49 tumor growth. Such antitumor activity may be augmented by TEV-enhanced immune cell infiltration into the tumors. Interestingly, MB49 EV priming was unable to completely prevent, but significantly delayed, unrelated syngeneic murine colon MC-38 tumor growth. Cytokine array analyses revealed that MB49 EVs were enriched with pro-inflammatory factors that might contribute to increasing tumor-infiltrating immune cells in EV-primed MC-38 tumors. These results support the potential application of TEVs in personalized medicine, and open new avenues for the development of adjuvant therapies based on patient-derived EVs aimed at preventing disease progression. Full article

(This article belongs to the Special Issue Bladder Cancer: Molecular Advances in Pathology, Diagnostics, and Therapeutics)

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Review

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13 pages, 713 KiB

Open AccessReview

Her-2 Targeted Therapy in Advanced Urothelial Cancer: From Monoclonal Antibodies to Antibody-Drug Conjugates

by Víctor Albarrán, Diana Isabel Rosero, Jesús Chamorro, Javier Pozas, María San Román, Ana María Barrill, Víctor Alía, Pilar Sotoca, Patricia Guerrero, Juan Carlos Calvo, Inmaculada Orejana, Patricia Pérez de Aguado and Pablo Gajate

Int. J. Mol. Sci. 2022, 23(20), 12659; https://doi.org/10.3390/ijms232012659 - 21 Oct 2022

Cited by 10 | Viewed by 2566

Abstract

Metastatic urothelial cancer, associated with a poor prognosis, is still major cause of cancer-related death, with scarce options of effective treatment after progression to platinum-based chemotherapy and immunotherapy. The human epithelial growth factor receptor 2 (Her-2) has been identified as a new therapeutic target in medical oncology. However, despite the encouraging results in breast and gastric cancers, clinical trials with anti-Her-2 monoclonal antibodies and tyrosine-kinase inhibitors have shown limited efficacy of this strategy in urothelial tumors. Notably, more favorable data have been recently shown that antibody-drug conjugates are currently emerging as a novel promising approach for Her-2 targeted therapy in advanced urothelial cancer. Full article

(This article belongs to the Special Issue Bladder Cancer: Molecular Advances in Pathology, Diagnostics, and Therapeutics)

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