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12 pages, 5418 KiB

Open AccessArticle

YTHDF1 Promotes Bladder Cancer Cell Proliferation via the METTL3/YTHDF1–RPN2–PI3K/AKT/mTOR Axis

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Int. J. Mol. Sci. 2023, 24(8), 6905; https://doi.org/10.3390/ijms24086905 - 07 Apr 2023

Cited by 4 | Viewed by 1147

Abstract

N6-methyladenosine (m6A) is the most common mRNA modification and it plays a critical role in tumor progression, prognoses and therapeutic response. In recent years, more and more studies have shown that m6A modifications play an important role in bladder carcinogenesis and development. However, [...] Read more.

N6-methyladenosine (m6A) is the most common mRNA modification and it plays a critical role in tumor progression, prognoses and therapeutic response. In recent years, more and more studies have shown that m6A modifications play an important role in bladder carcinogenesis and development. However, the regulatory mechanisms of m6A modifications are complex. Whether the m6A reading protein YTHDF1 is involved in the development of bladder cancer remains to be elucidated. The aims of this study were to determine the association between METTL3/YTHDF1 and bladder cancer cell proliferation and cisplatin resistance to explore the downstream target genes of METTL3/YTHDF1 and to explore the therapeutic implications for bladder cancer patients. The results showed that the reduced expression of METTL3/YTHDF1 could lead to decreased bladder cancer cell proliferation and cisplatin sensitivity. Meanwhile, overexpression of the downstream target gene, RPN2, could rescue the effect of reduced METTL3/YTHDF1 expression on bladder cancer cells. In conclusion, this study proposes a novel METTL3/YTHDF1–RPN2–PI3K/AKT/mTOR regulatory axis that affects bladder cancer cell proliferation and cisplatin sensitivity. Full article

(This article belongs to the Special Issue Urogenital Tumors: From Molecular Basis to Therapy)

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16 pages, 17016 KiB

Open AccessArticle

Crosstalk between Mesenchymal Stem Cells and Cancer Stem Cells Reveals a Novel Stemness-Related Signature to Predict Prognosis and Immunotherapy Responses for Bladder Cancer Patients

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Int. J. Mol. Sci. 2023, 24(5), 4760; https://doi.org/10.3390/ijms24054760 - 01 Mar 2023

Cited by 5 | Viewed by 1604

Abstract

Mesenchymal stem cells (MSCs) and cancer stem cells (CSCs) maintain bladder cancer (BCa) stemness and facilitate the progression, metastasis, drug resistance, and prognosis. Therefore, we aimed to decipher the communication networks, develop a stemness-related signature (Stem. Sig.), and identify a potential therapeutic target. [...] Read more.

Mesenchymal stem cells (MSCs) and cancer stem cells (CSCs) maintain bladder cancer (BCa) stemness and facilitate the progression, metastasis, drug resistance, and prognosis. Therefore, we aimed to decipher the communication networks, develop a stemness-related signature (Stem. Sig.), and identify a potential therapeutic target. BCa single-cell RNA-seq datasets (GSE130001 and GSE146137) were used to identify MSCs and CSCs. Pseudotime analysis was performed by Monocle. Stem. Sig. was developed by analyzing the communication network and gene regulatory network (GRN) that were decoded by NicheNet and SCENIC, respectively. The molecular features of the Stem. Sig. were evaluated in TCGA-BLCA and two PD-(L)1 treated datasets (IMvigor210 and Rose2021UC). A prognostic model was constructed based on a 101 machine-learning framework. Functional assays were performed to evaluate the stem traits of the hub gene. Three subpopulations of MSCs and CSCs were first identified. Based on the communication network, the activated regulons were found by GRN and regarded as the Stem. Sig. Following unsupervised clustering, two molecular subclusters were identified and demonstrated distinct cancer stemness, prognosis, immunological TME, and response to immunotherapy. Two PD-(L)1 treated cohorts further validated the performance of Stem. Sig. in prognosis and immunotherapeutic response prediction. A prognostic model was then developed, and a high-risk score indicated a poor prognosis. Finally, the hub gene SLC2A3 was found exclusively upregulated in extracellular matrix-related CSCs, predicting prognosis, and shaping an immunosuppressive tumor microenvironment. Functional assays uncovered the stem traits of SLC2A3 in BCa by tumorsphere formation and western blotting. The Stem. Sig. derived from MSCs and CSCs can predict prognosis and response to immunotherapy for BCa. Besides, SLC2A3 may serve as a promising stemness target facilitating cancer effective management. Full article

(This article belongs to the Special Issue Urogenital Tumors: From Molecular Basis to Therapy)

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15 pages, 2190 KiB

Open AccessArticle

Ex Vivo Fluorescence Confocal Microscopy (FCM) Ensures Representative Tissue in Prostate Cancer Biobanking: A Feasibility Study

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Christoph Brochhausen

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Karl-Dietrich Sievert

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Torsten Hansen

Int. J. Mol. Sci. 2022, 23(20), 12103; https://doi.org/10.3390/ijms232012103 - 11 Oct 2022

Viewed by 1292

Abstract

Background: Biobanking of prostate carcinoma is particularly challenging due to the actual cancer within the organ often without clear margins. Frozen sections are to date the only way to examine the biobank material for its tumor content. We used ex vivo fluorescence confocal [...] Read more.

Background: Biobanking of prostate carcinoma is particularly challenging due to the actual cancer within the organ often without clear margins. Frozen sections are to date the only way to examine the biobank material for its tumor content. We used ex vivo fluorescence confocal microscopy (FCM) to analyze biobank samples prior to cryoasservation. Methods: 127 punch biopsies were acquired from prostatectomy-specimens from 40 patients. These biopsies were analyzed with a Vivascope 2500-G4 prior to their transfer to the biobank. In difficult cases, larger samples of the prostatectomy specimens were FCM scanned in order to locate tumor foci. After patient acquisition, all samples were taken from the biobank and analyzed. We compared the results of the FCM examinations with the results of conventional histology and measured the DNA content. Results: With upstream FCM, the tumor content of biobank samples could be determined with high confidence. The detection rate of representative biobank samples was increased due to the rapid feedback. The biobank samples were suitable for further molecular analysis. Conclusion: FCM allows for the first time lossless microscopic analysis of biobank samples prior to their cryoasservation and guarantees representative tumor and normal tissue for further molecular analysis. Full article

(This article belongs to the Special Issue Urogenital Tumors: From Molecular Basis to Therapy)

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12 pages, 1355 KiB

Open AccessArticle

Preclinical Assessment of the Combination of PSMA-Targeting Radionuclide Therapy with PARP Inhibitors for Prostate Cancer Treatment

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Wytske M. Van Weerden

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Julie Nonnekens

Int. J. Mol. Sci. 2022, 23(14), 8037; https://doi.org/10.3390/ijms23148037 - 21 Jul 2022

Cited by 8 | Viewed by 2085

Abstract

Prostate specific membrane antigen targeted radionuclide therapy (PSMA-TRT) is a promising novel treatment for prostate cancer (PCa) patients. However, PSMA-TRT cannot be used for curative intent yet, thus additional research on how to improve the therapeutic efficacy is warranted. A potential way of [...] Read more.

Prostate specific membrane antigen targeted radionuclide therapy (PSMA-TRT) is a promising novel treatment for prostate cancer (PCa) patients. However, PSMA-TRT cannot be used for curative intent yet, thus additional research on how to improve the therapeutic efficacy is warranted. A potential way of achieving this, is combining TRT with poly ADP-ribosylation inhibitors (PARPi), which has shown promising results for TRT of neuroendocrine tumor cells. Currently, several clinical trials have been initiated for this combination for PCa, however so far, no evidence of synergism is available for PCa. Therefore, we evaluated the combination of PSMA-TRT with three classes of PARPi in preclinical PCa models. In vitro viability and survival assays were performed using PSMA-expressing PCa cell lines PC3-PIP and LNCaP to assess the effect of increasing concentrations of PARPi veliparib, olaparib or talazoparib in combination with PSMA-TRT compared to single PARPi treatment. Next, DNA damage analyses were performed by quantifying the number of DNA breaks by immunofluorescent stainings. Lastly, the potential of the combination treatments was studied in vivo in mice bearing PC3-PIP xenografts. Our results show that combining PSMA-TRT with PARPi did not synergistically affect the in vitro clonogenic survival or cell viability. DNA-damage analysis revealed only a significant increase in DNA breaks when combining PSMA-TRT with veliparib and not in the other combination treatments. Moreover, PSMA-TRT with PARPi treatment did not improve tumor control compared to PSMA-TRT monotherapy. Overall, the data presented do not support the assumption that combining PSMA-TRT with PARPi leads to a synergistic antitumor effect in PCa. These results underline that extensive preclinical research using various PCa models is imperative to validate the applicability of the combination strategy for PCa, as it is for other cancer types. Full article

(This article belongs to the Special Issue Urogenital Tumors: From Molecular Basis to Therapy)

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Review

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9 pages, 496 KiB

Open AccessReview

Spermatocytic Tumor: A Review

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Int. J. Mol. Sci. 2023, 24(11), 9529; https://doi.org/10.3390/ijms24119529 - 31 May 2023

Viewed by 902

Abstract

Spermatocytic tumor (ST) is a very rare disease, accounting for approximately 1% of testicular cancers. Previously classified as spermatocytic seminoma, it is currently classified within the non-germ neoplasia in-situ-derived tumors and has different clinical-pathologic features when compared with other forms of germ cell [...] Read more.

Spermatocytic tumor (ST) is a very rare disease, accounting for approximately 1% of testicular cancers. Previously classified as spermatocytic seminoma, it is currently classified within the non-germ neoplasia in-situ-derived tumors and has different clinical-pathologic features when compared with other forms of germ cell tumors (GCTs). A web-based search of MEDLINE/PubMed library data was performed in order to identify pertinent articles. In the vast majority of cases, STs are diagnosed at stage I and carry a very good prognosis. The treatment of choice is orchiectomy alone. Nevertheless, there are two rare variants of STs having very aggressive behavior, namely anaplastic ST and ST with sarcomatous transformation, that are resistant to systemic treatments and their prognosis is very poor. We have summarized all the epidemiological, pathological and clinical features available in the literature regarding STs that have to be considered as a specific entity compared to other germ GCTs, including seminoma. With the aim of improving the knowledge of this rare disease, an international registry is required. Full article

(This article belongs to the Special Issue Urogenital Tumors: From Molecular Basis to Therapy)

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14 pages, 1285 KiB

Open AccessReview

HER2 Expression in Bladder Cancer: A Focused View on Its Diagnostic, Prognostic, and Predictive Role

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Francesca Sanguedolce

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Maria Carmela Pedicillo

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Angelo Cormio

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Ugo Giovanni Falagario

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Giuseppe Carrieri

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Luigi Cormio

Int. J. Mol. Sci. 2023, 24(4), 3720; https://doi.org/10.3390/ijms24043720 - 13 Feb 2023

Cited by 6 | Viewed by 1886

Abstract

Bladder cancer (BC) is a heterogeneous disease from a molecular, morphological, and clinical standpoint. HER2 is a known oncogene involved in bladder carcinogenesis. Assessing HER2 overexpression as a result of its molecular changes in a routine pathology practice using immunohistochemistry might be a [...] Read more.

Bladder cancer (BC) is a heterogeneous disease from a molecular, morphological, and clinical standpoint. HER2 is a known oncogene involved in bladder carcinogenesis. Assessing HER2 overexpression as a result of its molecular changes in a routine pathology practice using immunohistochemistry might be a useful adjunct in several scenarios, namely (1) to correctly identify flat urothelial lesions and inverted urothelial lesions in the diagnostic setting; (2) to provide prognostic hints in both non-muscle invasive (NMI) and muscle invasive (MI) tumors, thus supplementing risk stratification tools, especially when evaluating higher-risk tumors such as those with variant morphology; (3) to improve antibody panels as a surrogate marker of BC molecular subtyping. Furthermore, the potential of HER2 as a therapeutic target has been only partly explored so far, in light of the ongoing development of novel target therapies. Full article

(This article belongs to the Special Issue Urogenital Tumors: From Molecular Basis to Therapy)

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18 pages, 404 KiB

Open AccessReview

Are We Ready to Implement Molecular Subtyping of Bladder Cancer in Clinical Practice? Part 2: Subtypes and Divergent Differentiation

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Francesca Sanguedolce

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Ugo Giovanni Falagario

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Luigi Cormio

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Giuseppe Carrieri

Int. J. Mol. Sci. 2022, 23(14), 7844; https://doi.org/10.3390/ijms23147844 - 16 Jul 2022

Cited by 5 | Viewed by 1528

Abstract

Following several attempts to achieve a molecular stratification of bladder cancer (BC) over the last decade, a “consensus” classification has been recently developed to provide a common base for the molecular classification of bladder cancer (BC), encompassing a six-cluster scheme with distinct prognostic [...] Read more.

Following several attempts to achieve a molecular stratification of bladder cancer (BC) over the last decade, a “consensus” classification has been recently developed to provide a common base for the molecular classification of bladder cancer (BC), encompassing a six-cluster scheme with distinct prognostic and predictive characteristics. In order to implement molecular subtyping (MS) as a risk stratification tool in routine practice, immunohistochemistry (IHC) has been explored as a readily accessible, relatively inexpensive, standardized surrogate method, achieving promising results in different clinical settings. The second part of this review deals with the pathological and clinical features of the molecular clusters, both in conventional and divergent urothelial carcinoma, with a focus on the role of IHC-based subtyping. Full article

(This article belongs to the Special Issue Urogenital Tumors: From Molecular Basis to Therapy)

21 pages, 625 KiB

Open AccessReview

Are We Ready to Implement Molecular Subtyping of Bladder Cancer in Clinical Practice? Part 1: General Issues and Marker Expression

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Francesca Sanguedolce

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Ugo Giovanni Falagario

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Luigi Cormio

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Giuseppe Carrieri

Int. J. Mol. Sci. 2022, 23(14), 7819; https://doi.org/10.3390/ijms23147819 - 15 Jul 2022

Cited by 4 | Viewed by 1989

Abstract

Bladder cancer (BC) is a heterogeneous disease with highly variable clinical and pathological features, and resulting in different outcomes. Such heterogeneity ensues from distinct pathogenetic mechanisms and may consistently affect treatment responses in single patients. Thus, over the last few years, several groups [...] Read more.

Bladder cancer (BC) is a heterogeneous disease with highly variable clinical and pathological features, and resulting in different outcomes. Such heterogeneity ensues from distinct pathogenetic mechanisms and may consistently affect treatment responses in single patients. Thus, over the last few years, several groups have developed molecular classification schemes for BC, mainly based on their mRNA expression profiles. A “consensus” classification has recently been proposed to combine the published systems, agreeing on a six-cluster scheme with distinct prognostic and predictive features. In order to implement molecular subtyping as a risk-stratification tool in routine practice, immunohistochemistry (IHC) has been explored as a readily accessible, relatively inexpensive, standardized surrogate method, achieving promising results in different clinical settings. The first part of this review deals with the steps resulting in the development of a molecular subtyping of BC, its prognostic and predictive implications, and the main features of immunohistochemical markers used as surrogates to stratify BC into pre-defined molecular clusters. Full article

(This article belongs to the Special Issue Urogenital Tumors: From Molecular Basis to Therapy)

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