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20 pages, 6556 KiB

Open AccessArticle

How Cancer Cells Invade Bladder Epithelium and Form Tumors: The Mouse Bladder Tumor Model as a Model of Tumor Recurrence in Patients

by Andreja Erman, Urška Kamenšek, Urška Dragin Jerman, Mojca Pavlin, Maja Čemažar, Peter Veranič and Rok Romih

Int. J. Mol. Sci. 2021, 22(12), 6328; https://doi.org/10.3390/ijms22126328 - 13 Jun 2021

Cited by 5 | Viewed by 2728

Abstract

Non-muscle-invasive bladder cancer is the most common form of bladder cancer. The main problem in managing bladder tumors is the high recurrence after the transurethral resection of bladder tumors (TURBT). Our study aimed to examine the fate of intravesically applied cancer cells as [...] Read more.

Non-muscle-invasive bladder cancer is the most common form of bladder cancer. The main problem in managing bladder tumors is the high recurrence after the transurethral resection of bladder tumors (TURBT). Our study aimed to examine the fate of intravesically applied cancer cells as the implantation of cancer cells after TURBT is thought to be a cause of tumor recurrence. We established an orthotopic mouse bladder tumor model with MB49-GFP cancer cells and traced them during the first three days to define their location and contacts with normal urothelial cells. Data were obtained by Western blot, immunolabeling, and light and electron microscopy. We showed that within the first two hours, applied cancer cells adhered to the traumatized epithelium by cell projections containing α3β1 integrin on their tips. Cancer cells then migrated through the epithelium and on day 3, they reached the basal lamina or even penetrated it. In established bladder tumors, E-cadherin and desmoplakin 1/2 were shown as feasible immunohistochemical markers of tumor margins based on the immunolabeling of various junctional proteins. Altogether, these results for the first time illustrate cancer cell implantation in vivo mimicking cellular events of tumor recurrence in bladder cancer patients. Full article

(This article belongs to the Special Issue Bladder Cancer)

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18 pages, 3642 KiB

Open AccessArticle

Attachment of Cancer Urothelial Cells to the Bladder Epithelium Occurs on Uroplakin-Negative Cells and Is Mediated by Desmosomal and Not by Classical Cadherins

by Urška Dragin Jerman, Tanja Višnjar, Iva Hafner Bratkovič, Nataša Resnik, Mojca Pavlin, Peter Veranič and Mateja Erdani Kreft

Int. J. Mol. Sci. 2021, 22(11), 5565; https://doi.org/10.3390/ijms22115565 - 25 May 2021

Cited by 4 | Viewed by 2227

Abstract

Urinary bladder cancer is often multifocal; however, the intraluminal dissemination of the urothelial cancer cells is poorly understood. The involvement of N-cadherin in the adhesion of the cancer urothelial cells to the urothelium had not previously been studied. Therefore, we herein explore the [...] Read more.

Urinary bladder cancer is often multifocal; however, the intraluminal dissemination of the urothelial cancer cells is poorly understood. The involvement of N-cadherin in the adhesion of the cancer urothelial cells to the urothelium had not previously been studied. Therefore, we herein explore the possibility of the intraluminal dissemination of the urothelial cancer cells by evaluating the role of classical cadherins in the adhesion of urothelial cancer cells to the urothelium. We used E-cadherin negative T24 cells and established a T24 Ncad^low cell line with an additionally decreased expression of N-cadherin in the plasma membrane and a decreased secretion of proform of metalloproteinase 2. The labelled T24 and T24 Ncad^low cells were seeded onto urothelial in vitro models. After 24 h in co-culture, unattached cancer cells were rinsed and urothelia with attached cancer urothelial cells were processed for fluorescence and electron microscopy. Both the T24 and T24 Ncad^low cells attached to the urothelium, yet only to the uroplakin-negative urothelial cells. The ultrastructural analysis showed that T24 and T24 Ncad^low cells adhere to poorly differentiated urothelial cells by desmosomes. To achieve this, they first disrupt tight junctions of superficial urothelial cells. This study indicates that the lack of E-cadherin expression and decreased expression of N-cadherin in the plasma membrane of T24 cells does not interfere with their adhesion to the urothelium; therefore, our results suggest that intraluminal dissemination of cancer urothelial cells along the urothelium occurs on uroplakin-negative cells and is desmosome-mediated. Full article

(This article belongs to the Special Issue Bladder Cancer)

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15 pages, 46272 KiB

Open AccessArticle

Cytotoxic Activity of LLO Y406A Is Targeted to the Plasma Membrane of Cancer Urothelial Cells

by Nataša Resnik, Larisa Tratnjek, Mateja Erdani Kreft, Matic Kisovec, Saša Aden, Apolonija Bedina Zavec, Gregor Anderluh, Marjetka Podobnik and Peter Veranič

Int. J. Mol. Sci. 2021, 22(7), 3305; https://doi.org/10.3390/ijms22073305 - 24 Mar 2021

Cited by 4 | Viewed by 2892

Abstract

Identification of novel agents for bladder cancer treatment is highly desirable due to the high incidence of tumor recurrence and the risk of progression to muscle-invasive disease. The key feature of the cholesterol-dependent toxin listeriolysin O mutant (LLO Y406A) is its preferential activity [...] Read more.

Identification of novel agents for bladder cancer treatment is highly desirable due to the high incidence of tumor recurrence and the risk of progression to muscle-invasive disease. The key feature of the cholesterol-dependent toxin listeriolysin O mutant (LLO Y406A) is its preferential activity at pH 5.7, which could be exploited either directly for selective targeting of cancer cells or the release of accumulated therapeutics from acidic endosomes. Therefore, our goal was to compare the cytotoxic effect of LLO Y406A on cancer cells (RT4) and normal urothelial cells (NPU), and to identify which cell membranes are the primary target of LLO Y406A by viability assays, life-cell imaging, fluorescence, and electron microscopy. LLO Y406A decreased viability, altered cell morphology, provoked membrane blebbing, and induced apoptosis in RT4 cells, while it did not affect NPU cells. LLO Y406A did not cause endosomal escape in RT4 cells, while the plasma membrane of RT4 cells was revealed as the primary target of LLO Y406A. It has been concluded that LLO Y406A has the ability to selectively eliminate cancer urothelial cells through pore-forming activity at the plasma membrane, without cytotoxic effects on normal urothelial cells. This promising selective activity merits further testing as an anti-cancer agent. Full article

(This article belongs to the Special Issue Bladder Cancer)

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17 pages, 4136 KiB

Open AccessArticle

Grainyhead-Like 3 Influences Migration and Invasion of Urothelial Carcinoma Cells

by Felix Wezel, Johannes Lustig, Anca Azoitei, Junnan Liu, Sabine Meessen, Gregoire Najjar, Viktor Zehe, Philipp Faustmann, Friedemann Zengerling, Axel John, Thomas Martini, Christian Bolenz and Cagatay Günes

Int. J. Mol. Sci. 2021, 22(6), 2959; https://doi.org/10.3390/ijms22062959 - 15 Mar 2021

Cited by 11 | Viewed by 2404

Abstract

Invasive urothelial carcinomas of the bladder (UCB) characteristically show a loss of differentiation markers. The transcription factor Grainyhead-like 3 (GRHL3) plays an important role in the development and differentiation of normal urothelium. The contribution to UCB progression is still elusive. Differential [...] Read more.

Invasive urothelial carcinomas of the bladder (UCB) characteristically show a loss of differentiation markers. The transcription factor Grainyhead-like 3 (GRHL3) plays an important role in the development and differentiation of normal urothelium. The contribution to UCB progression is still elusive. Differential expression of GRHL3 was assessed in normal human urothelium and in non-invasive and invasive bladder cancer cell lines. The contribution of GRHL3 to cell proliferation, viability and invasion in UCB cell lines was determined by gain- and loss-of-function assays in vitro and in an organ culture model using de-epithelialized porcine bladders. GRHL3 expression was detectable in normal human urothelial cells and showed significantly higher mRNA and protein levels in well-differentiated, non-invasive RT4 urothelial carcinoma cells compared to moderately differentiated RT112 cells. GRHL3 expression was absent in anaplastic and invasive T24 cells. Ectopic de novo expression of GRHL3 in T24 cells significantly impaired their migration and invasion properties in vitro and in organ culture. Its downregulation improved the invasive capacity of RT4 cells. The results indicate that GRHL3 may play a role in progression and metastasis in UCB. In addition, this work demonstrates that de-epithelialized porcine bladder organ culture can be a useful, standardized tool to assess the invasive capacity of cancer cells. Full article

(This article belongs to the Special Issue Bladder Cancer)

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16 pages, 3322 KiB

Open AccessArticle

A Molecular Signature Determines the Prognostic and Therapeutic Subtype of Non-Muscle-Invasive Bladder Cancer Responsive to Intravesical Bacillus Calmette-Guérin Therapy

by Seon-Kyu Kim, Seong-Hwan Park, Yeong Uk Kim, Young Joon Byun, Xuan-Mei Piao, Pildu Jeong, Kyeong Kim, Hee Youn Lee, Sung Pil Seo, Ho Won Kang, Won Tae Kim, Yong-June Kim, Sang-Cheol Lee, Sung-Kwon Moon, Yung Hyun Choi, Wun-Jae Kim, Seon-Young Kim and Seok Joong Yun

Int. J. Mol. Sci. 2021, 22(3), 1450; https://doi.org/10.3390/ijms22031450 - 1 Feb 2021

Cited by 10 | Viewed by 3362

Abstract

Non-muscle-invasive bladder cancer (NMIBC) is clinically heterogeneous; thus, many patients fail to respond to treatment and relapse. Here, we identified a molecular signature that is both prognostic and predictive for NMIBC heterogeneity and responses to Bacillus Calmette-Guérin (BCG) therapy. Transcriptomic profiling of 948 [...] Read more.

Non-muscle-invasive bladder cancer (NMIBC) is clinically heterogeneous; thus, many patients fail to respond to treatment and relapse. Here, we identified a molecular signature that is both prognostic and predictive for NMIBC heterogeneity and responses to Bacillus Calmette-Guérin (BCG) therapy. Transcriptomic profiling of 948 NMIBC patients identified a signature-based subtype predictor, MSP888, along with three distinct molecular subtypes: DP.BCG+ (related to progression and response to BCG treatment), REC.BCG+ (related to recurrence and response to BCG treatment), and EP (equivocal prognosis). Patients with the DP.BCG+ subtype showed worse progression-free survival but responded to BCG treatment, whereas those with the REC.BCG+ subtype showed worse recurrence-free survival but responded to BCG treatment. Multivariate analyses revealed that MSP888 showed independent clinical utility for predicting NMIBC prognosis (each p = 0.001 for progression and recurrence, respectively). Comparative analysis of this classifier and previously established molecular subtypes (i.e., Lund taxonomy and UROMOL class) revealed that a great proportion of patients were similar between subtypes; however, the MSP888 predictor better differentiated biological activity or responsiveness to BCG treatment. Our data increase our understanding of the mechanisms underlying the poor prognosis of NMIBC and the effectiveness of BCG therapy, which should improve clinical practice and complement other diagnostic tools. Full article

(This article belongs to the Special Issue Bladder Cancer)

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14 pages, 2789 KiB

Open AccessArticle

E2F1 Promotes Progression of Bladder Cancer by Modulating RAD54L Involved in Homologous Recombination Repair

by Jeong-Yeon Mun, Seung-Woo Baek, Won Young Park, Won-Tae Kim, Seon-Kyu Kim, Yun-Gil Roh, Mi-So Jeong, Gi-Eun Yang, Jong-Ho Lee, Jin Woong Chung, Yung Hyun Choi, In-Sun Chu and Sun-Hee Leem

Int. J. Mol. Sci. 2020, 21(23), 9025; https://doi.org/10.3390/ijms21239025 - 27 Nov 2020

Cited by 25 | Viewed by 3006

Abstract

DNA repair defects are important factors in cancer development. High DNA repair activity can affect cancer progression and chemoresistance. DNA double-strand breaks in cancer cells caused by anticancer agents can be restored by non-homologous end joining (NHEJ) and homologous recombination repair (HRR). Our [...] Read more.

DNA repair defects are important factors in cancer development. High DNA repair activity can affect cancer progression and chemoresistance. DNA double-strand breaks in cancer cells caused by anticancer agents can be restored by non-homologous end joining (NHEJ) and homologous recombination repair (HRR). Our previous study has identified E2F1 as a key gene in bladder cancer progression. In this study, DNA repair genes related to E2F1 were analyzed, and RAD54L involved in HRR was identified. In gene expression analysis of bladder cancer patients, the survival of patients with high RAD54L expression was shorter with cancer progression than in patients with low RAD54L expression. This study also revealed that E2F1 directly binds to the promoter region of RAD54L and regulates the transcription of RAD54L related to the HRR pathway. This study also confirmed that DNA breaks are repaired by RAD54L induced by E2F1 in bladder cancer cells treated with MMC. In summary, RAD54L was identified as a new target directly regulated by E2F1. Our results suggest that, E2F1 and RAD54L could be used as diagnostic markers for bladder cancer progression and represent potential therapeutic targets. Full article

(This article belongs to the Special Issue Bladder Cancer)

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Review

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14 pages, 754 KiB

Open AccessReview

Cell Therapies in Bladder Cancer Management

by Lucia Morales and Jesús M. Paramio

Int. J. Mol. Sci. 2021, 22(6), 2818; https://doi.org/10.3390/ijms22062818 - 10 Mar 2021

Cited by 9 | Viewed by 3202

Abstract

Currently, bladder cancer (BC) represents a challenging problem in the field of Oncology. The high incidence, prevalence, and progression of BC have led to the exploration of new avenues in its management, in particular in advanced metastatic stages. The recent inclusion of immune [...] Read more.

Currently, bladder cancer (BC) represents a challenging problem in the field of Oncology. The high incidence, prevalence, and progression of BC have led to the exploration of new avenues in its management, in particular in advanced metastatic stages. The recent inclusion of immune checkpoint blockade inhibitors as a therapeutic option for BC represents an unprecedented advance in BC management. However, although some patients show durable responses, the fraction of patients showing benefit is still limited. Notwithstanding, cell-based therapies, initially developed for the management of hematological cancers by infusing immune or trained immune cells or after the engineering of chimeric antigen receptor (CAR) expressing cells, are promising tools to control, or even cure, solid tumors. In this review, we summarize recent cell-based immunotherapy studies, with a special focus on BC. Full article

(This article belongs to the Special Issue Bladder Cancer)

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15 pages, 1160 KiB

Open AccessReview

Role of Exosomal miRNA in Bladder Cancer: A Promising Liquid Biopsy Biomarker

by Xuan-Mei Piao, Eun-Jong Cha, Seok Joong Yun and Wun-Jae Kim

Int. J. Mol. Sci. 2021, 22(4), 1713; https://doi.org/10.3390/ijms22041713 - 8 Feb 2021

Cited by 39 | Viewed by 4892

Abstract

Bladder cancer (BCa) is the most prevalent neoplasia of the urinary tract. Unfortunately, limited improvements in effective BCa management have meant that it remains a challenging disease. Cystoscopy has been the gold standard for BCa diagnosis and surveillance for over two centuries but [...] Read more.

Bladder cancer (BCa) is the most prevalent neoplasia of the urinary tract. Unfortunately, limited improvements in effective BCa management have meant that it remains a challenging disease. Cystoscopy has been the gold standard for BCa diagnosis and surveillance for over two centuries but is an invasive and expensive approach. Recently, liquid biopsy has been identified as a promising field of cancer research, due to its noninvasiveness and ease of sampling. Liquid biopsy samples could provide comprehensive information regarding the genetic landscape of cancer and could track genomic evolution of the disease over time. Exosomes, which contain RNAs, DNAs, and proteins, are a potential source of tumor biomarkers in liquid biopsy samples. In particular, exosomal miRNAs (exomiRs) hold great promise as biomarkers for tumor development and progression. In this review, we provide an overview of liquid biopsy biomarkers, with a particular focus on the use of exomiRs as biomarkers of cancer, and summarize their clinical implications for BCa. Finally, we discuss the future perspectives of these biomarkers in cancer research. Full article

(This article belongs to the Special Issue Bladder Cancer)

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