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Molecular Research Efforts in Urothelial Carcinoma 2.0

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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 (31 May 2021) | Viewed by 10741

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Special Issue Editor

Prof. Dr. Georg C. Hutterer

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Guest Editor

Department of Urology, Medizinische Universitat Graz, Graz, Austria
Interests: advanced; metastatic renal cell carcinoma; urologic surgery; urothelial carcinoma of the upper urinary tract; bladder cancer; oncologic outcomes research
Special Issues, Collections and Topics in MDPI journals

Special Issue Information

Dear Colleagues,

Urothelial carcinoma of the bladder (UCB), as well as urothelial carcinoma of the upper urinary tract, represent one of the most interesting and emerging fields in terms of molecular oncology and uro-oncologic discovery efforts over recent years. This Special Issue is a continuation of our previous Special Issue "Molecular Research Efforts in Urothelial Carcinoma".

The Cancer Genome Atlas (TCGA), the International Cancer Genome Consortium (ICGC) projects, and others are successful drivers in promoting genome sequencing efforts for the development of various genetic and molecular sub-classification systems in non-invasive, as well as muscle invasive UCB. Recently, several molecular subtypes of muscle-invasive UCB have been identified, of whom the basal subtype shared biomarkers with basal breast cancers and that were characterized by p63 activation, squamous differentiation, and aggressive disease at presentation [1]. Luminal muscle-invasive UCBs contained features of active PPARγ and estrogen receptor transcription, moreover they were enriched with activating FGFR3 mutations. p53-like UCBs were resistant to neoadjuvant MVAC-chemotherapy, adopting a p53-like phenotype after therapy. These findings have important implications for better prognostication, the future development of targeted agents, as well as disease management with chemotherapy.

Based on the progress in molecular oncology and cancer genetics in UCB, novel treatment options including immune-oncology drugs, FGFR inhibitors or other targeted agents are approved or under development. Research efforts should lead to the discovery of novel predictive biomarkers in this emerging field. In addition to alterations in transcriptome and proteome, epigenetic factors, DNA repair mechanisms and non-coding RNAs have been proposed as pathogenic drivers, tumor suppressors and factors in treatment resistance and patient’s clinical outcome.

Apart from the molecular viewpoint, the required treatment modalities (both surgical and medical), long-term follow-up of patients, as well enormous associated costs of UCB represent a tremendously growing and unsolved public health problem worldwide. Regarding the ten leading cancer types among males in the United States in 2018, estimated new UCB cases rank fourth, the associated estimated deaths rank at the eighth position, respectively [2].

Thus, an improved understanding of the underlying molecular mechanisms in UCB development is of paramount interest, not only to optimize treatment outcomes but to improve cost effective management modalities in this important malignancy. Original research articles, review articles, as well as research letters covering the large field of cancer genetics, molecular oncology, cell biology and newly discovered prognostic biomarkers of urothelial carcinoma are strongly invited.

References

Choi, W.; Porten, S.; Kim, S.; Willis, D.; Plimack, E.R.; Hoffman-Censits, J.; Roth, B.; Cheng, T.; Tran, M.; Lee, I.L.; et al. Identification of distinct basal and luminal subtypes of muscle-invasive bladder cancer with different sensitivities to frontline chemotherapy. Cancer Cell 2014, 25, 152–165.
Siegel, R.L.; Miller, K.D.; Jemal, A. Cancer statistics, 2018. CA Cancer J. Clin. 2018, 68, 7–30.

Prof. Dr. Georg C. Hutterer
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.

Please visit the Instructions for Authors page before submitting a manuscript. There is an Article Processing Charge (APC) for publication in this open access journal. For details about the APC please see here. 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

urothelial carcinoma of the bladder
urothelial carcinoma of the upper urinary tract
biomarkers
targeted agents
immune-oncology drugs
epigenetic factors
DNA repair
tumor suppressor factor

Published Papers (4 papers)

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Research

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16 pages, 3277 KiB

Open AccessArticle

Comprehensive Gene Expression Analyses of Immunohistochemically Defined Subgroups of Muscle-Invasive Urinary Bladder Urothelial Carcinoma

by Bohyun Kim, Insoon Jang, Kwangsoo Kim, Minsun Jung, Cheol Lee, Jeong Hwan Park, Young A. Kim and Kyung Chul Moon

Int. J. Mol. Sci. 2021, 22(2), 628; https://doi.org/10.3390/ijms22020628 - 10 Jan 2021

Cited by 8 | Viewed by 2567

Abstract

A number of urinary bladder urothelial carcinoma (UB UC) mRNA-based classification systems have been reported. It also has been observed that treatment response and prognosis are different for each molecular subtype. In this study, cytokeratin (CK)5/6 and CK20 immunohistochemistry (IHC) were performed, and IHC-based subgroup classification was applied. UB UC was classified into CK5/6 single-positive (SP), CK20 SP, double-positive (DP) and double-negative (DN) subgroups, and transcriptional analysis was performed. The results of gene ontology (GO) terms and functional analysis using differentially expressed genes indicate that, CK5/6 SP and DP subgroups were enriched in cell migration, immune activation, interleukin 6-Janus kinase-signal transducer and activator of transcription 3 (IL6-JAK-STAT3) signaling pathway and tumor necrosis factor-α signaling via the nuclear factor-κB (NF-κB) signaling pathway signature gene. In addition, compared with the other subgroups, the DN subgroup showed inhibited cell movement, cell migration, and cell activation. Furthermore, in survival analysis, the CK5/6 SP subgroup was significantly associated with poor progression-free survival (p = 0.008). The results of our study indicate that the CK5/6 positive subgroup exhibited high gene expression signature related to aggressive behavior and exhibited worse clinical outcome. Full article

(This article belongs to the Special Issue Molecular Research Efforts in Urothelial Carcinoma 2.0)

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18 pages, 45689 KiB

Open AccessArticle

Non-Muscle-Invasive Bladder Carcinoma with Respect to Basal Versus Luminal Keratin Expression

by Minsun Jung, Insoon Jang, Kwangsoo Kim and Kyung Chul Moon

Int. J. Mol. Sci. 2020, 21(20), 7726; https://doi.org/10.3390/ijms21207726 - 19 Oct 2020

Cited by 3 | Viewed by 1900

Abstract

Non-muscle-invasive bladder cancer (NMIBC) consists of transcriptional subtypes that are distinguishable from those of muscle-invasive cancer. We aimed to identify genetic signatures of NMIBC related to basal (K5/6) and luminal (K20) keratin expression. Based on immunohistochemical staining, papillary high-grade NMIBC was classified into K5/6-only (K5/6^High-K20^Low), K20-only (K5/6^Low-K20^High), double-high (K5/6^High-K20^High), and double-low (K5/6^Low-K20^Low) groups (n = 4 per group). Differentially expressed genes identified between each group using RNA sequencing were subjected to functional enrichment analyses. A public dataset was used for validation. Machine learning algorithms were implemented to predict our samples against UROMOL subtypes. Transcriptional investigation demonstrated that the K20-only group was enriched in the cell cycle, proliferation, and progression gene sets, and this result was also observed in the public dataset. The K5/6-only group was closely regulated by basal-type gene sets and showed activated invasive or adhesive functions. The double-high group was enriched in cell cycle arrest, macromolecule biosynthesis, and FGFR3 signaling. The double-low group moderately expressed genes related to cell cycle and macromolecule biosynthesis. All K20-only group tumors were classified as UROMOL “class 2” by the machine learning algorithms. K5/6 and K20 expression levels indicate the transcriptional subtypes of NMIBC. The K5/6^Low-K20^High expression is a marker of high-risk NMIBC. Full article

(This article belongs to the Special Issue Molecular Research Efforts in Urothelial Carcinoma 2.0)

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Review

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17 pages, 315 KiB

Open AccessReview

Perioperative Systemic Treatment for Muscle-Invasive Bladder Cancer: Current Evidence and Future Perspectives

by In-Ho Kim and Hyo-Jin Lee

Int. J. Mol. Sci. 2021, 22(13), 7201; https://doi.org/10.3390/ijms22137201 - 04 Jul 2021

Cited by 7 | Viewed by 3257

Abstract

Radical cystectomy is the primary treatment for muscle-invasive bladder cancer; however, approximately 50% of patients develop metastatic disease within 2 years of diagnosis, which results in dismal prognosis. Therefore, systemic treatment is important to improve the prognosis of muscle-invasive bladder cancer. Currently, several guidelines recommend cisplatin-based neoadjuvant chemotherapy before radical cystectomy, and adjuvant chemotherapy is recommended in patients who have not received neoadjuvant chemotherapy. Immune checkpoint inhibitors have recently become the standard treatment option for metastatic urothelial carcinoma. Owing to their clinical benefits, several immune checkpoint inhibitors, with or without other agents (including other immunotherapy, cytotoxic chemotherapy, and emerging agents such as antibody drug conjugates), are being extensively investigated in perioperative settings. Several studies for perioperative immunotherapy have shown that immune checkpoint inhibitors have promising efficacy with relatively low toxicity, and have explored the predictive molecular biomarkers. Herein, we review the current evidence and discuss the future perspectives of perioperative systemic treatment for muscle-invasive bladder cancer. Full article

(This article belongs to the Special Issue Molecular Research Efforts in Urothelial Carcinoma 2.0)

17 pages, 591 KiB

Open AccessReview

Treatment Strategies and Metabolic Pathway Regulation in Urothelial Cell Carcinoma: A Comprehensive Review

by Huang-Yu Yang, Chao-Yi Wu, Jia-Jin Chen and Tao-Han Lee

Int. J. Mol. Sci. 2020, 21(23), 8993; https://doi.org/10.3390/ijms21238993 - 26 Nov 2020

Cited by 9 | Viewed by 2392

Abstract

For a long time, cisplatin-based chemotherapy had been viewed as first-line chemotherapy for advanced and metastatic urothelial carcinoma (UC). However, many patients with UC had been classified as cisplatin-ineligible who can only receive alternative chemotherapy with poor treatment response, and the vast majority of the cisplatin-eligible patients eventually progressed, even those with objective response with cisplatin-based chemotherapy initially. By understanding tumor immunology in UC, immune checkpoint inhibitors, targeting on programmed death 1 (PD-1) and cytotoxic T lymphocyte-associated antigen 4 (CTLA-4) pathways, had been proven as first-line treatment for cisplatin-ineligible metastatic UC and as second-line treatment for patients with platinum-refractory metastatic UC by the U.S Food and Drug Administration (FDA). In 2020, JAVEIN bladder 100 further reported that PD-L1 inhibitors showed benefits on prolonged survival and progression-free survival as maintenance therapy. Besides targeting on immune checkpoint, manipulation of the tumor microenvironment by metabolic pathways intervention, including inhibition on tumor glycolysis, lactate accumulation and exogenous glutamine uptake, had been investigated in the past few years. In this comprehensive review, we start by introducing traditional chemotherapy of UC, and then we summarize current evidences supporting the use of immune checkpoint inhibitors and highlight ongoing clinical trials. Lastly, we reviewed the tumor metabolic characteristic and the anti-tumor treatments targeting on metabolic pathways. Full article

(This article belongs to the Special Issue Molecular Research Efforts in Urothelial Carcinoma 2.0)

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