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Recent Advances in the Field of Metastatic Renal Cell Carcinoma...
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Recent Advances in the Field of Metastatic Renal Cell Carcinoma Research—from Biology to Predictive Biomarkers towards Personalised Medicine

A special issue of Cells (ISSN 2073-4409). This special issue belongs to the section "Cellular Pathology".

Deadline for manuscript submissions: closed (1 June 2023) | Viewed by 10912

Special Issue Editors

Dr. Ondřej Fiala

E-Mail Website
Guest Editor
1. Department of Oncology and Radiotherapeutics, Faculty of Medicine and University Hospital in Pilsen, Charles University, Pilsen, Czech Republic
2. Laboratory of Cancer Treatment and Tissue Regeneration, Biomedical Center, Faculty of Medicine in Pilsen, Charles University, Pilsen, Czech Republic
Interests: colorectal cancer; urological malignancies; lung cancer; targeted therapy; immunotherapy; biomarkers
Special Issues, Collections and Topics in MDPI journals
Dr. Radka Vaclavikova

E-Mail Website
Guest Editor
1. Toxicogenomics Unit, National Institute of Public Health, 100 42 Prague 10, Czech Republic
2. Biomedical Center, Faculty of Medicine in Pilsen, Charles University, 323 00 Pilsen, Czech Republic
Interests: ovarian cancer; breast cancer; renal cell cancer; biomarkers; biotechnology
Special Issues, Collections and Topics in MDPI journals

Special Issue Information

Dear Colleagues,

Renal cell carcinoma (RCC) is a malignancy with an increasing incidence in developed countries. Despite advances in diagnostics, almost 20% of cases are metastatic at the time of primary diagnosis, and almost a further 20% of primary localised cases become metastatic during follow-up. The management of metastatic RCC (mRCC) has been markedly changing in recent years, and significant progress has been made in the systemic treatment of metastatic RCC (mRCC), leading to improvements in the survival and quality of life of patients. Tyrosine kinase inhibitors (TKIs) blocking angiogenesis and immunotherapy in the form of immune checkpoint inhibitors (ICIs) represent the most commonly used agents, as well as various combination regimens in the form of ICI+ICI or ICI+TKI, which have become a standard of care in the first-line treatment of mRCC. Although these novel regimens achieve excellent treatment responses, this treatment entails a wide range of side effects and there is no doubt that a signle therapy cannot suit every patient with mRCC. Thus, there is an urgent need for personalised medicine, which requires predictive biomarkers. In mRCC, relevant predictive biomarkers at the molecular level are still not available; only prognostic models are used (MSKCC, IMDC), but their value is limited from a predictive point of view.

This Special Issue of Cells will present research articles and reviews that cover the scope of mRCC from the perspectives of experimental and clinical researchers. These articles should focus on various aspects of mRCC, including the biological and predictive biomarkers useful for the personalised systemic treatment of patients with mRCC. All scientists working in these fields are cordially invited to submit their manuscripts.

We look forward to your contributions to this Special Issue.

Dr. Ondřej Fiala
Dr. Radka Vaclavikova
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. Cells 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 2700 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

  • renal cell cancer
  • systemic therapy
  • tyrosine kinase inhibitors
  • immunotherapy
  • prediction
  • prognosis
  • biomarkers

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Published Papers (4 papers)

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Research

15 pages, 11273 KiB  
Article
Integrated Metabolomic and Transcriptomic Analysis of Modified Nucleosides for Biomarker Discovery in Clear Cell Renal Cell Carcinoma
by Daniel A. Mohl, Simon Lagies, Kyra Zodel, Matthias Zumkeller, Asin Peighambari, Athina Ganner, Dietmar A. Plattner, Elke Neumann-Haefelin, Mojca Adlesic, Ian J. Frew and Bernd Kammerer
Cells 2023, 12(8), 1102; https://doi.org/10.3390/cells12081102 - 7 Apr 2023
Cited by 6 | Viewed by 2670
Abstract
Clear cell renal cell carcinoma (ccRCC) accounts for ~75% of kidney cancers. The biallelic inactivation of the von Hippel–Lindau tumor suppressor gene (VHL) is the truncal driver mutation of most cases of ccRCC. Cancer cells are metabolically reprogrammed and excrete modified [...] Read more.
Clear cell renal cell carcinoma (ccRCC) accounts for ~75% of kidney cancers. The biallelic inactivation of the von Hippel–Lindau tumor suppressor gene (VHL) is the truncal driver mutation of most cases of ccRCC. Cancer cells are metabolically reprogrammed and excrete modified nucleosides in larger amounts due to their increased RNA turnover. Modified nucleosides occur in RNAs and cannot be recycled by salvage pathways. Their potential as biomarkers has been demonstrated for breast or pancreatic cancer. To assess their suitability as biomarkers in ccRCC, we used an established murine ccRCC model, harboring Vhl, Trp53 and Rb1 (VPR) knockouts. Cell culture media of this ccRCC model and primary murine proximal tubular epithelial cells (PECs) were investigated by HPLC coupled to triple-quadrupole mass spectrometry using multiple-reaction monitoring. VPR cell lines were significantly distinguishable from PEC cell lines and excreted higher amounts of modified nucleosides such as pseudouridine, 5-methylcytidine or 2′-O-methylcytidine. The method’s reliability was confirmed in serum-starved VPR cells. RNA-sequencing revealed the upregulation of specific enzymes responsible for the formation of those modified nucleosides in the ccRCC model. These enzymes included Nsun2, Nsun5, Pus1, Pus7, Naf1 and Fbl. In this study, we identified potential biomarkers for ccRCC for validation in clinical trials. Full article
(This article belongs to the Special Issue Recent Advances in the Field of Metastatic Renal Cell Carcinoma Research—from Biology to Predictive Biomarkers towards Personalised Medicine)
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30 pages, 99652 KiB  
Article
Identification and Validation of the Prognostic Panel in Clear Cell Renal Cell Carcinoma Based on Resting Mast Cells for Prediction of Distant Metastasis and Immunotherapy Response
by Yang Su, Tianxiang Zhang, Jinsen Lu, Lei Qian, Yang Fei, Li Zhang, Song Fan, Jun Zhou, Jieqiong Tang, Haige Chen and Chaozhao Liang
Cells 2023, 12(1), 180; https://doi.org/10.3390/cells12010180 - 1 Jan 2023
Cited by 11 | Viewed by 3072
Abstract
Clear cell renal cell carcinoma (ccRCC) has a high metastatic rate, and its incidence and mortality are still rising. The aim of this study was to identify the key tumor-infiltrating immune cells (TIICs) affecting the distant metastasis and prognosis of patients with ccRCC [...] Read more.
Clear cell renal cell carcinoma (ccRCC) has a high metastatic rate, and its incidence and mortality are still rising. The aim of this study was to identify the key tumor-infiltrating immune cells (TIICs) affecting the distant metastasis and prognosis of patients with ccRCC and to construct a relevant prognostic panel to predict immunotherapy response. Based on ccRCC bulk RNA sequencing data, resting mast cells (RMCs) were screened and verified using the CIBERSORT algorithm, survival analysis, and expression analysis. Distant metastasis-associated genes were identified using single-cell RNA sequencing data. Subsequently, a three-gene (CFB, PPP1R18, and TOM1L1) panel with superior distant metastatic and prognostic performance was established and validated, which stratified patients into high- and low-risk groups. The high-risk group exhibited lower infiltration of RMCs, higher tumor mutation burden (TMB), and worse prognosis. Therapeutically, the high-risk group was more sensitive to anti-PD-1 and anti-CTLA-4 immunotherapy, whereas the low-risk group displayed a better response to anti-PD-L1 immunotherapy. Furthermore, two immune clusters revealing distinct immune, clinical, and prognosis heterogeneity were distinguished. Immunohistochemistry of ccRCC samples verified the expression patterns of the three key genes. Collectively, the prognostic panel based on RMCs is able to predict distant metastasis and immunotherapy response in patients with ccRCC, providing new insight for the treatment of advanced ccRCC. Full article
(This article belongs to the Special Issue Recent Advances in the Field of Metastatic Renal Cell Carcinoma Research—from Biology to Predictive Biomarkers towards Personalised Medicine)
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15 pages, 2712 KiB  
Article
Immune Checkpoint Inhibitor (ICI) Genes and Aging in Clear Cell Renal Cell Carcinoma (ccRCC): Clinical and Genomic Study
by Abdullah Al-Danakh, Mohammed Safi, Mohammed Alradhi, Qiwei Chen, Salem Baldi, Xinqing Zhu and Deyong Yang
Cells 2022, 11(22), 3641; https://doi.org/10.3390/cells11223641 - 17 Nov 2022
Cited by 6 | Viewed by 2194
Abstract
Background: It is anticipated that there will be a large rise in the number of tumor diagnoses and mortality in those aged 65 and older over the course of upcoming decades. Immune checkpoint inhibitors, often known as ICIs, boost immune system activity by [...] Read more.
Background: It is anticipated that there will be a large rise in the number of tumor diagnoses and mortality in those aged 65 and older over the course of upcoming decades. Immune checkpoint inhibitors, often known as ICIs, boost immune system activity by selectively targeting ICI genes. On the other hand, old age may be connected with unfavorable results. Methods: The Cancer Genome Atlas (TCGA) provided gene expression data from ccRCC tissue and key clinical variables. ICI gene databases were applied and verified using the GEO database. Results: We identified 14 ICI genes as risk gene signatures among 528 ccRCC patients using univariate and multivariable cox hazard models, and the elderly group was linked with poor survival. Then, by utilizing a new nomogram method, the TNFSF15 gene and age predicting values were estimated at one, three, and five years (85%, 81%, and 81%), respectively, and our age-related risk score was significant even after multivariable analysis (HR = 1.518, p = 0.009, CI = 1.1102.076). TNFSF15 gene expression was lower in elderly ccRCC patients (p = 0.0001). A negative connection between age and the TNFSF15 gene expression was discovered by correlation analysis (p = 0.0001). The verification of the gene by utilizing GEO (GSE167093) with 604 patients was obtained as external validation that showed significant differences in the TNFSF15 gene between young and elderly patients (p = 0.007). Additionally, the protein–protein interactions of the TNFSF15 gene with other ICI genes and aging-related genes was determined. In addition, the TNFSF15 expression was significantly correlated with pathological stages (p = 0.018). Furthermore, it was discovered that the biological processes of senescence, cellular senescence, the immune system, and many immune cell infiltration and immune function types are all closely tied. Conclusions: Along with the risk score evaluation, the ICI gene TNFSF15 was identified as a tumor suppressor gene related to inequalities in age survival and is associated with pathological stages and different immunity statuses. The aging responses of ccRCC patients and related gene expression need further investigation in order to identify potential therapeutic targets. Full article
(This article belongs to the Special Issue Recent Advances in the Field of Metastatic Renal Cell Carcinoma Research—from Biology to Predictive Biomarkers towards Personalised Medicine)
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11 pages, 1679 KiB  
Article
Adding Cyclooxygenase Inhibitors to Immune Checkpoint Inhibitors Did Not Improve Outcomes in Metastatic Renal Cell Carcinoma
by Yumeng Zhang, Premsai Kumar, Jacob J. Adashek, William P. Skelton IV, Jiannong Li, Aram Vosoughi, Jad Chahoud, Brandon J. Manley and Philippe E. Spiess
Cells 2022, 11(16), 2505; https://doi.org/10.3390/cells11162505 - 12 Aug 2022
Cited by 6 | Viewed by 2327
Abstract
Modulating the cyclooxygenase 2 (COX-2) pathway has improved responses to immune checkpoint inhibitors (ICIs) in certain solid tumors, such as melanoma. Little is known about COX-2 inhibition in response to ICIs in metastatic renal cell carcinoma (mRCC). In this retrospective cohort study, we [...] Read more.
Modulating the cyclooxygenase 2 (COX-2) pathway has improved responses to immune checkpoint inhibitors (ICIs) in certain solid tumors, such as melanoma. Little is known about COX-2 inhibition in response to ICIs in metastatic renal cell carcinoma (mRCC). In this retrospective cohort study, we examined the effect of COX-2 inhibitors on the long-term outcomes of mRCC patients undergoing ICI therapies. Among 211 patients with mRCC, 23 patients were excluded due to loss to follow-up. Among 188 included patients, 120 patients received either an NSAID or aspirin for at least three weeks during ICI therapies. Clear cell histology was present in 96% of cases. The median overall survival (OS) was similar regardless of the COX inhibitor (COXi) (i.e., NSAID or aspirin) use (27 months for COXi vs. 33 months for no-COXi groups; p = 0.73). The no-COXi group showed a trend toward longer median progression-free survival (8 months for COXi vs. 13 months for no-COXi groups; p = 0.13). When looking specifically at NSAID use in a multivariate analysis, NSAID use was associated with a higher risk of progression (HR = 1.52 [95% CI, 1.04–2.22]) and death (HR = 1.60 [95% CI, 1.02–2.52]). In summary, COXis did not improve disease control or survival among patients with mRCC who were undergoing ICI therapies. Instead, the concurrent use of NSAIDs was associated with worse outcomes. Larger studies are needed to validate our observation. Full article
(This article belongs to the Special Issue Recent Advances in the Field of Metastatic Renal Cell Carcinoma Research—from Biology to Predictive Biomarkers towards Personalised Medicine)
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