Editorial

5 pages, 210 KiB

Open AccessEditorial

Clear Cell Renal Cell Carcinoma: A Test Bench for Investigating Tumor Complexity

by Claudia Manini, Estíbaliz López-Fernández, Gorka Larrinaga and José I. López

Cancers 2024, 16(4), 829; https://doi.org/10.3390/cancers16040829 - 19 Feb 2024

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Clear cell renal cell carcinoma (CCRCC), by far the most common renal cancer subtype, is an aggressive tumor variant, serving in recent years as a prolific test bench in cancer research [...] Full article

(This article belongs to the Special Issue Clear Cell Renal Cell Carcinoma 2022–2023)

Research

Jump to: Editorial, Review, Other

11 pages, 2045 KiB

Open AccessArticle

Efficacy of Immune Checkpoint Inhibitors vs. Tyrosine Kinase Inhibitors/Everolimus in Adjuvant Renal Cell Carcinoma: Indirect Comparison of Disease-Free Survival

by Andrea Ossato, Lorenzo Gasperoni, Luna Del Bono, Andrea Messori and Vera Damuzzo

Cancers 2024, 16(3), 557; https://doi.org/10.3390/cancers16030557 - 28 Jan 2024

Cited by 1 | Viewed by 708

Abstract

Background: The proven efficacy of mTOR inhibitors (mTORIs), tyrosine kinase inhibitors (TKIs) or immune checkpoint inhibitors (ICIs) in metastatic renal cell carcinoma (RCC) suggests that these agents should be investigated as adjuvant therapy with the aim of eliminating undetectable microscopic residual disease after [...] Read more.

Background: The proven efficacy of mTOR inhibitors (mTORIs), tyrosine kinase inhibitors (TKIs) or immune checkpoint inhibitors (ICIs) in metastatic renal cell carcinoma (RCC) suggests that these agents should be investigated as adjuvant therapy with the aim of eliminating undetectable microscopic residual disease after curative resection. The aim of our study was to compare the efficacy of these treatments using an innovative method of reconstructing individual patient data. Methods: Nine phase III trials describing adjuvant RCC treatments were selected. The IPDfromKM method was used to reconstruct individual patient data from Kaplan–Meier (KM) curves. The combination treatments were compared with the control arm (placebo) for disease-free survival (DFS). Multi-treatment KM curves were used to summarize the results. Standard statistical tests were performed. These included hazard ratio and likelihood ratio tests for heterogeneity. Results: In the overall population, the study showed that two ICIs (nivolumab plus ipilimumab and pembrolizumab) and one TKI (sunitinib) were superior to the placebo, whereas both TKIs and mTORIs were inferior. As we assessed DFS as the primary endpoint for the adjuvant comparison, the overall survival benefit remains unknown. Conclusions: This novel approach to investigating survival has allowed us to conduct all indirect head-to-head comparisons between these agents in a context where no “real” comparative trials have been conducted. Full article

(This article belongs to the Special Issue Clear Cell Renal Cell Carcinoma 2022–2023)

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11 pages, 1767 KiB

Open AccessArticle

Targeting NPC1 in Renal Cell Carcinoma

by Rushaniya Fazliyeva, Peter Makhov, Robert G. Uzzo and Vladimir M. Kolenko

Cancers 2024, 16(3), 517; https://doi.org/10.3390/cancers16030517 - 25 Jan 2024

Cited by 1 | Viewed by 727

Abstract

Rapidly proliferating cancer cells have a greater requirement for cholesterol than normal cells. Tumor cells are largely dependent on exogenous lipids given that their growth requirements are not fully met by endogenous pathways. Our current study shows that ccRCC cells have redundant mechanisms [...] Read more.

Rapidly proliferating cancer cells have a greater requirement for cholesterol than normal cells. Tumor cells are largely dependent on exogenous lipids given that their growth requirements are not fully met by endogenous pathways. Our current study shows that ccRCC cells have redundant mechanisms of cholesterol acquisition. We demonstrate that all major lipoproteins (i.e., LDL, HDL, and VLDL) have a comparable ability to support the growth of ccRCC cells and are equally effective in counteracting the antitumor activities of TKIs. The intracellular trafficking of exogenous lipoprotein-derived cholesterol appears to be distinct from the movement of endogenously synthesized cholesterol. De novo synthetized cholesterol is transported from the endoplasmic reticulum directly to the plasma membrane and to the acyl-CoA: cholesterol acyltransferase, whereas lipoprotein-derived cholesterol is distributed through the NPC1-dependent endosomal trafficking system. Expression of NPC1 is increased in ccRCC at mRNA and protein levels, and high expression of NPC1 is associated with poor prognosis. Our current findings show that ccRCC cells are particularly sensitive to the inhibition of endolysosomal cholesterol export and underline the therapeutic potential of targeting NPC1 in ccRCC. Full article

(This article belongs to the Special Issue Clear Cell Renal Cell Carcinoma 2022–2023)

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18 pages, 4015 KiB

Open AccessArticle

Non-Metastatic Clear Cell Renal Cell Carcinoma Immune Cell Infiltration Heterogeneity and Prognostic Ability in Patients Following Surgery

by Daniel D. Shapiro, Taja Lozar, Lingxin Cheng, Elliot Xie, Israa Laklouk, Moon Hee Lee, Wei Huang, David F. Jarrard, Glenn O. Allen, Rong Hu, Toshi Kinoshita, Karla Esbona, Paul F. Lambert, Christian M. Capitini, Christina Kendziorski and Edwin Jason Abel

Cancers 2024, 16(3), 478; https://doi.org/10.3390/cancers16030478 - 23 Jan 2024

Cited by 1 | Viewed by 1170

Abstract

Predicting which patients will progress to metastatic disease after surgery for non-metastatic clear cell renal cell carcinoma (ccRCC) is difficult; however, recent data suggest that tumor immune cell infiltration could be used as a biomarker. We evaluated the quantity and type of immune [...] Read more.

Predicting which patients will progress to metastatic disease after surgery for non-metastatic clear cell renal cell carcinoma (ccRCC) is difficult; however, recent data suggest that tumor immune cell infiltration could be used as a biomarker. We evaluated the quantity and type of immune cells infiltrating ccRCC tumors for associations with metastatic progression following attempted curative surgery. We quantified immune cell densities in the tumor microenvironment and validated our findings in two independent patient cohorts with multi-region sampling to investigate the impact of heterogeneity on prognostic accuracy. For non-metastatic ccRCC, increased CD8⁺ T cell infiltration was associated with a reduced likelihood of progression to metastatic disease. Interestingly, patients who progressed to metastatic disease also had increased percentages of exhausted CD8⁺ T cells. Finally, we evaluated the spatial heterogeneity of the immune infiltration and demonstrated that patients without metastatic progression had CD8⁺ T cells in closer proximity to ccRCC cells. These data strengthen the evidence for CD8⁺ T cell infiltration as a prognostic biomarker in non-metastatic ccRCC and demonstrate that multi-region sampling may be necessary to fully characterize immune infiltration within heterogeneous tumors. Tumor CD8⁺ T cell infiltration should be investigated as a biomarker in adjuvant systemic therapy clinical trials for high-risk non-metastatic RCC. Full article

(This article belongs to the Special Issue Clear Cell Renal Cell Carcinoma 2022–2023)

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12 pages, 563 KiB

Open AccessArticle

Surgical Trends and Complications in Partial and Radical Nephrectomy: Results from the GRAND Study

by Nikolaos Pyrgidis, Gerald Bastian Schulz, Christian Stief, Iulia Blajan, Troya Ivanova, Annabel Graser and Michael Staehler

Cancers 2024, 16(1), 97; https://doi.org/10.3390/cancers16010097 - 24 Dec 2023

Cited by 1 | Viewed by 912

Abstract

Background: We aimed to evaluate the current trends in renal cancer surgery, as well as to compare the perioperative outcomes of partial versus radical nephrectomy. Methods: We used the GeRmAn Nationwide inpatient Data (GRAND), provided by the Research Data Center of the Federal [...] Read more.

Background: We aimed to evaluate the current trends in renal cancer surgery, as well as to compare the perioperative outcomes of partial versus radical nephrectomy. Methods: We used the GeRmAn Nationwide inpatient Data (GRAND), provided by the Research Data Center of the Federal Bureau of Statistics (2005–2021). We report the largest study in the field, with 317,843 patients and multiple patient-level analyses. Results: Overall, 123,924 (39%) patients underwent partial and 193,919 (61%) underwent radical nephrectomy in Germany from 2005 to 2021. Of them, 57,308 (18%) were operated on in low-, 142,702 (45%) in intermediate-, and 117,833 (37%) in high-volume centers. A total of 249,333 (78%) patients underwent open, 44,994 (14%) laparoscopic, and 23,516 (8%) robotic nephrectomy. The number of patients undergoing renal surgery remained relatively stable from 2005 to 2021. Over the study period, the utilization of partial nephrectomy increased threefold, while radical nephrectomy decreased by about 40%. After adjusting for major risk factors in the multivariate regression analysis, radical nephrectomy was associated with 3.2-fold higher odds (95% CI: 3.2 to 3.9, p < 0.001) of 30-day mortality, longer hospitalization by 1.9 days (95% CI: 1.9 to 2, p < 0.001), and higher inpatient costs by EUR 1778 (95% CI: 1694 to 1862, p < 0.001) compared to partial nephrectomy. Furthermore, radical nephrectomy had a higher risk of in-hospital transfusion (p < 0.001), sepsis (p < 0.001), acute respiratory failure (p < 0.001), acute kidney disease (p < 0.001), acute thromboembolism (p < 0.001), surgical wound infection (p < 0.001), ileus (p < 0.001), intensive care unit admission (p < 0.001), and pancreatitis (p < 0.001). Conclusions: More patients are offered partial nephrectomy in Germany. Patients undergoing radical nephrectomy present with a higher rate of concomitant risk factors and have increased perioperative morbidity and mortality, prolonged hospitalization, and increased in-hospital costs. Full article

(This article belongs to the Special Issue Clear Cell Renal Cell Carcinoma 2022–2023)

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15 pages, 4019 KiB

Open AccessArticle

The Association of Tumor Immune Microenvironment of the Primary Lesion with Time to Metastasis in Patients with Renal Cell Carcinoma: A Retrospective Analysis

by Kazutoshi Fujita, Go Kimura, Toyonori Tsuzuki, Taigo Kato, Eri Banno, Akira Kazama, Ryo Yamashita, Yuto Matsushita, Daisuke Ishii, Tomoya Fukawa, Yuki Nakagawa, Tamaki Fukuyama, Fumikazu Sano, Yukihiro Kondo and Hirotsugu Uemura

Cancers 2022, 14(21), 5258; https://doi.org/10.3390/cancers14215258 - 26 Oct 2022

Cited by 2 | Viewed by 1450

Abstract

Biological or immunological differences in primary lesions between synchronous and metachronous metastatic renal cell carcinoma (mRCC) have been reported. However, the association between the tumor immune microenvironment (TIME) of primary lesions and time to metastasis remains unknown. We investigated the differences in the [...] Read more.

Biological or immunological differences in primary lesions between synchronous and metachronous metastatic renal cell carcinoma (mRCC) have been reported. However, the association between the tumor immune microenvironment (TIME) of primary lesions and time to metastasis remains unknown. We investigated the differences in the TIME of primary lesions based on time intervals to metastasis, mainly between the synchronous group (SG; metastasis within 3 months) and metachronous group (MG; metastasis after 3 months), and its association with clinicopathological parameters in patients with mRCC. Overall, 568 patients treated first-line with vascular endothelial growth factor receptor inhibitors comprised the analysis population (SG: N = 307 [54.0%]; MG: N = 261 [46.0%]). SG had a higher proportion of patients with poor prognostic pathological feature tumors: WHO/ISUP grade 4, necrosis, lymphovascular invasion, infiltrative growth pattern, and sarcomatoid differentiation. Regarding the TIME, more immunogenic features were seen in SG than MG, with a higher PD-L1 positivity and a lower proportion of the desert phenotype. This is the first study to examine the differences in the TIME of primary lesions in patients with mRCC based on the time intervals to metastasis. The TIME of primary lesions could affect the time to metastasis. Full article

(This article belongs to the Special Issue Clear Cell Renal Cell Carcinoma 2022–2023)

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Review

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20 pages, 1156 KiB

Open AccessReview

The Role of the Complement in Clear Cell Renal Carcinoma (ccRCC)—What Future Prospects Are There for Its Use in Clinical Practice?

by Martina Panebianco, Chiara Ciccarese, Alessandro Strusi, Viria Beccia, Carmine Carbone, Antonio Agostini, Geny Piro, Giampaolo Tortora and Roberto Iacovelli

Cancers 2024, 16(3), 490; https://doi.org/10.3390/cancers16030490 - 23 Jan 2024

Cited by 1 | Viewed by 805

Abstract

In recent years, the first-line available therapeutic options for metastatic renal cell carcinoma (mRCC) have radically changed with the introduction into clinical practice of new immune checkpoint inhibitor (ICI)-based combinations. Many efforts are focusing on identifying novel prognostic and predictive markers in this [...] Read more.

In recent years, the first-line available therapeutic options for metastatic renal cell carcinoma (mRCC) have radically changed with the introduction into clinical practice of new immune checkpoint inhibitor (ICI)-based combinations. Many efforts are focusing on identifying novel prognostic and predictive markers in this setting. The complement system (CS) plays a central role in promoting the growth and progression of mRCC. In particular, mRCC has been defined as an “aggressive complement tumor”, which encompasses a group of malignancies with poor prognosie and highly expressed complement components. Several preclinical and retrospective studies have demonstrated the negative prognostic role of the complement in mRCC; however, there is little evidence on its possible role as a predictor of the response to ICIs. The purpose of this review is to explore more deeply the physio-pathological role of the complement in the development of RCC and its possible future use in clinical practice as a prognostic and predictive factor. Full article

(This article belongs to the Special Issue Clear Cell Renal Cell Carcinoma 2022–2023)

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20 pages, 2819 KiB

Open AccessReview

Disturbances in Nitric Oxide Cycle and Related Molecular Pathways in Clear Cell Renal Cell Carcinoma

by Corina Daniela Ene, Mircea Tampa, Simona Roxana Georgescu, Clara Matei, Iulia Maria Teodora Leulescu, Claudia Ioana Dogaru, Mircea Nicolae Penescu and Ilinca Nicolae

Cancers 2023, 15(24), 5797; https://doi.org/10.3390/cancers15245797 - 11 Dec 2023

Cited by 1 | Viewed by 956

Abstract

It is important to note that maintaining adequate levels of nitric oxide (NO), the turnover, and the oxidation level of nitrogen are essential for the optimal progression of cellular processes, and alterations in the NO cycle indicate a crucial step in the onset [...] Read more.

It is important to note that maintaining adequate levels of nitric oxide (NO), the turnover, and the oxidation level of nitrogen are essential for the optimal progression of cellular processes, and alterations in the NO cycle indicate a crucial step in the onset and progression of multiple diseases. Cellular accumulation of NO and reactive nitrogen species in many types of tumour cells is expressed by an increased susceptibility to oxidative stress in the tumour microenvironment. Clear cell renal cell carcinoma (ccRCC) is a progressive metabolic disease in which tumour cells can adapt to metabolic reprogramming to enhance NO production in the tumour space. Understanding the factors governing NO biosynthesis metabolites in ccRCC represents a relevant, valuable approach to studying NO-based anticancer therapy. Exploring the molecular processes mediated by NO, related disturbances in molecular pathways, and NO-mediated signalling pathways in ccRCC could have significant therapeutic implications in managing and treating this condition. Full article

(This article belongs to the Special Issue Clear Cell Renal Cell Carcinoma 2022–2023)

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14 pages, 557 KiB

Open AccessReview

Recent Advances in Single-Cell RNA-Sequencing of Primary and Metastatic Clear Cell Renal Cell Carcinoma

by Adele M. Alchahin, Ioanna Tsea and Ninib Baryawno

Cancers 2023, 15(19), 4734; https://doi.org/10.3390/cancers15194734 - 26 Sep 2023

Cited by 1 | Viewed by 1601

Abstract

Over the past two decades, significant progress has been made in the treatment of clear cell renal cell carcinoma (ccRCC), with a shift towards adopting new treatment approaches ranging from monotherapy to triple-combination therapy. This progress has been spearheaded by fundamental technological advancements [...] Read more.

Over the past two decades, significant progress has been made in the treatment of clear cell renal cell carcinoma (ccRCC), with a shift towards adopting new treatment approaches ranging from monotherapy to triple-combination therapy. This progress has been spearheaded by fundamental technological advancements that have allowed a deeper understanding of the various biological components of this cancer. In particular, the rapid commercialization of transcriptomics technologies, such as single-cell RNA-sequencing (scRNA-seq) methodologies, has played a crucial role in accelerating this understanding. Through precise measurements facilitated by these technologies, the research community has successfully identified and characterized diverse tumor, immune, and stromal cell populations, uncovering their interactions and pathways involved in disease progression. In localized ccRCC, patients have shown impressive response rates to treatment. However, despite the emerging findings and new knowledge provided in the field, there are still patients that do not respond to treatment, especially in advanced disease stages. One of the key challenges lies in the limited study of ccRCC metastases compared to localized cases. This knowledge gap may contribute to the relatively low survival rates and response rates observed in patients with metastatic ccRCC. To bridge this gap, we here delve into recent research utilizing scRNA-seq technologies in both primary and metastatic ccRCC. The goal of this review is to shed light on the current state of knowledge in the field, present existing treatment options, and emphasize the crucial steps needed to improve survival rates, particularly in cases of metastatic ccRCC. Full article

(This article belongs to the Special Issue Clear Cell Renal Cell Carcinoma 2022–2023)

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10 pages, 4087 KiB

Open AccessReview

Cystic Clear Cell Renal Cell Carcinoma: A Morphological and Molecular Reappraisal

by Giacomo Maria Pini, Roberta Lucianò and Maurizio Colecchia

Cancers 2023, 15(13), 3352; https://doi.org/10.3390/cancers15133352 - 26 Jun 2023

Cited by 1 | Viewed by 1700

Abstract

A wide variety of renal neoplasms can have cystic areas. These can occur for different reasons: some tumors have an intrinsic cystic architecture, while others exhibit pseudocystic degeneration of necrotic foci or they have cystically dilated renal tubules constrained by stromal neoplastic cells. [...] Read more.

A wide variety of renal neoplasms can have cystic areas. These can occur for different reasons: some tumors have an intrinsic cystic architecture, while others exhibit pseudocystic degeneration of necrotic foci or they have cystically dilated renal tubules constrained by stromal neoplastic cells. Clear cell renal cell carcinoma (CCRCC), either solid or cystic, is the most frequent type of renal cancer. While pseudocysts are found in high-grade aggressive CCRCC, cystic growth is associated with low-grade indolent cases. The latter also form through a cyst-dependent molecular pathway, and they are more frequent in patients suffering from VHL disease. The differential diagnosis of multilocular cystic renal neoplasm of low malignant potential and clear cell papillary renal cell tumor can be especially hard and requires a focused macroscopical and microscopical pathological analysis. As every class of renal tumor includes cystic forms, knowledge of the criteria required for a differential diagnosis is mandatory. Full article

(This article belongs to the Special Issue Clear Cell Renal Cell Carcinoma 2022–2023)

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20 pages, 1702 KiB

Open AccessReview

Understanding the Tumor Immune Microenvironment in Renal Cell Carcinoma

by Daniel D. Shapiro, Brendan Dolan, Israa A. Laklouk, Sahar Rassi, Taja Lozar, Hamid Emamekhoo, Andrew L. Wentland, Meghan G. Lubner and Edwin Jason Abel

Cancers 2023, 15(9), 2500; https://doi.org/10.3390/cancers15092500 - 27 Apr 2023

Cited by 2 | Viewed by 2215

Abstract

Scientific understanding of how the immune microenvironment interacts with renal cell carcinoma (RCC) has substantially increased over the last decade as a result of research investigations and applying immunotherapies, which modulate how the immune system targets and eliminates RCC tumor cells. Clinically, immune [...] Read more.

Scientific understanding of how the immune microenvironment interacts with renal cell carcinoma (RCC) has substantially increased over the last decade as a result of research investigations and applying immunotherapies, which modulate how the immune system targets and eliminates RCC tumor cells. Clinically, immune checkpoint inhibitor therapy (ICI) has revolutionized the treatment of advanced clear cell RCC because of improved outcomes compared to targeted molecular therapies. From an immunologic perspective, RCC is particularly interesting because tumors are known to be highly inflamed, but the mechanisms underlying the inflammation of the tumor immune microenvironment are atypical and not well described. While technological advances in gene sequencing and cellular imaging have enabled precise characterization of RCC immune cell phenotypes, multiple theories have been suggested regarding the functional significance of immune infiltration in RCC progression. The purpose of this review is to describe the general concepts of the anti-tumor immune response and to provide a detailed summary of the current understanding of the immune response to RCC tumor development and progression. This article describes immune cell phenotypes that have been reported in the RCC microenvironment and discusses the application of RCC immunophenotyping to predict response to ICI therapy and patient survival. Full article

(This article belongs to the Special Issue Clear Cell Renal Cell Carcinoma 2022–2023)

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15 pages, 321 KiB

Open AccessReview

Advances in Imaging-Based Biomarkers in Renal Cell Carcinoma: A Critical Analysis of the Current Literature

by Lina Posada Calderon, Lennert Eismann, Stephen W. Reese, Ed Reznik and Abraham Ari Hakimi

Cancers 2023, 15(2), 354; https://doi.org/10.3390/cancers15020354 - 05 Jan 2023

Cited by 8 | Viewed by 2520

Abstract

Cross-sectional imaging is the standard diagnostic tool to determine underlying biology in renal masses, which is crucial for subsequent treatment. Currently, standard CT imaging is limited in its ability to differentiate benign from malignant disease. Therefore, various modalities have been investigated to identify [...] Read more.

Cross-sectional imaging is the standard diagnostic tool to determine underlying biology in renal masses, which is crucial for subsequent treatment. Currently, standard CT imaging is limited in its ability to differentiate benign from malignant disease. Therefore, various modalities have been investigated to identify imaging-based parameters to improve the noninvasive diagnosis of renal masses and renal cell carcinoma (RCC) subtypes. MRI was reported to predict grading of RCC and to identify RCC subtypes, and has been shown in a small cohort to predict the response to targeted therapy. Dynamic imaging is promising for the staging and diagnosis of RCC. PET/CT radiotracers, such as ¹⁸F-fluorodeoxyglucose (FDG), ¹²⁴I-cG250, radiolabeled prostate-specific membrane antigen (PSMA), and ¹¹C-acetate, have been reported to improve the identification of histology, grading, detection of metastasis, and assessment of response to systemic therapy, and to predict oncological outcomes. Moreover, ⁹⁹Tc-sestamibi and SPECT scans have shown promising results in distinguishing low-grade RCC from benign lesions. Radiomics has been used to further characterize renal masses based on semantic and textural analyses. In preliminary studies, integrated machine learning algorithms using radiomics proved to be more accurate in distinguishing benign from malignant renal masses compared to radiologists’ interpretations. Radiomics and radiogenomics are used to complement risk classification models to predict oncological outcomes. Imaging-based biomarkers hold strong potential in RCC, but require standardization and external validation before integration into clinical routines. Full article

(This article belongs to the Special Issue Clear Cell Renal Cell Carcinoma 2022–2023)

Other

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28 pages, 731 KiB

Open AccessSystematic Review

Comprehensive Systematic Review of Biomarkers in Metastatic Renal Cell Carcinoma: Predictors, Prognostics, and Therapeutic Monitoring

by Komal A. Dani, Joseph M. Rich, Sean S. Kumar, Harmony Cen, Vinay A. Duddalwar and Anishka D’Souza

Cancers 2023, 15(20), 4934; https://doi.org/10.3390/cancers15204934 - 11 Oct 2023

Cited by 1 | Viewed by 1511

Abstract

Background: Challenges remain in determining the most effective treatment strategies and identifying patients who would benefit from adjuvant or neoadjuvant therapy in renal cell carcinoma. The objective of this review is to provide a comprehensive overview of biomarkers in metastatic renal cell carcinoma [...] Read more.

Background: Challenges remain in determining the most effective treatment strategies and identifying patients who would benefit from adjuvant or neoadjuvant therapy in renal cell carcinoma. The objective of this review is to provide a comprehensive overview of biomarkers in metastatic renal cell carcinoma (mRCC) and their utility in prediction of treatment response, prognosis, and therapeutic monitoring in patients receiving systemic therapy for metastatic disease. Methods: A systematic literature search was conducted using the PubMed database for relevant studies published between January 2017 and December 2022. The search focused on biomarkers associated with mRCC and their relationship to immune checkpoint inhibitors, targeted therapy, and VEGF inhibitors in the adjuvant, neoadjuvant, and metastatic settings. Results: The review identified various biomarkers with predictive, prognostic, and therapeutic monitoring potential in mRCC. The review also discussed the challenges associated with anti-angiogenic and immune-checkpoint monotherapy trials and highlighted the need for personalized therapy based on molecular signatures. Conclusion: This comprehensive review provides valuable insights into the landscape of biomarkers in mRCC and their potential applications in prediction of treatment response, prognosis, and therapeutic monitoring. The findings underscore the importance of incorporating biomarker assessment into clinical practice to guide treatment decisions and improve patient outcomes in mRCC. Full article

(This article belongs to the Special Issue Clear Cell Renal Cell Carcinoma 2022–2023)

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10 pages, 520 KiB

Open AccessCommentary

Role of Clock Genes and Circadian Rhythm in Renal Cell Carcinoma: Recent Evidence and Therapeutic Consequences

by Matteo Santoni, Javier Molina-Cerrillo, Giorgio Santoni, Elaine T. Lam, Francesco Massari, Veronica Mollica, Giulia Mazzaschi, Bernardo L. Rapoport, Enrique Grande and Sebastiano Buti

Cancers 2023, 15(2), 408; https://doi.org/10.3390/cancers15020408 - 07 Jan 2023

Cited by 3 | Viewed by 2307

Abstract

Circadian rhythm regulates cellular differentiation and physiology and shapes the immune response. Altered expression of clock genes might lead to the onset of common malignant cancers, including Renal Cell Carcinoma (RCC). Data from Cancer Genome Atlas (TCGA) indicate that clock genes PER1-3, [...] Read more.

Circadian rhythm regulates cellular differentiation and physiology and shapes the immune response. Altered expression of clock genes might lead to the onset of common malignant cancers, including Renal Cell Carcinoma (RCC). Data from Cancer Genome Atlas (TCGA) indicate that clock genes PER1-3, CRY2, CLOCK, NR1D2 and RORα are overexpressed in RCC tissues and correlate with patients’ prognosis. The expression of clock genes could finely tune transcription factor activity in RCC and is associated with the extent of immune cell infiltration. The clock system interacts with hypoxia-induced factor-1α (HIF-1α) and regulates the circadian oscillation of mammalian target of rapamycin (mTOR) activity thereby conditioning the antitumor effect of mTOR inhibitors. The stimulation of natural killer (NK) cell activity exerted by the administration of interferon-α, a cornerstone of the first era of immunotherapy for RCC, relevantly varies according to circadian dosing time. Recent evidence demonstrated that time-of-day infusion directly affects the efficacy of immune checkpoint inhibitors in cancer patients. Compounds targeting the circadian clock have been identified and their role in the era of immunotherapy deserves to be further investigated. In this review, we aimed at addressing the impact of clock genes on the natural history of kidney cancer and their potential therapeutic implications. Full article

(This article belongs to the Special Issue Clear Cell Renal Cell Carcinoma 2022–2023)

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