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Renal Cell Carcinoma: From Pathophysiology to Novel Therapeutic Approaches

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A special issue of Biomedicines (ISSN 2227-9059). This special issue belongs to the section "Molecular and Translational Medicine".

Deadline for manuscript submissions: closed (30 April 2022) | Viewed by 35228

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Dr. Silvio Maringhini

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Instituto Mediterraneo per i Trapianti e Terapie ad Alta Specializzazione, 90127 Palermo, Italy
Interests: clinical nephrology; renal disease; nephrology urinary; infections; nephrotic syndrome; pediatric nephrology
Special Issues, Collections and Topics in MDPI journals

Dr. Riuko Ohashi

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Division of Molecular and Diagnostic Pathology, Graduate School of Medical and Dental Sciences, Niigata University, 1-757 Asahimachi-dori, Chuo-ku, Niigata 951-8510, Japan
Interests: renal cell carcinoma; pathology; molecular pathology; biomarkers
Special Issues, Collections and Topics in MDPI journals

Special Issue Information

Dear Colleagues,

Renal cell carcinoma is a complex disease comprised of a variety of histological subtypes. The most common histological subtype is clear cell renal cell carcinoma (ccRCC), which accounts for 70–80% of kidney cancer. Recent diagnostic and therapeutic advances are improving the survival rate of kidney cancer patients. The loss of tumor suppressor genes and activation of oncogenes allow tumors to reprogram the pathways. A large number of biomarkers have been proposed for predicting RCC recurrence. Some molecular-targeted therapies, such as tyrosine kinase inhibitors, mTOR inhibitors, and immunotherapies, have dramatically improved the outcome of RCCs. Ultrasonography is the most frequently used imaging modality for the initial diagnosis of renal masses, but a multimodality imaging approach is routinely performed in RCC. The medical treatment of RCC has greatly changed in recent years, thanks to new information acquired on the molecular pathogenesis and of its histology. However, acquired drug resistance and treatment for a prognostically unfavorable subgroup of ccRCCs and other histological subtypes remain a major challenge. Novel biomarkers to predict outcomes, drug responses, and a novel therapeutic target are highly desirable.

This Special Issue of Biomedicines focuses on recent discoveries on clinicopathological, physiological, and molecular approaches to the diagnosis, classification, and novel multidisciplinary treatment. Considering the complexity of the molecular biological background of each histological subtype of renal cell carcinoma, we welcome contributions aimed at both major and emerging histological subtypes of renal cell carcinoma.

Dr. Silvio Maringhini
Dr. Riuko Ohashi
Guest Editors

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Keywords

renal cell carcinoma
pathology
physiology
diagnosis
multimodal treatment
drug resistance
biomarkers

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Published Papers (11 papers)

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Research

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14 pages, 2169 KiB

Open AccessArticle

Histologic-Based Tumor-Associated Immune Cells Status in Clear Cell Renal Cell Carcinoma Correlates with Gene Signatures Related to Cancer Immunity and Clinical Outcomes

by Chisato Ohe, Takashi Yoshida, Junichi Ikeda, Toyonori Tsuzuki, Riuko Ohashi, Haruyuki Ohsugi, Naho Atsumi, Ryosuke Yamaka, Ryoichi Saito, Yoshiki Yasukochi, Koichiro Higasa, Hidefumi Kinoshita and Koji Tsuta

Biomedicines 2022, 10(2), 323; https://0-doi-org.brum.beds.ac.uk/10.3390/biomedicines10020323 - 29 Jan 2022

Cited by 6 | Viewed by 2580

Abstract

The three-tier immunophenotype (desert, excluded, and inflamed) and the four-tier immunophenotype (cold, immunosuppressed, excluded, and hot) have been linked to prognosis and immunotherapy response. This study aims to evaluate whether immunophenotypes of clear cell renal cell carcinoma, identified on hematoxylin and eosin-stained slides, correlate with gene expression signatures related to cancer immunity, and clinical outcomes. We evaluated tumor-associated immune cells (TAICs) status using three methodologies: three-tier immunophenotype based on the location of TAICs, four-tier immunophenotype considering both the location and degree of TAICs and inflammation score focusing only on the degree of TAICs, using a localized clear cell renal cell carcinoma cohort (n = 436) and The Cancer Genome Atlas (TCGA)-KIRC cohort (n = 162). We evaluated the association of the TAICs status assessed by three methodologies with CD8 and PD-L1 immunohistochemistry and immune gene expression signatures by TCGA RNA-sequencing data. All three methodologies correlated with immunohistochemical and immune gene expression signatures. The inflammation score and the four-tier immunophenotype showed similarly higher accuracy in predicting recurrence-free survival and overall survival compared to the three-tier immunophenotype. In conclusion, a simple histologic assessment of TIACs may predict clinical outcomes and immunotherapy responses. Full article

(This article belongs to the Special Issue Renal Cell Carcinoma: From Pathophysiology to Novel Therapeutic Approaches)

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15 pages, 2459 KiB

Open AccessArticle

Gene Expression Analysis of Aggressive Adult Xp11.2 Translocation Renal Cell Carcinoma at Clinical Stage T1N0M0 to Identify Potential Prognostic and Therapeutic Biomarkers

by Jee Soo Park, Myung Eun Lee, Won Sik Jang, Jongchan Kim, Se Mi Park and Won Sik Ham

Biomedicines 2022, 10(2), 321; https://0-doi-org.brum.beds.ac.uk/10.3390/biomedicines10020321 - 29 Jan 2022

Cited by 1 | Viewed by 2167

Abstract

Xp11.2 translocation renal cell carcinoma (tRCC), involving transcription factor E3 (TFE3) gene fusions, is a rare and aggressive RCC variant when present in adults and has been recently recognized as a unique entity in RCC. Biomarkers and treatment guidelines do not exist for patients with aggressive Xp11.2 tRCC. The aim was to identify and evaluate therapeutic biomarkers for aggressive Xp11.2 tRCC. RNA sequencing was performed using formalin-fixed, paraffin-embedded tissues from 11 adult patients with clinical T1N0M0 Xp11.2 tRCC, including three patients with aggressive characteristics (recurrence or cancer-specific death after nephrectomy). Thirty genes were differentially expressed between the aggressive and non-aggressive groups, even after adjustment, and were associated with KEGG pathways related to the aggressiveness of Xp11.2 tRCC. PIK3R2, involved in various KEGG pathways, including the PI3K/AKT/mTOR pathway, was overexpressed in the Xp11.2 tRCC cell lines UOK120 and UOK146. The PI3K pathway inhibitor LY294002 showed a significant therapeutic benefit. This study provides the first candidate biomarker, PIK3R2, for aggressive clinical T1N0M0 Xp11.2 tRCC. Furthermore, this study is the first to recommend a targeted drug, LY294002, for aggressive Xp11.2 tRCC based on the molecular pathophysiology. Full article

(This article belongs to the Special Issue Renal Cell Carcinoma: From Pathophysiology to Novel Therapeutic Approaches)

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9 pages, 723 KiB

Open AccessArticle

SERS Liquid Biopsy Profiling of Serum for the Diagnosis of Kidney Cancer

by Tudor Moisoiu, Stefania D. Iancu, Dan Burghelea, Mihnea P. Dragomir, Gheorghita Iacob, Andrei Stefancu, Ramona G. Cozan, Oana Antal, Zoltán Bálint, Valentin Muntean, Radu I. Badea, Emilia Licarete, Nicolae Leopold and Florin I. Elec

Biomedicines 2022, 10(2), 233; https://0-doi-org.brum.beds.ac.uk/10.3390/biomedicines10020233 - 22 Jan 2022

Cited by 14 | Viewed by 3293

Abstract

Renal cancer (RC) represents 3% of all cancers, with a 2% annual increase in incidence worldwide, opening the discussion about the need for screening. However, no established screening tool currently exists for RC. To tackle this issue, we assessed surface-enhanced Raman scattering (SERS) profiling of serum as a liquid biopsy strategy to detect renal cell carcinoma (RCC), the most prevalent histologic subtype of RC. Thus, serum samples were collected from 23 patients with RCC and 27 controls (CTRL) presenting with a benign urological pathology such as lithiasis or benign prostatic hypertrophy. SERS profiling of deproteinized serum yielded SERS band spectra attributed mainly to purine metabolites, which exhibited higher intensities in the RCC group, and Raman bands of carotenoids, which exhibited lower intensities in the RCC group. Principal component analysis (PCA) of the SERS spectra showed a tendency for the unsupervised clustering of the two groups. Next, three machine learning algorithms (random forest, kNN, naïve Bayes) were implemented as supervised classification algorithms for achieving discrimination between the RCC and CTRL groups, yielding an AUC of 0.78 for random forest, 0.78 for kNN, and 0.76 for naïve Bayes (average AUC 0.77 ± 0.01). The present study highlights the potential of SERS liquid biopsy as a diagnostic and screening strategy for RCC. Further studies involving large cohorts and other urologic malignancies as controls are needed to validate the proposed SERS approach. Full article

(This article belongs to the Special Issue Renal Cell Carcinoma: From Pathophysiology to Novel Therapeutic Approaches)

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15 pages, 4064 KiB

Open AccessArticle

Lactotransferrin Downregulation Serves as a Potential Predictor for the Therapeutic Effectiveness of mTOR Inhibitors in the Metastatic Clear Cell Renal Cell Carcinoma without PTEN Mutation

by Jing-Quan Zheng, Che-Hsuan Lin, Hsun-Hua Lee, Wen-Ke Wang, Yiu-Shun Tong, Kang-Yun Lee, Hui-Wen Chiu and Yuan-Feng Lin

Biomedicines 2021, 9(12), 1896; https://0-doi-org.brum.beds.ac.uk/10.3390/biomedicines9121896 - 13 Dec 2021

Cited by 3 | Viewed by 2074

Abstract

Approximately 30% of clear cell renal cell carcinoma (ccRCC) patients develop metastatic spread at the first diagnosis. Therefore, identifying a useful biomarker to predict ccRCC metastasis or therapeutic effectiveness in ccRCC patients is urgently needed. Previously, we demonstrated that lactotransferrin (LTF) downregulation enhanced the metastatic potential of ccRCC. Here, we show that LTF expression conversely associates with the mTORC1 activity as simulated by gene set enrichment analysis (GSEA). Moreover, Western blot analyses revealed that the LTF knockdown promoted, but the inclusion of recombinant human LTF protein suppressed, the phosphorylation of Akt/mTOR proteins in the detected ccRCC cells. Kaplan–Meier analyses demonstrated that the signature of combining an upregulated mTORC1 activity with a downregulated LTF expression referred to a worse overall and progression-free survival probabilities and associated with distant cancer metastasis in TCGA ccRCC patients. Furthermore, we found that the LTF-suppressed Akt/mTOR activation triggered an increased formation of autophagy in the highly metastatic ccRCC cells. The addition of autophagy inhibitor 3-methyadenine restored the LTF-suppressed cellular migration ability of highly metastatic ccRCC cells. Receiver operating characteristic (ROC) analyses showed that the expression of the LTF and MTORC1 gene set, not the autophagy gene set, could be the useful biomarkers to predict 5-year overall survival rate and cancer progression in ccRCC patients. Significantly, the signature of combining mTORC1 upregulation and LTF downregulation was shown as an independent prognostic factor in a multivariate analysis under the progression-free survival condition using the TCGA ccRCC database. Finally, the treatment with mTOR inhibitor rapamycin predominantly reduced the formation of autophagy and ultimately mitigated the cellular migration ability of ccRCC cells with LTF knockdown. Our findings suggest that LTF downregulation is a biomarker for guiding the use of mTOR inhibitors to combat metastatic ccRCC in the clinic. Full article

(This article belongs to the Special Issue Renal Cell Carcinoma: From Pathophysiology to Novel Therapeutic Approaches)

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26 pages, 21460 KiB

Open AccessArticle

The Morphological Spectrum of Papillary Renal Cell Carcinoma and Prevalence of Provisional/Emerging Renal Tumor Entities with Papillary Growth

by João Lobo, Riuko Ohashi, Birgit M. Helmchen, Niels J. Rupp, Jan H. Rüschoff and Holger Moch

Biomedicines 2021, 9(10), 1418; https://0-doi-org.brum.beds.ac.uk/10.3390/biomedicines9101418 - 09 Oct 2021

Cited by 17 | Viewed by 6320

Abstract

Renal cell carcinoma (RCC) represents a heterogeneous disease, encompassing an increasing number of tumor subtypes. Post-2016, the World Health Organization (WHO) classification recognized that the spectrum of papillary renal cell carcinoma is evolving and has long surpassed the dichotomic simplistic “type 1 versus type 2” classification. The differential diagnosis of pRCC includes several new provisional/emerging entities with papillary growth. Type 2 tumors have been cleared out of several confounding entities, now regarded as independent tumors with specific clinical and molecular backgrounds. In this work we describe the prevalence and characteristics of emerging papillary tumor entities in two renal tumor cohorts (one consisting of consecutive papillary tumors from a single institute, the other consisting of consultation cases from several centers). After a review of 154 consecutive pRCC cases, 58% remained type 1 pRCC, and 34% type 2 pRCC. Papillary renal neoplasm with reversed polarity (1.3%), biphasic hyalinizing psammomatous RCC (1.3%), and biphasic squamoid/alveolar RCC (4.5%) were rare. Among 281 consultation cases, 121 (43%) tumors had a dominant papillary growth (most frequently MiT family translocation RCCs, mucinous tubular and spindle cell carcinoma and clear cell papillary RCC). Our data confirm that the spectrum of RCCs with papillary growth represents a major diagnostical challenge, frequently requiring a second expert opinion. Papillary renal neoplasm with reversed polarity, biphasic hyalinizing psammomatous RCC, and biphasic squamoid/alveolar RCC are rarely sent out for a second opinion, but correct classification and knowledge of these variants will improve our understanding of the clinical behavior of renal tumors with papillary growth. Full article

(This article belongs to the Special Issue Renal Cell Carcinoma: From Pathophysiology to Novel Therapeutic Approaches)

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Review

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13 pages, 1882 KiB

Open AccessReview

p53 and Its Isoforms in Renal Cell Carcinoma—Do They Matter?

by Agata Swiatkowska

Biomedicines 2022, 10(6), 1330; https://0-doi-org.brum.beds.ac.uk/10.3390/biomedicines10061330 - 06 Jun 2022

Cited by 2 | Viewed by 2073

Abstract

p53 is a transcription al factor responsible for the maintenance of cellular homeostasis. It has been shown that more than 50% of tumors are connected with mutations in the Tp53 gene. These mutations cause a disturbance in cellular response to stress, and eventually, cancer development. Apart from the full-length p53, at least twelve isoforms of p53 have been characterized. They are able to modulate p53 activity under stress conditions. In 2020, almost a half of million people around the world were diagnosed with renal cancer. One genetic disturbance which is linked to the most common type of kidney cancer, renal cell carcinoma, RCC, occurs from mutations in the VHL gene. Recent data has revealed that the VHL protein is needed to fully activate p53. Disturbance of the interplay between p53 and VHL seems to explain the lack of efficient response to chemotherapy in RCC. Moreover, it has been observed that changes in the expression of p53 isoforms are associated with different stages of RCC and overall survival. Thus, herein, an attempt was made to answer the question whether p53 and its isoforms are important factors in the development of RCC on the one hand, and in positive response to anti-RCC therapy on the other hand. Full article

(This article belongs to the Special Issue Renal Cell Carcinoma: From Pathophysiology to Novel Therapeutic Approaches)

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18 pages, 6726 KiB

Open AccessReview

Renal Cell Carcinoma in End-Stage Renal Disease: A Review and Update

by Ziad M. El-Zaatari and Luan D. Truong

Biomedicines 2022, 10(3), 657; https://0-doi-org.brum.beds.ac.uk/10.3390/biomedicines10030657 - 11 Mar 2022

Cited by 9 | Viewed by 2992

Abstract

Renal cell carcinoma (RCC) occurring in the setting of end-stage renal disease (ESRD) shows unique clinicopathological characteristics. The two most frequent types of ESRD-associated RCC are acquired cystic kidney disease-associated renal cell carcinoma (ACKD-RCC) and clear-cell papillary renal cell carcinoma (ccpRCC). Other types of RCC also occur in ESRD, albeit with different frequencies from the non-ESRD general population. The histological features of RCC do not vary in the setting of ESRD vs. non-ESRD, yet other findings, such as multifocality and multiple tumor types, are more frequent in ESRD. Studies have generated novel and important knowledge of the etiology, epidemiology, diagnosis, treatment, immunophenotype, and molecular characteristics of ESRD-associated RCC. Knowledge of these data is important for both pathologists and other physicians who may encounter ESRD patients with RCC. This review presents a comprehensive summary and update of the literature on RCC in ESRD, with a focus on the two most frequent types, ACKD-RCC and ccpRCC. Full article

(This article belongs to the Special Issue Renal Cell Carcinoma: From Pathophysiology to Novel Therapeutic Approaches)

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11 pages, 3414 KiB

Open AccessReview

TSC/mTOR Pathway Mutation Associated Eosinophilic/Oncocytic Renal Neoplasms: A Heterogeneous Group of Tumors with Distinct Morphology, Immunohistochemical Profile, and Similar Genetic Background

by Kristyna Pivovarcikova, Reza Alaghehbandan, Tomas Vanecek, Riuko Ohashi, Tomas Pitra and Ondrej Hes

Biomedicines 2022, 10(2), 322; https://0-doi-org.brum.beds.ac.uk/10.3390/biomedicines10020322 - 29 Jan 2022

Cited by 11 | Viewed by 3028

Abstract

A number of recently described renal tumor entities share an eosinophilic/oncocytic morphology, somewhat solid architectural growth pattern, and tendency to present as low-stage tumors. The vast majority of such tumors follow a non-aggressive clinical behavior. In this review, we discuss the morphological, immunohistochemical, and molecular genetic profiles of the three most recent novel/emerging renal entities associated with TSC/mTOR pathway mutations. These are eosinophilic solid and cystic renal cell carcinoma, eosinophilic vacuolated tumors, and low-grade oncocytic tumors, which belong to a heterogeneous group of renal tumors, demonstrating mostly solid architecture, eosinophilic/oncocytic cytoplasm, and overlapping morphological and immunohistochemical features between renal oncocytoma and chromophobe renal cell carcinoma. All three tumors also share a molecular genetic background with mutations in the mTORC1 pathway (TSC1/TSC2/mTOR/RHEB). Despite the common genetic background, it appears that the tumors with TSC/mTOR mutations represent a diverse group of distinct renal neoplasms. Full article

(This article belongs to the Special Issue Renal Cell Carcinoma: From Pathophysiology to Novel Therapeutic Approaches)

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23 pages, 647 KiB

Open AccessReview

The Frontline Immunotherapy-Based Treatment of Advanced Clear Cell Renal Cell Carcinoma: Current Evidence and Clinical Perspective

by In-Ho Kim and Hyo Jin Lee

Biomedicines 2022, 10(2), 251; https://0-doi-org.brum.beds.ac.uk/10.3390/biomedicines10020251 - 24 Jan 2022

Cited by 13 | Viewed by 3230

Abstract

Approximately 400,000 patients are diagnosed with kidney cancer annually worldwide, leading to approximately 170,000 deaths. Renal cell carcinoma (RCC) accounts for more than 90% of kidney cancers. The most common histological subtype is clear cell RCC, which is found in approximately 85% of metastatic RCC cases. The VHL-HIF-VEGF axis is well known; therefore, targeting VEGF has been the mainstay for managing advanced clear cell RCC. Recently, the treatment landscape for advanced clear cell RCC has changed extensively. In particular, immune checkpoint inhibitor-based treatment showed promising results in front-line treatment and became the standard of care. Herein, we review the current evidence on front-line treatment options and discuss the clinical and future perspective. Full article

(This article belongs to the Special Issue Renal Cell Carcinoma: From Pathophysiology to Novel Therapeutic Approaches)

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23 pages, 979 KiB

Open AccessReview

The Role of Circulating Biomarkers in the Oncological Management of Metastatic Renal Cell Carcinoma: Where Do We Stand Now?

by Alessandra Cinque, Anna Capasso, Riccardo Vago, Michael W Lee, Matteo Floris and Francesco Trevisani

Biomedicines 2022, 10(1), 90; https://0-doi-org.brum.beds.ac.uk/10.3390/biomedicines10010090 - 31 Dec 2021

Cited by 5 | Viewed by 2366

Abstract

Renal cell carcinoma (RCC) is an increasingly common malignancy that can progress to metastatic renal cell carcinoma (mRCC) in approximately one-third of RCC patients. The 5-year survival rate for mRCC is abysmally low, and, at the present time, there are sparingly few if any effective treatments. Current surgical and pharmacological treatments can have a long-lasting impact on renal function, as well. Thus, there is a compelling unmet need to discover novel biomarkers and surveillance methods to improve patient outcomes with more targeted therapies earlier in the course of the disease. Circulating biomarkers, such as circulating tumor DNA, noncoding RNA, proteins, extracellular vesicles, or cancer cells themselves potentially represent a minimally invasive tool to fill this gap and accelerate both diagnosis and treatment. Here, we discuss the clinical relevance of different circulating biomarkers in metastatic renal cell carcinoma by clarifying their potential role as novel biomarkers of response or resistance to treatments but also by guiding clinicians in novel therapeutic approaches. Full article

(This article belongs to the Special Issue Renal Cell Carcinoma: From Pathophysiology to Novel Therapeutic Approaches)

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Other

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15 pages, 1738 KiB

Open AccessSystematic Review

Immune Checkpoint Inhibitor Combination Therapy versus Sunitinib as First-Line Treatment for Favorable-IMDC-Risk Advanced Renal Cell Carcinoma Patients: A Meta-Analysis of Randomized Clinical Trials

by Ray Manneh, Mauricio Lema, Lucía Carril-Ajuria, Linda Ibatá, Susan Martínez, Daniel Castellano and Guillermo de Velasco

Biomedicines 2022, 10(3), 577; https://0-doi-org.brum.beds.ac.uk/10.3390/biomedicines10030577 - 01 Mar 2022

Cited by 7 | Viewed by 3157

Abstract

Background: Novel combination therapies have been shown to improve the outcomes of treatment-naive patients with locally advanced or metastatic renal cell carcinoma (aRCC). However, the optimal systemic therapy for aRCC of favorable risk has yet to be clarified. We aimed to evaluate the efficacy and safety of different immunotherapy (IO) combinations, either with another IO (IO–IO) or with an antiangiogenic (IO–TKI), versus sunitinib in the first-line setting in aRCC patients with favorable IMDC risk. Methods: We conducted a systematic search for evidence in PubMed, Ovid MEDLINE, Embase, and the Cochrane Central Register of Controlled Trials published up to February 2021. The GRADE approach was used to assess the quality of evidence. Survival hazard ratios were extracted for analysis in the favorable-risk aRCC subgroup (IMDC). A sensitivity analysis was performed excluding trials of combination therapy without TKI. Results: Five randomized controlled phase III trials with a total of 1088 patients were included in the analysis. The studies compared different combinations versus sunitinib monotherapy. All clinical trials reported overall survival (OS), progression-free survival (PFS), and objective response rate (ORR) data. Four out of five trials reported complete response (CR). There was no difference in OS nor PFS between treatment arms in the IMDC favorable-risk subgroup analysis (OS: HR = 1.07, 95% CI = 0.81–1.41; PFS: HR = 0.74, 95% CI = 0.46–1.19). A benefit in ORR and CR was found for combination therapy vs. sunitinib (ORR: HR = 1.89, 95% CI = 1.29–2.76; CR: HR = 3.58, 95% CI = 2.04–6.28). In the sensitivity analysis, including only IO–TKI vs. sunitinib, no difference in OS was found; however, an advantage in PFS was observed (OS: HR = 0.99, 95% CI 0.69–1.43; PFS: HR = 0.60 (0.45–0.81). The safety profile reported is consistent with previous reports. We did not find differences in the incidence of any adverse event (AE) or of grade ≥3 AEs. Conclusion: This meta-analysis shows that combinations of IO–KI as first-line treatment in favorable-IMDC-risk aRCC improve PFS, ORR, and CR, but not OS, versus sunitinib. Full article

(This article belongs to the Special Issue Renal Cell Carcinoma: From Pathophysiology to Novel Therapeutic Approaches)

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