Editorial

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6 pages, 242 KiB

Open AccessEditorial

The Labyrinth of Renal Cell Carcinoma

by Claudia Manini and José I. López

Cancers 2020, 12(2), 521; https://doi.org/10.3390/cancers12020521 - 24 Feb 2020

Cited by 10 | Viewed by 2345

Abstract

Renal cell carcinoma (RCC) ranks in the top-ten list of malignancies both in males and females [...] Full article

(This article belongs to the Special Issue Renal Cell Carcinoma)

Research

Jump to: Editorial, Review, Other

13 pages, 1485 KiB

Open AccessArticle

Loss of CDKN1A mRNA and Protein Expression Are Independent Predictors of Poor Outcome in Chromophobe Renal Cell Carcinoma Patients

by Riuko Ohashi, Silvia Angori, Aashil A. Batavia, Niels J. Rupp, Yoichi Ajioka, Peter Schraml and Holger Moch

Cancers 2020, 12(2), 465; https://doi.org/10.3390/cancers12020465 - 17 Feb 2020

Cited by 20 | Viewed by 3419

Abstract

Chromophobe renal cell carcinoma (chRCC) patients have good prognosis. Only 5%–10% patients die of metastatic disease after tumorectomy, but tumor progression cannot be predicted by histopathological parameters alone. chRCC are characterized by losses of many chromosomes, whereas gene mutations are rare. In this [...] Read more.

Chromophobe renal cell carcinoma (chRCC) patients have good prognosis. Only 5%–10% patients die of metastatic disease after tumorectomy, but tumor progression cannot be predicted by histopathological parameters alone. chRCC are characterized by losses of many chromosomes, whereas gene mutations are rare. In this study, we aim at identifying genes indicating chRCC progression. A bioinformatic approach was used to correlate chromosomal loss and mRNA expression from 15287 genes from The Cancer Genome Atlas (TCGA) database. All genes in TCGA chromophobe renal cancer dataset (KICH) for which a significant correlation between chromosomal loss and mRNA expression was shown, were identified and their associations with outcome was assessed. Genome-wide DNA copy-number alterations were analyzed by Affymetrix OncoScan^® CNV FFPE Microarrays in a second cohort of Swiss chRCC. In both cohorts, tumors with loss of chromosomes 2, 6, 10, 13, 17 and 21 had signs of tumor progression. There were 4654 genes located on these chromosomes, and 13 of these genes had reduced mRNA levels, which was associated with poor outcome in chRCC. Decreased CDKN1A expression at mRNA (p = 0.02) and protein levels (p = 0.02) were associated with short overall survival and were independent predictors of prognosis (p < 0.01 and <0.05 respectively). CDKN1A expression status is a prognostic biomarker independent of tumor stage. CDKN1A immunohistochemistry may be used to identify chRCC patients at greater risk of disease progression. Full article

(This article belongs to the Special Issue Renal Cell Carcinoma)

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17 pages, 2311 KiB

Open AccessArticle

Deletion of Von Hippel–Lindau Interferes with Hyper Osmolality Induced Gene Expression and Induces an Unfavorable Gene Expression Pattern

by Alexander Groß, Dmitry Chernyakov, Lisa Gallwitz, Nicola Bornkessel and Bayram Edemir

Cancers 2020, 12(2), 420; https://doi.org/10.3390/cancers12020420 - 12 Feb 2020

Cited by 4 | Viewed by 3062

Abstract

Loss of von Hippel–Lindau (VHL) protein function can be found in more than 90% of patients with clear cell renal carcinoma (ccRCC). Mice lacking Vhl function in the kidneys have urine concentration defects due to postulated reduction of the hyperosmotic gradient. Hyperosmolality is [...] Read more.

Loss of von Hippel–Lindau (VHL) protein function can be found in more than 90% of patients with clear cell renal carcinoma (ccRCC). Mice lacking Vhl function in the kidneys have urine concentration defects due to postulated reduction of the hyperosmotic gradient. Hyperosmolality is a kidney-specific microenvironment and induces a unique gene expression pattern. This gene expression pattern is inversely regulated in patients with ccRCC with consequences for cancer-specific survival. Within this study, we tested the hypothesis if Vhl function influences the hyperosmolality induced changes in gene expression. We made use of the Clustered Regularly Interspaced Short Palindromic Repeats (CRISPR)/Cas9 technology to inhibit functional Vhl expression in murine collecting duct cell line. Loss of Vhl function induced morphological changes within the cells similar to epithelial to mesenchymal transition like phenotype. Vhl-deficient cells migrated faster and proliferated slower compared to control cells. Gene expression profiling showed significant changes in gene expression patterns in Vhl-deficient cells compared to control cells. Several genes with unfavorable outcomes showed induced and genes with favorable outcomes for patients with renal cancer reduced gene expression level. Under hyperosmotic condition, the expression of several hyperosmolality induced genes, with favorable prognostic value, was downregulated in cells that do not express functional Vhl. Taken together, this study shows that Vhl interferes with hyperosmotic signaling pathway and hyperosmolality affected pathways might represent new promising targets. Full article

(This article belongs to the Special Issue Renal Cell Carcinoma)

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16 pages, 4044 KiB

Open AccessArticle

Low Dosed Curcumin Combined with Visible Light Exposure Inhibits Renal Cell Carcinoma Metastatic Behavior in Vitros

by Jochen Rutz, Sebastian Maxeiner, Saira Justin, Beatrice Bachmeier, August Bernd, Stefan Kippenberger, Nadja Zöller, Felix K.-H. Chun and Roman A. Blaheta

Cancers 2020, 12(2), 302; https://doi.org/10.3390/cancers12020302 - 28 Jan 2020

Cited by 11 | Viewed by 2711

Abstract

Recent documentation shows that a curcumin-induced growth arrest of renal cell carcinoma (RCC) cells can be amplified by visible light. This study was designed to investigate whether this strategy may also contribute to blocking metastatic progression of RCC. Low dosed curcumin (0.2 µg/mL; [...] Read more.

Recent documentation shows that a curcumin-induced growth arrest of renal cell carcinoma (RCC) cells can be amplified by visible light. This study was designed to investigate whether this strategy may also contribute to blocking metastatic progression of RCC. Low dosed curcumin (0.2 µg/mL; 0.54 µM) was applied to A498, Caki1, or KTCTL-26 cells for 1 h, followed by exposure to visible light for 5 min (400–550 nm, 5500 lx). Adhesion to human vascular endothelial cells or immobilized collagen was then evaluated. The influence of curcumin on chemotaxis and migration was also investigated, as well as curcumin induced alterations of α and β integrin expression. Curcumin without light exposure or light exposure without curcumin induced no alterations, whereas curcumin plus light significantly inhibited RCC adhesion, migration, and chemotaxis. This was associated with a distinct reduction of α3, α5, β1, and β3 integrins in all cell lines. Separate blocking of each of these integrin subtypes led to significant modification of tumor cell adhesion and chemotactic behavior. Combining low dosed curcumin with light considerably suppressed RCC binding activity and chemotactic movement and was associated with lowered integrin α and β subtypes. Therefore, curcumin combined with visible light holds promise for inhibiting metastatic processes in RCC. Full article

(This article belongs to the Special Issue Renal Cell Carcinoma)

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12 pages, 3209 KiB

Open AccessArticle

EVI1 as a Prognostic and Predictive Biomarker of Clear Cell Renal Cell Carcinoma

by Luis Palomero, Lubomir Bodnar, Francesca Mateo, Carmen Herranz-Ors, Roderic Espín, Mar García-Varelo, Marzena Jesiotr, Gorka Ruiz de Garibay, Oriol Casanovas, José I. López and Miquel Angel Pujana

Cancers 2020, 12(2), 300; https://doi.org/10.3390/cancers12020300 - 28 Jan 2020

Cited by 11 | Viewed by 2754

Abstract

The transcription factor EVI1 plays an oncogenic role in several types of neoplasms by promoting aggressive cancer features. EVI1 contributes to epigenetic regulation and transcriptional control, and its overexpression has been associated with enhanced PI3K-AKT-mTOR signaling in some settings. These observations raise the [...] Read more.

The transcription factor EVI1 plays an oncogenic role in several types of neoplasms by promoting aggressive cancer features. EVI1 contributes to epigenetic regulation and transcriptional control, and its overexpression has been associated with enhanced PI3K-AKT-mTOR signaling in some settings. These observations raise the possibility that EVI1 influences the prognosis and everolimus-based therapy outcome of clear cell renal cell carcinoma (ccRCC). Here, gene expression and protein immunohistochemical studies of ccRCC show that EVI1 overexpression is associated with advanced disease features and with poorer outcome—particularly in the CC-e.3 subtype defined by The Cancer Genome Atlas. Overexpression of an oncogenic EVI1 isoform in RCC cell lines confers substantial resistance to everolimus. The EVI1 rs1344555 genetic variant is associated with poorer survival and greater progression of metastatic ccRCC patients treated with everolimus. This study leads us to propose that evaluation of EVI1 protein or gene expression, and of EVI1 genetic variants may help improve estimates of prognosis and the benefit of everolimus-based therapy in ccRCC. Full article

(This article belongs to the Special Issue Renal Cell Carcinoma)

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18 pages, 1625 KiB

Open AccessArticle

In-Depth Mapping of the Urinary N-Glycoproteome: Distinct Signatures of ccRCC-related Progression

by Lucia Santorelli, Giulia Capitoli, Clizia Chinello, Isabella Piga, Francesca Clerici, Vanna Denti, Andrew Smith, Angelica Grasso, Francesca Raimondo, Marco Grasso and Fulvio Magni

Cancers 2020, 12(1), 239; https://doi.org/10.3390/cancers12010239 - 18 Jan 2020

Cited by 14 | Viewed by 3715

Abstract

Protein N-glycosylation is one of the most important post-translational modifications and is involved in many biological processes, with aberrant changes in protein N-glycosylation patterns being closely associated with several diseases, including the progression and spreading of tumours. In light of this, [...] Read more.

Protein N-glycosylation is one of the most important post-translational modifications and is involved in many biological processes, with aberrant changes in protein N-glycosylation patterns being closely associated with several diseases, including the progression and spreading of tumours. In light of this, identifying these aberrant protein glycoforms in tumours could be useful for understanding the molecular mechanism of this multifactorial disease, developing specific biomarkers and finding novel therapeutic targets. We investigated the urinary N-glycoproteome of clear cell renal cell carcinoma (ccRCC) patients at different stages (n = 15 at pT1 and n = 15 at pT3), and of non-ccRCC subjects (n = 15), using an N-glyco-FASP-based method. Using label-free nLC-ESI MS/MS, we identified and quantified several N-glycoproteins with altered expression and abnormal changes affecting the occupancy of the glycosylation site in the urine of RCC patients compared to control. In particular, nine of them had a specific trend that was directly related to the stage progression: CD97, COCH and P3IP1 were up-expressed whilst APOB, FINC, CERU, CFAH, HPT and PLTP were down-expressed in ccRCC patients. Overall, these results expand our knowledge related to the role of this post-translational modification in ccRCC and translation of this information into pre-clinical studies could have a significant impact on the discovery of novel biomarkers and therapeutic target in kidney cancer. Full article

(This article belongs to the Special Issue Renal Cell Carcinoma)

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18 pages, 10204 KiB

Open AccessArticle

Ex-Vivo Treatment of Tumor Tissue Slices as a Predictive Preclinical Method to Evaluate Targeted Therapies for Patients with Renal Carcinoma

by Caroline Roelants, Catherine Pillet, Quentin Franquet, Clément Sarrazin, Nicolas Peilleron, Sofia Giacosa, Laurent Guyon, Amina Fontanell, Gaëlle Fiard, Jean-Alexandre Long, Jean-Luc Descotes, Claude Cochet and Odile Filhol

Cancers 2020, 12(1), 232; https://doi.org/10.3390/cancers12010232 - 17 Jan 2020

Cited by 36 | Viewed by 5048

Abstract

Clear cell renal cell carcinoma (ccRCC) is the third type of urologic cancer. At time of diagnosis, 30% of cases are metastatic with no effect of chemotherapy or radiotherapy. Current targeted therapies lead to a high rate of relapse and resistance after a [...] Read more.

Clear cell renal cell carcinoma (ccRCC) is the third type of urologic cancer. At time of diagnosis, 30% of cases are metastatic with no effect of chemotherapy or radiotherapy. Current targeted therapies lead to a high rate of relapse and resistance after a short-term response. Thus, a major hurdle in the development and use of new treatments for ccRCC is the lack of good pre-clinical models that can accurately predict the efficacy of new drugs and allow the stratification of patients into the correct treatment regime. Here, we describe different 3D cultures models of ccRCC, emphasizing the feasibility and the advantage of ex-vivo treatment of fresh, surgically resected human tumor slice cultures of ccRCC as a robust preclinical model for identifying patient response to specific therapeutics. Moreover, this model based on precision-cut tissue slices enables histopathology measurements as tumor architecture is retained, including the spatial relationship between the tumor and tumor-infiltrating lymphocytes and the stromal components. Our data suggest that acute treatment of tumor tissue slices could represent a benchmark of further exploration as a companion diagnostic tool in ccRCC treatment and a model to develop new therapeutic drugs. Full article

(This article belongs to the Special Issue Renal Cell Carcinoma)

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17 pages, 5242 KiB

Open AccessArticle

RNA Sequencing of Collecting Duct Renal Cell Carcinoma Suggests an Interaction between miRNA and Target Genes and a Predominance of Deregulated Solute Carrier Genes

by Sven Wach, Helge Taubert, Katrin Weigelt, Nora Hase, Marcel Köhn, Danny Misiak, Stefan Hüttelmaier, Christine G. Stöhr, Andreas Kahlmeyer, Florian Haller, Julio Vera, Arndt Hartmann, Bernd Wullich and Xin Lai

Cancers 2020, 12(1), 64; https://doi.org/10.3390/cancers12010064 - 24 Dec 2019

Cited by 14 | Viewed by 3722

Abstract

Collecting duct carcinoma (CDC) is a rare renal cell carcinoma subtype with a very poor prognosis. There have been only a few studies on gene expression analysis in CDCs. We compared the gene expression profiles of two CDC cases with those of eight [...] Read more.

Collecting duct carcinoma (CDC) is a rare renal cell carcinoma subtype with a very poor prognosis. There have been only a few studies on gene expression analysis in CDCs. We compared the gene expression profiles of two CDC cases with those of eight normal tissues of renal cell carcinoma patients. At a threshold of |log2fold-change| ≥1, 3349 genes were upregulated and 1947 genes were downregulated in CDCs compared to the normal samples. Pathway analysis of the deregulated genes revealed that cancer pathways and cell cycle pathways were most prominent in CDCs. The most upregulated gene was keratin 17, and the most downregulated gene was cubilin. Among the most downregulated genes were four solute carrier genes (SLC3A1, SLC9A3, SLC26A7, and SLC47A1). The strongest negative correlations between miRNAs and mRNAs were found between the downregulated miR-374b-5p and its upregulated target genes HIST1H3B, HK2, and SLC7A11 and between upregulated miR-26b-5p and its downregulated target genes PPARGC1A, ALDH6A1, and MARC2. An upregulation of HK2 and a downregulation of PPARGC1A, ALDH6A1, and MARC2 were observed at the protein level. Survival analysis of the cancer genome atlas (TCGA) dataset showed for the first time that low gene expression of MARC2, cubilin, and SLC47A1 and high gene expression of KRT17 are associated with poor overall survival in clear cell renal cell carcinoma patients. Altogether, we identified dysregulated protein-coding genes, potential miRNA-target interactions, and prognostic markers that could be associated with CDC. Full article

(This article belongs to the Special Issue Renal Cell Carcinoma)

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18 pages, 3203 KiB

Open AccessArticle

GSTO1*CC Genotype (rs4925) Predicts Shorter Survival in Clear Cell Renal Cell Carcinoma Male Patients

by Tanja Radic, Vesna Coric, Zoran Bukumiric, Marija Pljesa-Ercegovac, Tatjana Djukic, Natasa Avramovic, Marija Matic, Smiljana Mihailovic, Dejan Dragicevic, Zoran Dzamic, Tatjana Simic and Ana Savic-Radojevic

Cancers 2019, 11(12), 2038; https://doi.org/10.3390/cancers11122038 - 17 Dec 2019

Cited by 8 | Viewed by 3261

Abstract

Omega class glutathione transferases, GSTO1-1 and GSTO2-2, exhibit different activities involved in regulation of inflammation, apoptosis and redox homeostasis. We investigated the the prognostic significance of GSTO1 (rs4925) and GSTO2 (rs156697 and rs2297235) polymorphisms in clear cell renal cell carcinoma (ccRCC) patients. GSTO1-1 [...] Read more.

Omega class glutathione transferases, GSTO1-1 and GSTO2-2, exhibit different activities involved in regulation of inflammation, apoptosis and redox homeostasis. We investigated the the prognostic significance of GSTO1 (rs4925) and GSTO2 (rs156697 and rs2297235) polymorphisms in clear cell renal cell carcinoma (ccRCC) patients. GSTO1-1 and GSTO2-2 expression and phosphorylation status of phosphoinositide 3-kinase (PI3K)/protein kinase B (Akt)/ /mammalian target of rapamycin (mTOR) and Raf/MEK/extracellular signal-regulated kinase (ERK) signaling pathways in non-tumor and tumor ccRCC tissue, as well as possible association of GSTO1-1 with signaling molecules were also assessed. GSTO genotyping was performed by quantitative PCR in 228 ccRCC patients, while expression and immunoprecipitation were analyzed by Western blot in 30 tissue specimens. Shorter survival in male carriers of GSTO1*C/C wild-type genotype compared to the carriers of at least one variant allele was demonstrated (p = 0.049). GSTO1*C/C genotype independently predicted higher risk of overall mortality among male ccRCC patients (p = 0.037). Increased expression of GSTO1-1 and GSTO2-2 was demonstrated in tumor compared to corresponding non-tumor tissue (p = 0.002, p = 0.007, respectively), while GSTO1 expression was correlated with interleukin-1β (IL-1β)/pro-interleukin-1β (pro-IL-1β) ratio (r = 0.260, p = 0.350). Interaction of GSTO1 with downstream effectors of investigated pathways was shown in ccRCC tumor tissue. This study demonstrated significant prognostic role of GSTO1 polymorphism in ccRCC. Up-regulated GSTO1-1 and GSTO2-2 in tumor tissue might contribute to aberrant ccRCC redox homeostasis. Full article

(This article belongs to the Special Issue Renal Cell Carcinoma)

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16 pages, 3793 KiB

Open AccessArticle

MTA2 as a Potential Biomarker and Its Involvement in Metastatic Progression of Human Renal Cancer by miR-133b Targeting MMP-9

by Yong-Syuan Chen, Tung-Wei Hung, Shih-Chi Su, Chia-Liang Lin, Shun-Fa Yang, Chu-Che Lee, Chang-Fang Yeh, Yi-Hsien Hsieh and Jen-Pi Tsai

Cancers 2019, 11(12), 1851; https://doi.org/10.3390/cancers11121851 - 23 Nov 2019

Cited by 17 | Viewed by 2936

Abstract

Metastasis-associated protein 2 (MTA2) was previously known as a requirement to maintain malignant potentials in several human cancers. However, the role of MTA2 in the progression of renal cell carcinoma (RCC) has not yet been delineated. In this study, MTA2 expression was significantly [...] Read more.

Metastasis-associated protein 2 (MTA2) was previously known as a requirement to maintain malignant potentials in several human cancers. However, the role of MTA2 in the progression of renal cell carcinoma (RCC) has not yet been delineated. In this study, MTA2 expression was significantly increased in RCC tissues and cell lines. Increased MTA2 expression was significantly associated with tumour grade (p = 0.002) and was an independent prognostic factor for overall survival with a high RCC tumour grade. MTA2 knockdown inhibited the migration, invasion, and in vivo metastasis of RCC cells without effects on cell proliferation. Regarding molecular mechanisms, MTA2 knockdown reduced the activity, protein level, and mRNA expression of matrix metalloproteinase-9 (MMP-9) in RCC cells. Further analyses demonstrated that patients with lower miR-133b expression had poorer survival rates than those with higher expression from The Cancer Genome Atlas database. Moreover, miR-133b modulated the 3′untranslated region (UTR) of MMP-9 promoter activities and subsequently the migratory and invasive abilities of these dysregulated expressions of MTA2 in RCC cells. The inhibition of MTA2 could contribute to human RCC metastasis by regulating the expression of miR-133b targeting MMP-9 expression. Full article

(This article belongs to the Special Issue Renal Cell Carcinoma)

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21 pages, 6529 KiB

Open AccessArticle

MicroRNA-Mediated Metabolic Reprograming in Renal Cancer

by Joanna Bogusławska, Piotr Popławski, Saleh Alseekh, Marta Koblowska, Roksana Iwanicka-Nowicka, Beata Rybicka, Hanna Kędzierska, Katarzyna Głuchowska, Karolina Hanusek, Zbigniew Tański, Alisdair R. Fernie and Agnieszka Piekiełko-Witkowska

Cancers 2019, 11(12), 1825; https://doi.org/10.3390/cancers11121825 - 20 Nov 2019

Cited by 23 | Viewed by 4849

Abstract

Metabolic reprogramming is one of the hallmarks of renal cell cancer (RCC). We hypothesized that altered metabolism of RCC cells results from dysregulation of microRNAs targeting metabolically relevant genes. Combined large-scale transcriptomic and metabolic analysis of RCC patients tissue samples revealed a group [...] Read more.

Metabolic reprogramming is one of the hallmarks of renal cell cancer (RCC). We hypothesized that altered metabolism of RCC cells results from dysregulation of microRNAs targeting metabolically relevant genes. Combined large-scale transcriptomic and metabolic analysis of RCC patients tissue samples revealed a group of microRNAs that contribute to metabolic reprogramming in RCC. miRNAs expressions correlated with their predicted target genes and with gas chromatography-mass spectrometry (GC-MS) metabolome profiles of RCC tumors. Assays performed in RCC-derived cell lines showed that miR-146a-5p and miR-155-5p targeted genes of PPP (the pentose phosphate pathway) (G6PD and TKT), the TCA (tricarboxylic acid cycle) cycle (SUCLG2), and arginine metabolism (GATM), respectively. miR-106b-5p and miR-122-5p regulated the NFAT5 osmoregulatory transcription factor. Altered expressions of G6PD, TKT, SUCLG2, GATM, miR-106b-5p, miR-155-5p, and miR-342-3p correlated with poor survival of RCC patients. miR-106b-5p, miR-146a-5p, and miR-342-3p stimulated proliferation of RCC cells. The analysis involving >6000 patients revealed that miR-34a-5p, miR-106b-5p, miR-146a-5p, and miR-155-5p are PanCancer metabomiRs possibly involved in global regulation of cancer metabolism. In conclusion, we found that microRNAs upregulated in renal cancer contribute to disturbed expression of key genes involved in the regulation of RCC metabolome. miR-146a-5p and miR-155-5p emerge as a key “metabomiRs” that target genes of crucial metabolic pathways (PPP (the pentose phosphate pathway), TCA cycle, and arginine metabolism). Full article

(This article belongs to the Special Issue Renal Cell Carcinoma)

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13 pages, 1929 KiB

Open AccessArticle

Prognostic Implication of pAMPK Immunohistochemical Staining by Subcellular Location and Its Association with SMAD Protein Expression in Clear Cell Renal Cell Carcinoma

by Minsun Jung, Jeong Hoon Lee, Cheol Lee, Jeong Hwan Park, Yu Rang Park and Kyung Chul Moon

Cancers 2019, 11(10), 1602; https://doi.org/10.3390/cancers11101602 - 21 Oct 2019

Cited by 8 | Viewed by 3236

Abstract

Although cytoplasmic AMP-activated protein kinase (AMPK) has been known as a tumor-suppressor protein, nuclear AMPK is suggested to support clear cell renal cell carcinoma (ccRCC). In addition, pAMPK interacts with TGF-β/SMAD, which is one of the frequently altered pathways in ccRCC. In this [...] Read more.

Although cytoplasmic AMP-activated protein kinase (AMPK) has been known as a tumor-suppressor protein, nuclear AMPK is suggested to support clear cell renal cell carcinoma (ccRCC). In addition, pAMPK interacts with TGF-β/SMAD, which is one of the frequently altered pathways in ccRCC. In this study, we investigated the prognostic significance of pAMPK with respect to subcellular location and investigated its interaction with TGF-β/SMAD in ccRCC. Immunohistochemical staining for pAMPK, pSMAD2 and SMAD4 was conducted on tissue microarray of 987 ccRCC specimens. Moreover, the levels of pSMAD2 were measured in Caki-1 cells treated with 5-aminoimidazole-4-carboxamide ribonucleotide. The relationship between AMPK/pAMPK and TGFB1 expression was determined using the TCGA database. As a result, pAMPK positivity, either in the cytoplasm or nuclei, was independently associated with improved ccRCC prognosis, after adjusting for TNM stage and WHO grade. Furthermore, pAMPK-positive ccRCC displayed increased pSMAD2 and SMAD4 expression, while activation of pAMPK increased pSMAD2 in Caki-1 cells. However, AMPK/pAMPK expression was inversely correlated with TGFB1 expression in the TCGA database. Therefore, pAMPK immunostaining, both in the cytoplasm and nuclei, is a useful prognostic biomarker for ccRCC. pAMPK targets TGF-β-independent phosphorylation of SMAD2 and activates pSMAD2/SMAD4, representing a novel anti-tumoral mechanism of pAMPK in ccRCC. Full article

(This article belongs to the Special Issue Renal Cell Carcinoma)

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14 pages, 2353 KiB

Open AccessArticle

Classic Chromophobe Renal Cell Carcinoma Incur a Larger Number of Chromosomal Losses Than Seen in the Eosinophilic Subtype

by Riuko Ohashi, Peter Schraml, Silvia Angori, Aashil A. Batavia, Niels J. Rupp, Chisato Ohe, Yoshiro Otsuki, Takashi Kawasaki, Hiroshi Kobayashi, Kazuhiro Kobayashi, Tatsuhiko Miyazaki, Hiroyuki Shibuya, Hiroyuki Usuda, Hajime Umezu, Fumiyoshi Fujishima, Bungo Furusato, Mitsumasa Osakabe, Tamotsu Sugai, Naoto Kuroda, Toyonori Tsuzuki, Yoji Nagashima, Yoichi Ajioka and Holger Moch Show full author list Hide full author list

Cancers 2019, 11(10), 1492; https://doi.org/10.3390/cancers11101492 - 03 Oct 2019

Cited by 29 | Viewed by 9168

Abstract

Chromophobe renal cell carcinoma (chRCC) is a renal tumor subtype with a good prognosis, characterized by multiple chromosomal copy number variations (CNV). The World Health Organization (WHO) chRCC classification guidelines define a classic and an eosinophilic variant. Large cells with reticular cytoplasm and [...] Read more.

Chromophobe renal cell carcinoma (chRCC) is a renal tumor subtype with a good prognosis, characterized by multiple chromosomal copy number variations (CNV). The World Health Organization (WHO) chRCC classification guidelines define a classic and an eosinophilic variant. Large cells with reticular cytoplasm and prominent cell membranes (pale cells) are characteristic for classic chRCC. Classic and eosinophilic variants were defined in 42 Swiss chRCCs, 119 Japanese chRCCs and in whole-slide digital images of 66 chRCCs from the Cancer Genome Atlas (TCGA) kidney chromophobe (KICH) dataset. 32 of 42 (76.2%) Swiss chRCCs, 90 of 119 (75.6%) Japanese chRCCs and 53 of 66 (80.3%) TCGA-KICH were classic chRCCs. There was no survival difference between eosinophilic and classic chRCC in all three cohorts. To identify a genotype/phenotype correlation, we performed a genome-wide CNV analysis using Affymetrix OncoScan^® CNV Assay (Affymetrix/Thermo Fisher Scientific, Waltham, MA, USA) in 33 Swiss chRCCs. TCGA-KICH subtypes were compared with TCGA CNV data. In the combined Swiss and TCGA-KICH cohorts, losses of chromosome 1, 2, 6, 10, 13, and 17 were significantly more frequent in classic chRCC (p < 0.05, each), suggesting that classic chRCC are characterized by higher chromosomal instability. This molecular difference justifies the definition of two chRCC variants. Absence of pale cells could be used as main histological criterion to define the eosinophilic variant of chRCC. Full article

(This article belongs to the Special Issue Renal Cell Carcinoma)

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23 pages, 3925 KiB

Open AccessArticle

Circular RNAs in Clear Cell Renal Cell Carcinoma: Their Microarray-Based Identification, Analytical Validation, and Potential Use in a Clinico-Genomic Model to Improve Prognostic Accuracy

by Antonia Franz, Bernhard Ralla, Sabine Weickmann, Monika Jung, Hannah Rochow, Carsten Stephan, Andreas Erbersdobler, Ergin Kilic, Annika Fendler and Klaus Jung

Cancers 2019, 11(10), 1473; https://doi.org/10.3390/cancers11101473 - 30 Sep 2019

Cited by 41 | Viewed by 3579

Abstract

Circular RNAs (circRNAs) may act as novel cancer biomarkers. However, a genome-wide evaluation of circRNAs in clear cell renal cell carcinoma (ccRCC) has yet to be conducted. Therefore, the objective of this study was to identify and validate circRNAs in ccRCC tissue with [...] Read more.

Circular RNAs (circRNAs) may act as novel cancer biomarkers. However, a genome-wide evaluation of circRNAs in clear cell renal cell carcinoma (ccRCC) has yet to be conducted. Therefore, the objective of this study was to identify and validate circRNAs in ccRCC tissue with a focus to evaluate their potential as prognostic biomarkers. A genome-wide identification of circRNAs in total RNA extracted from ccRCC tissue samples was performed using microarray analysis. Three relevant differentially expressed circRNAs were selected (circEGLN3, circNOX4, and circRHOBTB3), their circular nature was experimentally confirmed, and their expression—along with that of their linear counterparts—was measured in 99 malignant and 85 adjacent normal tissue samples using specifically established RT-qPCR assays. The capacity of circRNAs to discriminate between malignant and adjacent normal tissue samples and their prognostic potential (with the endpoints cancer-specific, recurrence-free, and overall survival) after surgery were estimated by C-statistics, Kaplan-Meier method, univariate and multivariate Cox regression analysis, decision curve analysis, and Akaike and Bayesian information criteria. CircEGLN3 discriminated malignant from normal tissue with 97% accuracy. We generated a prognostic for the three endpoints by multivariate Cox regression analysis that included circEGLN3, circRHOBT3 and linRHOBTB3. The predictive outcome accuracy of the clinical models based on clinicopathological factors was improved in combination with this circRNA-based signature. Bootstrapping as well as Akaike and Bayesian information criteria confirmed the statistical significance and robustness of the combined models. Limitations of this study include its retrospective nature and the lack of external validation. The study demonstrated the promising potential of circRNAs as diagnostic and particularly prognostic biomarkers in ccRCC patients. Full article

(This article belongs to the Special Issue Renal Cell Carcinoma)

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24 pages, 4028 KiB

Open AccessArticle

Interleukin4Rα (IL4Rα) and IL13Rα1 Are Associated with the Progress of Renal Cell Carcinoma through Janus Kinase 2 (JAK2)/Forkhead Box O3 (FOXO3) Pathways

by Mi-Ae Kang, Jongsung Lee, Sang Hoon Ha, Chang Min Lee, Kyoung Min Kim, Kyu Yun Jang and See-Hyoung Park

Cancers 2019, 11(9), 1394; https://doi.org/10.3390/cancers11091394 - 18 Sep 2019

Cited by 18 | Viewed by 3993

Abstract

Specific kinds of interleukin (IL) receptors are known to mediate lymphocyte proliferation and survival. However, recent reports have suggested that the high expression of IL4Rα and IL13Rα1 in tumor tissue might be associated with tumorigenesis in several kinds of tumor. We found that [...] Read more.

Specific kinds of interleukin (IL) receptors are known to mediate lymphocyte proliferation and survival. However, recent reports have suggested that the high expression of IL4Rα and IL13Rα1 in tumor tissue might be associated with tumorigenesis in several kinds of tumor. We found that a significant association between mRNA level of IL4Rα or IL13Rα1 and the poor prognosis of renal cell carcinoma (RCC) from the public database (http://www.oncolnc.org/). Then, we evaluated the clinicopathological significance of the immunohistochemical expression of IL4Rα and IL13Rα1 in 199 clear cell RCC (CCRCC) patients. The individual and co-expression patterns of IL4Rα and IL13Rα1 were significantly associated with cancer-specific survival (CSS) and relapse-free survival (RFS) in univariate analysis. Multivariate analysis indicated IL4Rα-positivity and co-expression of IL4Rα and IL13Rα1 as the independent indicators of shorter CSS and RFS of CCRCC patients. For the in vitro evaluation of the oncogenic role of IL4Rα and IL13Rα1 in RCC, we knock-downed IL4Rα or IL13Rα1 and observed that the cell proliferation rate was decreased, and the apoptosis rate was increased in A498 and ACHN cells. Furthermore, we examined the possible role of Janus kinase 2 (JAK2), well-known down-stream tyrosine kinase under the heterodimeric receptor complex of IL4Rα and IL13Rα1. Interestingly, JAK2 interacted with Forkhead box O3 (FOXO3) to cause tyrosine-phosphorylation of FOXO3. Silencing IL4Rα or JAK2 in A498 and ACHN cells reduced the interaction between JAK2 and FOXO3. Moreover, pharmacological inhibition of JAK2 induced the nuclear localization of FOXO3, leading to increase apoptosis and decrease cell proliferation rate in A498 and ACHN cells. Taken together, these results suggest that IL4Rα and IL13Rα1 might be involved in the progression of RCC through JAK2/FOXO3 pathway, and their expression might be used as the novel prognostic factor and therapeutic target for RCC patients. Full article

(This article belongs to the Special Issue Renal Cell Carcinoma)

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22 pages, 2187 KiB

Open AccessArticle

Papillary Renal Cell Carcinomas Rewire Glutathione Metabolism and Are Deficient in Both Anabolic Glucose Synthesis and Oxidative Phosphorylation

by Ayham Al Ahmad, Vanessa Paffrath, Rosanna Clima, Jonas Felix Busch, Anja Rabien, Ergin Kilic, Sonia Villegas, Bernd Timmermann, Marcella Attimonelli, Klaus Jung and David Meierhofer

Cancers 2019, 11(9), 1298; https://doi.org/10.3390/cancers11091298 - 03 Sep 2019

Cited by 16 | Viewed by 4033

Abstract

Papillary renal cell carcinoma (pRCC) is a malignant kidney cancer with a prevalence of 7–20% of all renal tumors. Proteome and metabolome profiles of 19 pRCC and patient-matched healthy kidney controls were used to elucidate the regulation of metabolic pathways and the underlying [...] Read more.

Papillary renal cell carcinoma (pRCC) is a malignant kidney cancer with a prevalence of 7–20% of all renal tumors. Proteome and metabolome profiles of 19 pRCC and patient-matched healthy kidney controls were used to elucidate the regulation of metabolic pathways and the underlying molecular mechanisms. Glutathione (GSH), a main reactive oxygen species (ROS) scavenger, was highly increased and can be regarded as a new hallmark in this malignancy. Isotope tracing of pRCC derived cell lines revealed an increased de novo synthesis rate of GSH, based on glutamine consumption. Furthermore, profound downregulation of gluconeogenesis and oxidative phosphorylation was observed at the protein level. In contrast, analysis of the The Cancer Genome Atlas (TCGA) papillary RCC cohort revealed no significant change in transcripts encoding oxidative phosphorylation compared to normal kidney tissue, highlighting the importance of proteomic profiling. The molecular characteristics of pRCC are increased GSH synthesis to cope with ROS stress, deficient anabolic glucose synthesis, and compromised oxidative phosphorylation, which could potentially be exploited in innovative anti-cancer strategies. Full article

(This article belongs to the Special Issue Renal Cell Carcinoma)

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13 pages, 2395 KiB

Open AccessArticle

Comprehensive Profiling of Primary and Metastatic ccRCC Reveals a High Homology of the Metastases to a Subregion of the Primary Tumour

by Paranita Ferronika, Joost Hof, Gursah Kats-Ugurlu, Rolf H. Sijmons, Martijn M. Terpstra, Kim de Lange, Annemarie Leliveld-Kors, Helga Westers and Klaas Kok

Cancers 2019, 11(6), 812; https://doi.org/10.3390/cancers11060812 - 12 Jun 2019

Cited by 17 | Viewed by 4599

Abstract

While intratumour genetic heterogeneity of primary clear cell renal cell carcinoma (ccRCC) is well characterized, the genomic profiles of metastatic ccRCCs are seldom studied. We profiled the genomes and transcriptomes of a primary tumour and matched metastases to better understand the evolutionary processes [...] Read more.

While intratumour genetic heterogeneity of primary clear cell renal cell carcinoma (ccRCC) is well characterized, the genomic profiles of metastatic ccRCCs are seldom studied. We profiled the genomes and transcriptomes of a primary tumour and matched metastases to better understand the evolutionary processes that lead to metastasis. In one ccRCC patient, four regions of the primary tumour, one region of the thrombus in the inferior vena cava, and four lung metastases (including one taken after pegylated (PEG)-interferon therapy) were analysed separately. Each sample was analysed for copy number alterations and somatic mutations by whole exome sequencing. We also evaluated gene expression profiles for this patient and 15 primary tumour and 15 metastasis samples from four additional patients. Copy number profiles of the index patient showed two distinct subgroups: one consisted of three primary tumours with relatively minor copy number changes, the other of a primary tumour, the thrombus, and the lung metastases, all with a similar copy number pattern and tetraploid-like characteristics. Somatic mutation profiles indicated parallel clonal evolution with similar numbers of private mutations in each primary tumour and metastatic sample. Expression profiling of the five patients revealed significantly changed expression levels of 57 genes between primary tumours and metastases, with enrichment in the extracellular matrix cluster. The copy number profiles suggest a punctuated evolution from a subregion of the primary tumour. This process, which differentiated the metastases from the primary tumours, most likely occurred rapidly, possibly even before metastasis formation. The evolutionary patterns we deduced from the genomic alterations were also reflected in the gene expression profiles. Full article

(This article belongs to the Special Issue Renal Cell Carcinoma)

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14 pages, 1966 KiB

Open AccessArticle

Rising Serum Uric Acid Level Is Negatively Associated with Survival in Renal Cell Carcinoma

by Kendrick Yim, Ahmet Bindayi, Rana McKay, Reza Mehrazin, Omer A. Raheem, Charles Field, Aaron Bloch, Robert Wake, Stephen Ryan, Anthony Patterson and Ithaar H. Derweesh

Cancers 2019, 11(4), 536; https://doi.org/10.3390/cancers11040536 - 15 Apr 2019

Cited by 12 | Viewed by 3344

Abstract

Aim and Background: To investigate the association of serum uric acid (SUA) levels along with statin use in Renal Cell Carcinoma (RCC), as statins may be associated with improved outcomes in RCC and SUA elevation is associated with increased risk of chronic kidney [...] Read more.

Aim and Background: To investigate the association of serum uric acid (SUA) levels along with statin use in Renal Cell Carcinoma (RCC), as statins may be associated with improved outcomes in RCC and SUA elevation is associated with increased risk of chronic kidney disease (CKD). Methods: Retrospective study of patients undergoing surgery for RCC with preoperative/postoperative SUA levels between 8/2005–8/2018. Analysis was carried out between patients with increased postoperative SUA vs. patients with decreased/stable postoperative SUA. Kaplan-Meier analysis (KMA) calculated overall survival (OS) and recurrence free survival (RFS). Multivariable analysis (MVA) was performed to identify factors associated with increased SUA levels and all-cause mortality. The prognostic significance of variables for OS and RFS was analyzed by cox regression analysis. Results: Decreased/stable SUA levels were noted in 675 (74.6%) and increased SUA levels were noted in 230 (25.4%). A higher proportion of patients with decreased/stable SUA levels took statins (27.9% vs. 18.3%, p = 0.0039). KMA demonstrated improved 5- and 10-year OS (89% vs. 47% and 65% vs. 9%, p < 0.001) and RFS (94% vs. 45% and 93% vs. 34%, p < 0.001), favoring patients with decreased/stable SUA levels. MVA revealed that statin use (Odds ratio (OR) 0.106, p < 0.001), dyslipidemia (OR 2.661, p = 0.004), stage III and IV disease compared to stage I (OR 1.887, p = 0.015 and 10.779, p < 0.001, respectively), and postoperative de novo CKD stage III (OR 5.952, p < 0.001) were predictors for increased postoperative SUA levels. MVA for all-cause mortality showed that increasing BMI (OR 1.085, p = 0.002), increasing ASA score (OR 1.578, p = 0.014), increased SUA levels (OR 4.698, p < 0.001), stage IV disease compared to stage I (OR 7.702, p < 0.001), radical nephrectomy (RN) compared to partial nephrectomy (PN) (OR 1.620, p = 0.019), and de novo CKD stage III (OR 7.068, p < 0.001) were significant factors. Cox proportional hazard analysis for OS revealed that increasing age (HR 1.017, p = 0.004), increasing BMI (Hazard Ratio (HR) 1.099, p < 0.001), increasing SUA (HR 4.708, p < 0.001), stage III and IV compared to stage I (HR 1.537, p = 0.013 and 3.299, p < 0.001), RN vs. PN (HR 1.497, p = 0.029), and de novo CKD stage III (HR 1.684, p < 0.001) were significant factors. Cox proportional hazard analysis for RFS demonstrated that increasing ASA score (HR 1.239, p < 0.001, increasing SUA (HR 9.782, p < 0.001), and stage II, III, and IV disease compared to stage I (HR 2.497, p < 0.001 and 3.195, p < 0.001 and 6.911, p < 0.001) were significant factors. Conclusions: Increasing SUA was associated with poorer outcomes. Decreased SUA levels were associated with statin intake and lower stage disease as well as lack of progression to CKD and anemia. Further investigation is requisite. Full article

(This article belongs to the Special Issue Renal Cell Carcinoma)

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14 pages, 4102 KiB

Open AccessArticle

Ghrelin Upregulates Oncogenic Aurora A to Promote Renal Cell Carcinoma Invasion

by Tsung-Chieh Lin, Yuan-Ming Yeh, Wen-Lang Fan, Yu-Chan Chang, Wei-Ming Lin, Tse-Yen Yang and Michael Hsiao

Cancers 2019, 11(3), 303; https://doi.org/10.3390/cancers11030303 - 04 Mar 2019

Cited by 9 | Viewed by 2971

Abstract

Ghrelin is a peptide hormone, originally identified from the stomach, that functions as an endogenous ligand of the growth hormone secretagogue receptor (GHSR) and promotes growth hormone (GH) release and food intake. Increasing reports point out ghrelin’s role in cancer progression. We previously [...] Read more.

Ghrelin is a peptide hormone, originally identified from the stomach, that functions as an endogenous ligand of the growth hormone secretagogue receptor (GHSR) and promotes growth hormone (GH) release and food intake. Increasing reports point out ghrelin’s role in cancer progression. We previously characterized ghrelin’s prognostic significance in the clear cell subtype of renal cell carcinoma (ccRCC), and its pro-metastatic ability via Snail-dependent cell migration. However, ghrelin’s activity in promoting cell invasion remains obscure. In this study, an Ingenuity Pathway Analysis (IPA)-based investigation of differentially expressed genes in Cancer Cell Line Encyclopedia (CCLE) dataset indicated the potential association of Aurora A with ghrelin in ccRCC metastasis. In addition, a significant correlation between ghrelin and Aurora A expression level in 15 ccRCC cell line was confirmed by variant probes. ccRCC patients with high ghrelin and Aurora A status were clinically associated with poor outcome. We further observed that ghrelin upregulated Aurora A at the protein and RNA levels and that ghrelin-induced ccRCC in vitro invasion and in vivo metastasis occurred in an Aurora A-dependent manner. Furthermore, MMP1, 2, 9 and 10 expressions are associated with poor outcome. In particular, MMP10 is significantly upregulated and required for the ghrelin-Aurora A axis to promote ccRCC invasion. The results of this study indicated a novel signaling mechanism in ccRCC metastasis. Full article

(This article belongs to the Special Issue Renal Cell Carcinoma)

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Review

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24 pages, 1518 KiB

Open AccessReview

NK Cell-Based Immunotherapy in Renal Cell Carcinoma

by Iñigo Terrén, Ane Orrantia, Idoia Mikelez-Alonso, Joana Vitallé, Olatz Zenarruzabeitia and Francisco Borrego

Cancers 2020, 12(2), 316; https://doi.org/10.3390/cancers12020316 - 29 Jan 2020

Cited by 22 | Viewed by 6213

Abstract

Natural killer (NK) cells are cytotoxic lymphocytes that are able to kill tumor cells without prior sensitization. It has been shown that NK cells play a pivotal role in a variety of cancers, highlighting their relevance in tumor immunosurveillance. NK cell infiltration has [...] Read more.

Natural killer (NK) cells are cytotoxic lymphocytes that are able to kill tumor cells without prior sensitization. It has been shown that NK cells play a pivotal role in a variety of cancers, highlighting their relevance in tumor immunosurveillance. NK cell infiltration has been reported in renal cell carcinoma (RCC), the most frequent kidney cancer in adults, and their presence has been associated with patients’ survival. However, the role of NK cells in this disease is not yet fully understood. In this review, we summarize the biology of NK cells and the mechanisms through which they are able to recognize and kill tumor cells. Furthermore, we discuss the role that NK cells play in renal cell carcinoma, and review current strategies that are being used to boost and exploit their cytotoxic capabilities. Full article

(This article belongs to the Special Issue Renal Cell Carcinoma)

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16 pages, 30790 KiB

Open AccessReview

ESC, ALK, HOT and LOT: Three Letter Acronyms of Emerging Renal Entities Knocking on the Door of the WHO Classification

by Farshid Siadat and Kiril Trpkov

Cancers 2020, 12(1), 168; https://doi.org/10.3390/cancers12010168 - 09 Jan 2020

Cited by 55 | Viewed by 6798

Abstract

Kidney neoplasms are among the most heterogeneous and diverse tumors. Continuous advancement of this field is reflected in the emergence of new tumour entities and an increased recognition of the expanding morphologic, immunohistochemical, molecular, epidemiologic and clinical spectrum of renal tumors. Most recent [...] Read more.

Kidney neoplasms are among the most heterogeneous and diverse tumors. Continuous advancement of this field is reflected in the emergence of new tumour entities and an increased recognition of the expanding morphologic, immunohistochemical, molecular, epidemiologic and clinical spectrum of renal tumors. Most recent advances after the 2016 World Health Organization (WHO) classification of renal cell tumors have provided new evidence on some emerging entities, such as anaplastic lymphoma kinase rearrangement-associated RCC (ALK-RCC), which has already been included in the WHO 2016 classification as a provisional entity. Additionally, several previously unrecognized entities, not currently included in the WHO classification, have also been introduced, such as eosinophilic solid and cystic renal cell carcinoma (ESC RCC), low-grade oncocytic renal tumor (LOT) and high-grade oncocytic renal tumor (HOT) of kidney. Although pathologists play a crucial role in the recognition and classification of these new tumor entities and are at the forefront of the efforts to characterize them, the awareness and the acceptance of these entities among clinicians will ultimately translate into more nuanced management and improved prognostication for individual patients. In this review, we summarise the current knowledge and the novel data on these emerging renal entities, with an aim to promote their increased diagnostic recognition and better characterization, and to facilitate further studies that will hopefully lead to their formal recognition and consideration in the future classifications of kidney tumors. Full article

(This article belongs to the Special Issue Renal Cell Carcinoma)

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13 pages, 498 KiB

Open AccessEditor’s ChoiceReview

The Future of Immunotherapy-Based Combination Therapy in Metastatic Renal Cell Carcinoma

by Rohan Garje, Josiah An, Austin Greco, Raju Kumar Vaddepally and Yousef Zakharia

Cancers 2020, 12(1), 143; https://doi.org/10.3390/cancers12010143 - 07 Jan 2020

Cited by 37 | Viewed by 5337

Abstract

In the past two decades, there has been a significant improvement in the understanding of the molecular pathogenesis of Renal Cell Carcinoma (RCC). These insights in the biological pathways have resulted in the development of multiple agents targeting vascular endothelial growth factor (VEGF), [...] Read more.

In the past two decades, there has been a significant improvement in the understanding of the molecular pathogenesis of Renal Cell Carcinoma (RCC). These insights in the biological pathways have resulted in the development of multiple agents targeting vascular endothelial growth factor (VEGF), as well as inhibitors of the mammalian target of the rapamycin (mTOR) pathway. Most recently, checkpoint inhibitors were shown to have excellent clinical efficacy. Although the patients are living longer, durable complete responses are rarely seen. Historically, high dose interleukin 2 (IL2) therapy has produced durable complete responses in 5% to 8% highly selected patients—albeit with significant toxicity. A durable complete response is a surrogate for a long-term response in the modern era of targeted therapy and checkpoint immunotherapy. Numerous clinical trials are currently exploring the combination of immunotherapy with various targeted therapeutic agents to develop therapies with a higher complete response rate with acceptable toxicity. in this study, we provide a comprehensive review of multiple reported and ongoing clinical trials evaluating the combination of PD-1/PD-L1 inhibitors with either ipilimumab (a cytotoxic T-lymphocyte-associated protein 4, CTLA-4 inhibitor) or with anti-VEGF targeted therapy. Full article

(This article belongs to the Special Issue Renal Cell Carcinoma)

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12 pages, 1119 KiB

Open AccessReview

Sarcomatoid Dedifferentiation in Renal Cell Carcinoma: From Novel Molecular Insights to New Clinical Opportunities

by Véronique Debien, Jonathan Thouvenin, Véronique Lindner, Philippe Barthélémy, Hervé Lang, Ronan Flippot and Gabriel G. Malouf

Cancers 2020, 12(1), 99; https://doi.org/10.3390/cancers12010099 - 31 Dec 2019

Cited by 23 | Viewed by 4916

Abstract

Sarcomatoid features in renal cell carcinoma (RCC) have long been associated with dismal prognosis and poor response to therapy, while biological mechanisms underpinning sarcomatoid dedifferentiation remained obscure. Several efforts have been conducted to break down the molecular profile of sarcomatoid RCC and investigate [...] Read more.

Sarcomatoid features in renal cell carcinoma (RCC) have long been associated with dismal prognosis and poor response to therapy, while biological mechanisms underpinning sarcomatoid dedifferentiation remained obscure. Several efforts have been conducted to break down the molecular profile of sarcomatoid RCC and investigate different targeted therapeutic approaches. Mutations enriched for in sarcomatoid RCC involve, notably, TP53, BAP1, cell cycle, and chromatin-remodeling genes. The immunological landscape of these tumors is also gradually being uncovered, showing frequent expression of programmed cell death ligand-1 (PD-L1) and high levels of tumor-infiltrating lymphocytes. These features may be major determinants for the activity of immune checkpoint inhibitors in this population, which has been confirmed by retrospective studies and subgroup analyses of large randomized phase 3 trials. Combinations based on PD-1/PD-L1 inhibition have demonstrated response rates and complete responses in >50% and >10% of patients in the first-line metastatic setting, respectively, with median overall survival exceeding two years. This remarkable improvement in outcomes effectively establishes immune checkpoint inhibitor combinations as a new standard of care in patients with sarcomatoid RCC. New research fields, including epigenetic regulations and tumor–microenvironment interactions, may further sharpen understanding of sarcomatoid RCC and advance therapeutic developments. Full article

(This article belongs to the Special Issue Renal Cell Carcinoma)

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24 pages, 4083 KiB

Open AccessReview

Molecular Genetics of Renal Cell Tumors: A Practical Diagnostic Approach

by Reza Alaghehbandan, Delia Perez Montiel, Ana Silvia Luis and Ondrej Hes

Cancers 2020, 12(1), 85; https://doi.org/10.3390/cancers12010085 - 30 Dec 2019

Cited by 15 | Viewed by 5082

Abstract

Renal epithelial cell tumors are composed of a heterogeneous group of tumors with variable morphologic, immunohistochemical, and molecular features. A “histo-molecular” approach is now an integral part of defining renal tumors, aiming to be clinically and therapeutically pertinent. Most renal epithelial tumors including [...] Read more.

Renal epithelial cell tumors are composed of a heterogeneous group of tumors with variable morphologic, immunohistochemical, and molecular features. A “histo-molecular” approach is now an integral part of defining renal tumors, aiming to be clinically and therapeutically pertinent. Most renal epithelial tumors including the new and emerging entities have distinct molecular and genetic features which can be detected using various methods. Most renal epithelial tumors can be diagnosed easily based on pure histologic findings with or without immunohistochemical examination. Furthermore, molecular-genetic testing can be utilized to assist in arriving at an accurate diagnosis. In this review, we presented the most current knowledge concerning molecular-genetic aspects of renal epithelial neoplasms, which potentially can be used in daily diagnostic practice. Full article

(This article belongs to the Special Issue Renal Cell Carcinoma)

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15 pages, 1234 KiB

Open AccessReview

Prognostic and Predictive Value of PBRM1 in Clear Cell Renal Cell Carcinoma

by Lucía Carril-Ajuria, María Santos, Juan María Roldán-Romero, Cristina Rodriguez-Antona and Guillermo de Velasco

Cancers 2020, 12(1), 16; https://doi.org/10.3390/cancers12010016 - 19 Dec 2019

Cited by 67 | Viewed by 7261

Abstract

Renal cell carcinoma (RCC) is the most frequent kidney solid tumor, the clear cell RCC (ccRCC) being the major histological subtype. The probability of recurrence and the clinical behavior of ccRCC will greatly depend on the different clinical and histopathological features, already incorporated [...] Read more.

Renal cell carcinoma (RCC) is the most frequent kidney solid tumor, the clear cell RCC (ccRCC) being the major histological subtype. The probability of recurrence and the clinical behavior of ccRCC will greatly depend on the different clinical and histopathological features, already incorporated to different scoring systems, and on the genomic landscape of the tumor. In this sense, ccRCC has for a long time been known to be associated to the biallelic inactivation of Von Hippel-Lindau (VHL) gene which causes aberrant hypoxia inducible factor (HIF) accumulation. Recently, next generation-sequencing technologies have provided the bases for an in-depth molecular characterization of ccRCC, identifying additional recurrently mutated genes, such as PBRM1 (≈40–50%), SETD2 (≈12%), or BAP1 (≈10%). PBRM1, the second most common mutated gene in ccRCC after VHL, is a component of the SWI/SNF chromatin remodeling complex. Different studies have investigated the biological consequences and the potential role of PBRM1 alterations in RCC prognosis and as a drug response modulator, although some results are contradictory. In the present article, we review the current evidence on PBRM1 as potential prognostic and predictive marker in both localized and metastatic RCC. Full article

(This article belongs to the Special Issue Renal Cell Carcinoma)

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23 pages, 901 KiB

Open AccessReview

The Interplay between Inflammation, Anti-Angiogenic Agents, and Immune Checkpoint Inhibitors: Perspectives for Renal Cell Cancer Treatment

by Nicole Brighi, Alberto Farolfi, Vincenza Conteduca, Giorgia Gurioli, Stefania Gargiulo, Valentina Gallà, Giuseppe Schepisi, Cristian Lolli, Chiara Casadei and Ugo De Giorgi

Cancers 2019, 11(12), 1935; https://doi.org/10.3390/cancers11121935 - 04 Dec 2019

Cited by 21 | Viewed by 3471

Abstract

Treatment options for metastatic renal cell carcinoma (RCC) have been expanding in the last years, from the consolidation of several anti-angiogenic agents to the approval of immune checkpoint inhibitors (ICIs). The rationale for the use of immunomodulating agents derived from the observation that [...] Read more.

Treatment options for metastatic renal cell carcinoma (RCC) have been expanding in the last years, from the consolidation of several anti-angiogenic agents to the approval of immune checkpoint inhibitors (ICIs). The rationale for the use of immunomodulating agents derived from the observation that RCC usually shows a diffuse immune-cell infiltrate. ICIs target Cytotoxic T Lymphocytes Antigen 4 (CTLA-4), programmed death 1 (PD-1), or its ligand (PD-L1), showing promising therapeutic efficacy in RCC. PD-L1 expression is associated with poor prognosis; however, its predictive role remains debated. In fact, ICIs may be a valid option even for PD-L1 negative patients. The establishment of valid predictors of treatment response to available therapeutic options is advocated to identify those patients who could benefit from these agents. Both local and systemic inflammation contribute to tumorigenesis and development of cancer. The interplay of tumor-immune status and of cancer-related systemic inflammation is pivotal for ICI-treatment outcome, but there is an unmet need for a more precise characterization. To date, little is known on the role of inflammation markers on PD-1 blockade in RCC. In this paper, we review the current knowledge on the interplay between inflammation markers, PD-1 axis, and anti-angiogenic agents in RCC, focusing on biological rationale, implications for treatment, and possible future perspectives. Full article

(This article belongs to the Special Issue Renal Cell Carcinoma)

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13 pages, 574 KiB

Open AccessReview

The Changing Therapeutic Landscape of Metastatic Renal Cancer

by Javier C. Angulo and Oleg Shapiro

Cancers 2019, 11(9), 1227; https://doi.org/10.3390/cancers11091227 - 22 Aug 2019

Cited by 47 | Viewed by 6127

Abstract

The practising clinician treating a patient with metastatic clear cell renal cell carcinoma (CCRCC) faces a difficult task of choosing the most appropriate therapeutic regimen in a rapidly developing field with recommendations derived from clinical trials. NCCN guidelines for kidney cancer initiated a [...] Read more.

The practising clinician treating a patient with metastatic clear cell renal cell carcinoma (CCRCC) faces a difficult task of choosing the most appropriate therapeutic regimen in a rapidly developing field with recommendations derived from clinical trials. NCCN guidelines for kidney cancer initiated a major shift in risk categorization and now include emerging treatments in the neoadjuvant setting. Updates of European Association of Urology clinical guidelines also include immune checkpoint inhibition as the first-line treatment. Randomized trials have demonstrated a survival benefit for ipilimumab and nivolumab combination in the intermediate and poor-risk group, while pembrolizumab plus axitinib combination is recommended not only for unfavorable disease but also for patients who fit the favorable risk category. Currently vascular endothelial growth factor (VEGF) targeted therapy based on tyrosine kinase inhibitors (TKI), sunitinib and pazopanib is the alternative regimen for patients who cannot tolerate immune checkpoint inhibitors (ICI). Cabozantinib remains a valid alternative option for the intermediate and high-risk group. For previously treated patients with TKI with progression, nivolumab, cabozantinib, axitinib, or the combination of ipilimumab and nivolumab appear the most plausible alternatives. For patients previously treated with ICI, any VEGF-targeted therapy, not previously used in combination with ICI therapy, seems to be a valid option, although the strength of this recommendation is weak. The indication for cytoreductive nephrectomy (CN) is also changing. Neoadjuvant systemic therapy does not add perioperative morbidity and can help identify non-responders, avoiding unnecessary surgery. However, the role of CN should be investigated under the light of new immunotherapeutic interventions. Also, markers of response to ICI need to be identified before the optimal selection of therapy could be determined for a particular patient. Full article

(This article belongs to the Special Issue Renal Cell Carcinoma)

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12 pages, 30603 KiB

Open AccessReview

MiT Family Translocation Renal Cell Carcinoma: from the Early Descriptions to the Current Knowledge

by Anna Caliò, Diego Segala, Enrico Munari, Matteo Brunelli and Guido Martignoni

Cancers 2019, 11(8), 1110; https://doi.org/10.3390/cancers11081110 - 03 Aug 2019

Cited by 86 | Viewed by 8411

Abstract

The new category of MiT family translocation renal cell carcinoma has been included into the World Health Organization (WHO) classification in 2016. The MiT family translocation renal cell carcinoma comprises Xp11 translocation renal cell carcinoma harboring TFE3 gene fusions and t(6;11) renal cell [...] Read more.

The new category of MiT family translocation renal cell carcinoma has been included into the World Health Organization (WHO) classification in 2016. The MiT family translocation renal cell carcinoma comprises Xp11 translocation renal cell carcinoma harboring TFE3 gene fusions and t(6;11) renal cell carcinoma harboring TFEB gene fusion. At the beginning, they were recognized in childhood; nevertheless, it has been demonstrated that these neoplasms can occur in adults as well. In the nineties, among Xp11 renal cell carcinoma, ASPL, PRCC, and SFPQ (PSF) were the first genes recognized as partners in TFE3 rearrangement. Recently, many other genes have been identified, and a wide spectrum of morphologies has been described. For this reason, the diagnosis may be challenging based on the histology, and the differential diagnosis includes the most common renal cell neoplasms and pure epithelioid PEComa/epithelioid angiomyolipoma of the kidney. During the last decades, many efforts have been made to identify immunohistochemical markers to reach the right diagnosis. To date, staining for PAX8, cathepsin K, and melanogenesis markers are the most useful identifiers. However, the diagnosis requires the demonstration of the chromosomal rearrangement, and fluorescent in situ hybridization (FISH) is considered the gold standard. The outcome of Xp11 translocation renal cell carcinoma is highly variable, with some patients surviving decades with indolent disease and others dying rapidly of progressive disease. Despite most instances of t(6;11) renal cell carcinoma having an indolent clinical course, a few published cases demonstrate aggressive behavior. Recently, renal cell carcinomas with TFEB amplification have been described in connection with t(6;11) renal cell carcinoma. Those tumors appear to be associated with a more aggressive clinical course. For the aggressive cases of MiT family translocation carcinoma, the optimal therapy remains to be determined; however, new target therapies seem to be promising, and the search for predictive markers is mandatory. Full article

(This article belongs to the Special Issue Renal Cell Carcinoma)

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Other

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9 pages, 1337 KiB

Open AccessFeature PaperBrief Report

Hypertonicity-Affected Genes Are Differentially Expressed in Clear Cell Renal Cell Carcinoma and Correlate with Cancer-Specific Survival

by Siarhei Kandabarau, Janna Leiz, Knut Krohn, Stefan Winter, Jens Bedke, Matthias Schwab, Elke Schaeffeler and Bayram Edemir

Cancers 2020, 12(1), 6; https://doi.org/10.3390/cancers12010006 - 18 Dec 2019

Cited by 5 | Viewed by 3884

Abstract

The heterogeneity of renal cell carcinoma (RCC) subtypes reflects the cell type of origin in the nephron, with consequences for therapy and prognosis. The transcriptional cues that determine segment-specific gene expression patterns are poorly understood. We recently showed that hypertonicity in the renal [...] Read more.

The heterogeneity of renal cell carcinoma (RCC) subtypes reflects the cell type of origin in the nephron, with consequences for therapy and prognosis. The transcriptional cues that determine segment-specific gene expression patterns are poorly understood. We recently showed that hypertonicity in the renal medulla regulates nephron-specific gene expression. Here, we analyzed a set of 223 genes, which were identified in the present study by RNA-Seq to be differentially expressed by hypertonicity, for the prediction of cancer-specific survival (CSS). Cluster analyses of these genes showed discrimination between tumor and non-tumor samples of clear cell RCC (ccRCC). Refinement of this gene signature to a four-gene score (OSM score) through statistical analyses enabled prediction of CSS in ccRCC patients of The Cancer Genome Atlas (TCGA) (n = 436) in univariate (HR = 4.1; 95% CI: 2.78−6.07; p = 4.39 × 10⁻¹³), and multivariate analyses including primary tumor (T); regional lymph node (N); distant metastasis (M); grading (G)(p = 2.3 × 10⁻⁵). The OSM score could be validated in an independent ccRCC study (n = 52) in univariate (HR = 1.29; 95% CI = 1.05–1.59; p = 0.011) and multivariate analyses (p = 0.016). Cell culture experiments using RCC cell lines demonstrated that the expression of the tumor suppressor ELF5 could be restored by hypertonicity. The innovation of our novel gene signature is that these genes are physiologically regulated only by hypertonicity, thereby providing the possibility to be targeted for therapy. Full article

(This article belongs to the Special Issue Renal Cell Carcinoma)

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5 pages, 1620 KiB

Open AccessCommentary

Renal Cell Carcinoma with Sarcomatoid Features: Finally New Therapeutic Hope?

by Renate Pichler, Eva Compérat, Tobias Klatte, Martin Pichler, Wolfgang Loidl, Lukas Lusuardi and Manuela Schmidinger

Cancers 2019, 11(3), 422; https://doi.org/10.3390/cancers11030422 - 25 Mar 2019

Cited by 40 | Viewed by 5196

Abstract

Renal cell carcinoma (RCC) with sarcomatoid differentiation belongs to the most aggressive clinicopathologic phenotypes of RCC. It is characterized by a high propensity for primary metastasis and limited therapeutic options due to its relative resistance to established systemic targeted therapy. Most trials report [...] Read more.

Renal cell carcinoma (RCC) with sarcomatoid differentiation belongs to the most aggressive clinicopathologic phenotypes of RCC. It is characterized by a high propensity for primary metastasis and limited therapeutic options due to its relative resistance to established systemic targeted therapy. Most trials report on a poor median overall survival of 5 to 12 months. Sarcomatoid RCC can show the typical features of epithelial-mesenchymal transition (EMT) and may contain epithelial and mesenchymal features on both the morphological and immunhistochemical level. On the molecular level, next-generation sequencing confirmed differences in driver mutations between sarcomatoid RCC and non-sarcomatoid RCC. In contrast, mutational profiles within the epithelial and sarcomatoid components of sarcomatoid RCC were shown to be identical, with TP53 being the most frequently altered gene. These data suggest that both epithelial and sarcomatoid components of RCC originate from the same progenitor cell, segregating primarily according to the underlying histologic epithelial subtype of RCC (clear cell, papillary or chromophobe). Current studies have shown that sarcomatoid RCC express programmed death 1 (PD-1) and its ligand (PD-L1) at a much higher level than non-sarcomatoid RCC, suggesting that blockade of the PD-1/PD-L1 axis may be an attractive new therapeutic strategy. Preliminary results of clinical trials evaluating checkpoint inhibitors in patients with sarcomatoid RCC showed encouraging survival data and objective response and complete response rates of up to 62% and 18%, respectively. These findings may establish a new standard of care in the management of patients with sarcomatoid RCC. Full article

(This article belongs to the Special Issue Renal Cell Carcinoma)

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