Search Results (398)

Background: Clear cell renal cell carcinoma (ccRCC) is the most prevalent kidney cancer subtype and, in most cases, it is incidentally diagnosed, as early-stage disease is often asymptomatic. Therefore, the identification of stable, noninvasive biomarkers is a major unmet clinical need. Urinary microRNAs (miRNAs) have emerged as promising candidates since they are extraordinarily stable in urine and show a close relationship with tumour biology. Methods: In this study, urinary expression levels of five miRNAs (miR-15a, miR-15b, miR-16, miR-210, and miR-let-7b) were analysed in RCC patients before surgery, 5 days after, and one month after surgery, and compared to healthy controls. Results: Non-parametric analyses revealed significant postoperative decreases for miR-15a (p = 0.002), miR-16 (p = 0.025), miR-210 (p = 0.030), and in the overall miRNA Sum (p = 0.002), suggesting that these miRNAs are directly linked to tumour presence. In the comparison between preoperative and one-month postoperative samples, miR-let-7b (p = 0.049) and the global miRNA Sum (p = 0.037) remained significantly reduced after intervention, indicating a partial normalisation of urinary miRNA profiles. Correlation analyses demonstrated positive associations between specific miRNAs and clinical parameters such as age, ischemia time, and surgical time, reinforcing their potential relevance to tumour biology and treatment response. Conclusions: These findings support urinary miRNAs as promising, minimally invasive biomarkers for ccRCC diagnosis and postoperative monitoring. Full article

Background/Objectives: Kidney cancer (RC) is a significant global health burden. Renal cell carcinoma (RCC) is the most common form of kidney cancer. Its predominant histological subtype is clear cell renal cell carcinoma (ccRCC), which is frequently diagnosed at an advanced local stage or with metastases. Detecting cancer at an early stage significantly increases the likelihood of a cure; therefore, research on new markers and a thorough understanding of tumor biology are essential. This study investigated the significance of aromatase (ARO), cathepsin S (CTSS), and matrix metalloproteinase 1 (MMP-1) as potential biomarkers in ccRCC. Methods: ARO, CTSS, and MMP-1 concentrations in plasma were determined using SPRi biosensors. Appropriate antibodies were used as biorecognition molecules in the biosensors. The samples analyzed came from 60 patients with histopathologically confirmed clear cell renal cell carcinoma (ccRCC) and from 26 patients diagnosed with chronic cystitis or benign prostatic hyperplasia (BPH). Results: A statistically significant increase (p < 0.00001) in the concentration of all proteins compared with the control samples was observed at the T3–T4 stage. The ARO concentration was already statistically significantly higher at the T1–T2 stage (p < 0.00001). The ROC curve for aromatase demonstrated high sensitivity and specificity for detecting ccRCC, with a cut-off point of 7.53 ng mL⁻¹. A moderate positive correlation was also found between the concentrations of the three tested substances in renal cancer, which may indicate potential interactions in the tumor’s pathogenesis. Conclusions: SPRI testing has been shown to be an alternative to standard methods for detecting potential ccRCC markers. The biosensors used in the study can simultaneously determine ARO, CTSS, and MMP-1. The results obtained suggest the potential importance of these proteins in the development of ccRCC, and our work proposes a new diagnostic technique that may aid in the diagnosis of ccRCC. Full article

Background: Clear cell renal cell carcinoma (ccRCC) is the most common subtype of kidney cancer and is marked by pronounced intra-tumoural heterogeneity that complicates therapeutic response. Patient-derived organoids offer a physiologically relevant model to capture this diversity and evaluate treatment effects. When integrated with spatial transcriptomics, they might enable the mapping of spatially resolved transcriptional and isoform-level changes within the tumour microenvironment. Methods: We established a robust workflow for generating patient-derived ccRCC organoids, that are not passaged and retain original cellular components. These retain key features of the original tumours, including cancer cell, stromal, and immune components. Results: Spatial transcriptomic profiling revealed multiple transcriptionally distinct regions within and across organoids, reflecting the intrinsic heterogeneity of ccRCC. Isoform-level analysis identified spatially variable expression of glutaminase (GLS) isoforms, with heterogeneous distributions of both the GAC and KGA variants. Treatment with NUC-7738, a phosphoramidate derivative of 3′-deoxyadenosine, induced marked transcriptional remodelling of organoids, including alterations in ribosomal and mitochondrial gene expression. Conclusions: This study demonstrates that combining long-read spatial transcriptomics with patient-derived organoid models provides a powerful and scalable approach for dissecting gene and isoform-level heterogeneity in ccRCC and for elucidating spatially resolved transcriptional responses to novel therapeutics. Full article

Background and Clinical Significance: Percutaneous ablation is an increasingly used nephron-sparing treatment for small renal masses (SRMs). Although generally considered safe, tumor seeding along the applicator tract is rare (<0.1%) and may be underreported. This study reviews the existing literature to synthesize patterns, potential risk factors, and clinical presentation of this complication following percutaneous thermal ablation of renal cell carcinoma (RCC). Case Presentation: We report the case of an 84-year-old man who developed late subcutaneous abdominal-wall tumor seeding more than ten years after nephron-sparing surgery for a T1a renal mass and following three sessions of percutaneous cryo- and microwave ablation for recurrent clear-cell renal cell carcinoma (ccRCC). The lesion was surgically excised, and histology confirmed ccRCC with negative margins. A descriptive literature review was conducted using PubMed and ScienceDirect to identify English-language case reports and case series (CS) documenting tumor seeding after RCC percutaneous ablation. Eight studies involving nine patients met the inclusion criteria. The median age was 66 years (interquartile range [IQR] 64–74; range 47–84). The median follow-up duration was 11 months (IQR, 4.5–18.5; range 3–60), and the median interval to tumor seeding was 11 months (IQR, 6–18.5; range 3–60). Management included surgical excision (50%), repeat cryoablation (25%), and systemic therapy or supportive care (25%). Conclusions: Tumor tract seeding following percutaneous ablation for RCC is rare, with variable latency and presentation. Procedural factors such as the absence of tract ablation, multiple probe passes, and intra-procedural biopsy may increase risk. Awareness of this complication and long-term surveillance should be incorporated into follow-up protocols. Despite this risk, percutaneous ablation remains a safe and effective option for appropriately selected patients. Full article

Clear cell renal cell carcinoma (ccRCC) represents the predominant histological subtype of renal cell carcinoma (RCC), constituting approximately 85% of all RCC cases. Recent advancements in therapies aimed at targeting angiogenesis have marked a significant breakthrough in the treatment of ccRCC, with several of these therapies receiving approval for clinical use. Furthermore, the introduction of immune checkpoint inhibitors (ICIs) has demonstrated efficacy in the management of ccRCC. Nonetheless, there is an urgent need for the identification of predictive and prognostic biomarkers, which are currently under investigation. This review offers an extensive examination of the pathological, genomic, and molecular characteristics of ccRCC, with particular emphasis on its immune attributes. Additionally, it addresses the clinical implications of targeted therapies and immunotherapies, whether administered as monotherapy or in combination with traditional or novel agents, while also evaluating the results of pertinent clinical trials. By encompassing a wide range of topics related to ccRCC, from foundational knowledge to clinical applications, this review aims to deepen the understanding of the essential features of ccRCC and to establish a theoretical basis for the formulation of clinical strategies. Full article

FDG PET/CT often underperforms in characterizing hyper-enhancing, FDG-non-avid renal masses. We present two cases illustrating the potential of ⁶⁸Ga-NY104, a novel small-molecule tracer targeting carbonic anhydrase IX (CAIX), for this differential diagnosis. Both patients presented with a hyper-enhancing right renal mass suspicious for clear cell renal carcinoma (ccRCC) and subsequently underwent both ¹⁸F-FDG and ⁶⁸Ga-NY104 PET/CT, with histopathology and CAIX immunohistochemistry (IHC) as the reference standard. On ¹⁸F-FDG, both lesions were non-avid (SUVmax 2.6 and 2.2, Tumor-to-Liver Ratio [TLR] 0.87 and 0.69, respectively). However, on ⁶⁸Ga-NY104 PET/CT, Patient 1 (a 65-year-old man) showed intense, homogeneous uptake (SUVmax 26.0, TLR 4.64), while Patient 2 (a 67-year-old woman) showed negligible uptake (SUVmax 2.5, TLR 0.68). It was consistent with histopathology and IHC results that Patient 1 was CAIX-positive ccRCC, while Patient 2 was CAIX-negative hemangioma. Our preliminary cases suggest the potential utility of CAIX-targeted PET/CT imaging with ⁶⁸Ga-NY104 in differentiating ccRCC from benign mimickers like renal hemangioma, which warrants further prospective evaluation. Full article

Background: Shikonin, a natural compound derived from Lithospermum erythrorhizon, exhibits anticancer properties by inducing apoptosis in various tumor types, including clear cell renal cell carcinoma (ccRCC) cell lines CAKI-2 and A-498. This study investigates the mechanisms underlying shikonin-induced apoptosis, focusing on microRNAs miR-15b, miR-99b, and miR-181a in ccRCC. Materials and Methods: ccRCC cells were treated with 5 µM shikonin. Expression levels of miR-15b, miR-99b, and miR-181a were measured by TaqMan PCR. Apoptosis-related targets (AKT3, PDCD4, FOXO1, FOXO3, JNK1, and LAMTOR3) were identified in silico and validated by qRT-PCR and Western blot. Spearman’s correlation was used to evaluate miRNA–target relationships. Ingenuity Pathway Analysis explored relevant pathways. Results: Shikonin decreased miR-15b, miR-99b, and miR-181a levels in CAKI-2 cells, whereas these miRNAs were increased in A-498 cells, demonstrating cell-line-specific effects. qRT-PCR and Western blot confirmed changes in target expression, suggesting regulation by these miRNAs. In A-498 cells, miR-181a expression positively correlated with the studied target levels during 24–72 h of treatment, indicating that its potential regulatory role may be cell-type-dependent. MiR-15b and miR-99b showed linear correlations with targets in both cell lines, but expression patterns differed, suggesting direct regulation alongside potential involvement in additional pathways contributing to shikonin-induced apoptosis. Conclusions: Shikonin induces apoptosis in renal cancer cells by modulating the MAPK/ERK pathway and through cell-line-specific, cell-type-dependent regulation of miR-15b, miR-99b, and miR-181a. These findings highlight the importance of cell-type-dependent miRNA regulation and underscore the therapeutic potential of shikonin in ccRCC. Full article

Background: Modeling precancerous stages holds the promise to understand early transformation events, thereby offering the potential for personalized, targeted treatment. Because cancer hijacks developmental pathways, precancerous stages could potentially be modeled by reprogramming cancer cells to an induced pluripotent stem cell state and subsequently differentiating them to the target organs using organoid models. Methods: We attempted reprogramming of patient-derived clear cell renal cell carcinoma (ccRCC) cell lines and adjacent normal renal epithelial cell lines using lentivirus or episomal reprogramming vectors. Results: The cancer cells failed to reprogram while the adjacent normal cells reprogrammed with high efficiency. The von Hippel–Lindau factor (VHL) gene was re-expressed in ccRCC cells in an attempt to restore the wild-type phenotype and restore reprogramming. The VHL gene is the major tumor suppressor in ccRCC pathogenesis and a conductor of oxidative-glycolytic glucose metabolism. While its re-expression did restore the epithelial phenotype and oxidative regulation of ccRCC cells, they still failed to stably reprogram. With an optimized reprogramming workflow, VHL-corrected ccRCC cells generate NANOG+ cells; however, they remained dependent on the ectopic expression of the reprogramming factors. Conclusions: We concluded that while VHL expression is necessary for cellular reprogramming of ccRCC cells, other genetic lesions in the ccRCC cells could be preventing the stabilization of the pluripotent state. Full article

Despite advances in the management of advanced clear cell renal cell carcinoma (ccRCC), robust biomarkers for prognosis and therapeutic response prediction remain elusive. Fibroblast activation protein-α (FAP), a marker of activated cancer-associated fibroblasts (CAFs), has emerged as a potential indicator of tumor aggressiveness and resistance to systemic therapies in various solid tumors. This study evaluated the clinical relevance of stromal FAP expression in a cohort of 137 patients with advanced ccRCC and long-term follow-up. FAP immunohistochemistry (IHC) was performed on primary tumor specimens and correlated with key clinicopathological features, disease-free survival (DFS), overall survival (OS), and radiological response to first-line tyrosine kinase inhibitors (TKIs). A significantly higher percentage of FAP-positive CAFs was observed in primary tumors with high histological grade, extensive local invasion (pT3–4), and advanced clinical stage (NCCN stage III–IV). Stromal FAP expression was associated with shorter DFS and OS. Moreover, tumors lacking FAP expression were more likely to achieve complete response to TKI therapy as defined by RECIST criteria. These findings highlight the potential of FAP IHC as a prognostic and predictive tool in advanced ccRCC and support further clinical validation. Full article

Background: Clear cell renal cell carcinoma (ccRCC) is a prevalent urological malignancy, accounting for approximately 1.6% of all cancer-related deaths in 2022. While endocrine-disrupting chemicals (EDCs) have been implicated as risk factors for ccRCC, the toxicological profiles and immune mechanisms underlying Bisphenol A (BPA) exposure in ccRCC progression remain inadequately understood. Materials and Methods: Protein–protein interaction (PPI) analysis and visualization were performed on overlapping genes between ccRCC and BPA exposure. This was followed by Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) enrichment analyses to elucidate potential underlying mechanisms. Subsequently, 108 distinct machine learning algorithm combinations were evaluated to identify the optimal predictive model. An integrated CoxBoost and Ridge regression model was constructed to develop a prognostic signature, the performance of which was rigorously validated across two independent external datasets. Finally, molecular docking analyses were employed to investigate interactions between key genes and BPA. Results: A total of 114 overlapping targets associated with both ccRCC and BPA were identified. GO and KEGG analyses revealed enrichment in cancer-related pathways, including pathways in cancer, endocrine resistance, PD-L1 expression and PD-1 checkpoint signaling, T-cell receptor signaling, endocrine function, and immune responses. Machine learning algorithm selection identified the combined CoxBoost-Ridge approach as the optimal predictive model (achieving a training set concordance index (C-index) of 0.77). This model identified eight key genes (CHRM3, GABBR1, CCR4, KCNN4, PRKCE, CYP2C9, HPGD, FASN), which were the top-ranked by coefficient magnitude in the prognostic model. The prognostic signature demonstrated robust predictive performance in two independent external validation cohorts (C-index = 0.74 in cBioPortal; C-index = 0.81 in E-MTAB-1980). Furthermore, molecular docking analyses predicted strong binding affinities between BPA and these key targets (Vina scores all <−6.5 kcal/mol), suggesting a potential mechanism through which BPA may modulate their activity to promote renal carcinogenesis. Collectively, These findings suggested potential molecular mechanisms that may underpin BPA-induced ccRCC progression, generating hypotheses for future experimental validation. Conclusions: These findings enhance our understanding of the molecular mechanisms by which BPA induces ccRCC and highlight potential targets for therapeutic intervention, particularly in endocrine and immune-related pathways. This underscores the need for collaborative efforts to mitigate the impact of environmental toxins like BPA on public health. Full article

Non-clear cell renal cell carcinoma (nccRCC) constitutes a biologically diverse category of renal malignancies. The 2022 WHO classification framework has significantly evolved to incorporate molecularly defined entities alongside traditional histologic subtypes, reflecting the growing recognition of distinct pathogenic drivers. Current therapeutic paradigms for advanced disease remain suboptimal, with treatment strategies often extrapolated from clear cell renal cell carcinoma (ccRCC). In this review, we highlight transformative multi-omics approaches to address nccRCC’s profound heterogeneity, which enables molecular stratification beyond conventional pathology, identifying novel subtypes characterized by unique immune microenvironment features, metabolic profiles, and genomic instability patterns. This molecular reclassification provides a foundational framework for precision oncology, facilitating patient selection for targeted therapies and immunomodulatory strategies. Advancements in multi-omics subtyping represent a pivotal shift toward biologically guided clinical management and underscore the imperative for biomarker-driven therapeutic development in nccRCC. Full article

This study aimed to investigate the role and underlying mechanism of apolipoprotein C2 (APOC2) in the progression of clear cell renal cell carcinoma (ccRCC). Analysis of The Cancer Genome Atlas (TCGA) datasets, combined with validation in ccRCC cell lines, revealed that APOC2 was markedly upregulated in ccRCC tissues and cells and was associated with poor patient prognosis. Functional assays demonstrated that APOC2 knockdown significantly suppressed cell proliferation, colony formation, migration, and invasion, while promoting apoptosis. Mechanistic studies showed that silencing APOC2 reduced the phosphorylation levels of key components of the JAK-STAT signaling pathway, including Jak1/2 and STAT3, without affecting their total protein expression. Gene enrichment analysis further indicated the involvement of JAK-STAT signaling, and functional rescue experiments using the STAT3 agonist Colivelin partially reversed the decreased cell viability and increased apoptosis caused by APOC2 knockdown, confirming the pathway’s mediating role. Collectively, these findings suggest that APOC2 promotes ccRCC cell proliferation and inhibits apoptosis, at least in part, through activation of the JAK-STAT signaling pathway, highlighting APOC2 as a novel oncogenic regulator and potential therapeutic target, and providing new insight into the metabolic–inflammatory axis in ccRCC progression. Clinically, APOC2 may serve as a biomarker to identify ccRCC patients with hyperactivated JAK-STAT signaling and could potentially guide combination therapies involving JAK/STAT inhibitors or metabolic-targeted agents. Full article

Clear cell renal cell carcinoma (ccRCC), accounting for 80–90% of renal malignancies, is frequently driven by VHL inactivation—either through mutation or promoter hypermethylation—resulting in constitutive HIF2$\alpha$ activation and pseudohypoxic signaling. VHL gene inactivation is a hallmark of von Hippel–Lindau syndrome, a hereditary disorder predisposing patients to ccRCC and other tumors, underscoring its central role in disease pathogenesis. While VHL dysfunction promotes aggressive tumor phenotypes, the therapeutic potential of VHL restoration remains underexplored. Here, using the Cas9 induced VHL-mutation in the Caki-1 cell line model, we demonstrate that VHL inactivation augments hypoxia-like pathways and enhances anaerobic glycolysis. Rescue of functional VHL reversed these activation patterns and modulated the expression of genes associated with angiogenesis. Using single cell transcriptomics, we show that the VHL-positive and -negative Caki-1 cells are characterized with different proportions of benign and aggressive cells as seen by analysis of specific gene expression. Furthermore, the identified angiogenesis-related genes were linked to affect clinical outcomes in ccRCC patients, suggesting that VHL restoration may mitigate high-risk molecular features. Full article

Background: The purpose of this study was to investigate the value of machine learning models for preoperative non-invasive prediction of International Society of Urological Pathology (ISUP) grading in clear cell renal cell carcinoma (ccRCC) based on CT urography (CTU)-related peritumoral area (PAT) radiomics features. Methods: We retrospectively analysed 328 ccRCC patients from our institution, along with an external validation cohort of 175 patients from The Cancer Genome Atlas. A total of 1218 radiomics features were extracted from contrast-enhanced CT images, with LASSO regression used to select the most predictive features. We employed four machine learning models, namely, Logistic Regression (LR), Multilayer Perceptron (MLP), Support Vector Machine (SVM), and Extreme Gradient Boosting (XGBoost), for training and evaluation using Receiver Operating Characteristic (ROC) analysis. The model performance was assessed in training, internal validation, and external validation sets. Results: The XGBoost model demonstrated consistently superior discriminative ability across all datasets, achieving AUCs of 0.95 (95% CI: 0.92–0.98) in the training set, 0.93 (95% CI: 0.89–0.96) in the internal validation set, and 0.92 (95% CI: 0.87–0.95) in the external validation set. The model significantly outperformed LR, MLP, and SVM (p < 0.001) and demonstrated prognostic value (Log-rank p = 0.018). Transcriptomic analysis of model-stratified groups revealed distinct biological signatures, with high-grade predictions showing significant enrichment in metabolic pathways (DPEP3/THRSP) and immune-related processes (lymphocyte-mediated immunity, MHC complex activity). These findings suggest that peritumoral imaging characteristics provide valuable biological insights into tumor aggressiveness. Conclusions: The machine learning models based on PAT radiomics features of CTU demonstrated significant value in the non-invasive preoperative prediction of ISUP grading for ccRCC, and the XGBoost modeling had the best predictive ability. This non-invasive approach may enhance preoperative risk stratification and guide clinical decision-making, reducing reliance on invasive biopsy procedures. Full article

Clear cell renal cell carcinoma (ccRCC) is the most common and aggressive subtype of kidney cancer. This study aimed to construct a prognostic model for ccRCC based on glycosyltransferase genes, which play important roles in cell processes like proliferation, apoptosis. Glycosyltransferase genes were collected from four public databases and analyzed using RNA-seq data with clinical information from three ccRCC datasets. Prognostic models were constructed using eight machine learning algorithms, generating a total of 117 combinatorial algorithm models, and the StepCox[forward]+Ridge model with the highest predictive accuracy (C-index = 0.753) which selected and named the Glycosyltransferases Risk Score (GTRS) model. The GTRS effectively stratified patients into high- and low-risk groups with significantly different overall survival and maintained robust performance across TCGA, CPTAC, and E-MTAB1980 cohorts (AUC > 0.75). High-risk patients exhibited higher tumor mutational burden, immunosuppressive microenvironment, and poorer response to immunotherapy. TYMP and GCNT4 were experimentally validated as key genes, functioning as oncogenic and tumor-suppressive factors. In conclusion, GTRS serves as a reliable prognostic tool for ccRCC and provides mechanistic insights into glycosylation-related tumor progression. Full article