Defining candidate mRNA and protein EV biomarkers to discriminate ccRCC and pRCC from non-malignant renal cells in vitro

Zieren, Richard C.; Dong, Liang; Clark, David; Kuczler, Morgan D.; Horie, Kengo; Moreno, Leandro Ferreira; Lih, Tung-Shing Mamie; Schnaubelt, Michael; Vermeulen, Louis; Zhang, Hui; Reijke, Theo M. de; Pienta, Kenneth J.; Amend, Sarah R.

doi:10.1007/s12032-021-01554-2

Cited by 8 publications

(4 citation statements)

References 54 publications

(77 reference statements)

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“…This will require the development of integrative protocols that are easily applicable. First steps in this direction have already been taken [ 81 ].…”

Section: Discussionmentioning

confidence: 99%

Identification of novel snoRNA-based biomarkers for clear cell renal cell carcinoma from urine-derived extracellular vesicles

Grützmann,

Salomo,

Krüger

et al. 2024

Biol Direct

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Background Clear cell renal cell carcinoma (ccRCC) is the most common subtype of RCC with high rates of metastasis. Targeted therapies such as tyrosine kinase and checkpoint inhibitors have improved treatment success, but therapy-related side effects and tumor recurrence remain a challenge. As a result, ccRCC still have a high mortality rate. Early detection before metastasis has great potential to improve outcomes, but no suitable biomarker specific for ccRCC is available so far. Therefore, molecular biomarkers derived from body fluids have been investigated over the past decade. Among them, RNAs from urine-derived extracellular vesicles (EVs) are very promising. Methods RNA was extracted from urine-derived EVs from a cohort of 78 subjects (54 ccRCC patients, 24 urolithiasis controls). RNA-seq was performed on the discovery cohort, a subset of the whole cohort (47 ccRCC, 16 urolithiasis). Reads were then mapped to the genome, and expression was quantified based on 100 nt long contiguous genomic regions. Cluster analysis and differential region expression analysis were performed with adjustment for age and gender. The candidate biomarkers were validated by qPCR in the entire cohort. Receiver operating characteristic, area under the curve and odds ratios were used to evaluate the diagnostic potential of the models. Results An initial cluster analysis of RNA-seq expression data showed separation by the subjects’ gender, but not by tumor status. Therefore, the following analyses were done, adjusting for gender and age. The regions differentially expressed between ccRCC and urolithiasis patients mainly overlapped with small nucleolar RNAs (snoRNAs). The differential expression of four snoRNAs (SNORD99, SNORD22, SNORD26, SNORA50C) was validated by quantitative PCR. Confounder-adjusted regression models were then used to classify the validation cohort into ccRCC and tumor-free subjects. Corresponding accuracies ranged from 0.654 to 0.744. Models combining multiple genes and the risk factors obesity and hypertension showed improved diagnostic performance with an accuracy of up to 0.811 for SNORD99 and SNORA50C (p = 0.0091). Conclusions Our study uncovered four previously unrecognized snoRNA biomarkers from urine-derived EVs, advancing the search for a robust, easy-to-use ccRCC screening method.

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“…This will require the development of integrative protocols that are easily applicable. First steps in this direction have already been taken [ 81 ].…”

Section: Discussionmentioning

confidence: 99%

Identification of novel snoRNA-based biomarkers for clear cell renal cell carcinoma from urine-derived extracellular vesicles

Grützmann,

Salomo,

Krüger

et al. 2024

Biol Direct

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“…A total of 1,726 proteins and 461 mRNAs were quantified in EVs derived from clear cell renal cell carcinoma, papillary renal cell carcinoma, and benign kidney cell lines. Among them, 181 proteins and 159 mRNAs were detected in all samples (Zieren et al, 2021). Shared proteins represent factors involved in biogenesis, whereas unique proteins reflected the characteristics of their cell of origin and were therefore proposed as biomarkers.…”

Section: Component Specificitymentioning

confidence: 99%

Biological Features of Extracellular Vesicles and Challenges

Zeng

Qiu

Jiang

et al. 2022

Front. Cell Dev. Biol.

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Extracellular vesicles (EVs) are vesicles with a lipid bilayer membrane on the outside, which are widely found in various body fluids and contain biological macromolecules such as DNA, RNA, lipids and proteins on the inside. EVs were once thought to be vesicles for the removal of waste materials, but are now known to be involved in a variety of pathophysiological processes in many diseases. This study examines the advantage of EVs and the challenges associated with their application. A more rational use of the advantageous properties of EVs such as composition specificity, specific targeting, circulatory stability, active penetration of biological barriers, high efficient drug delivery vehicles and anticancer vaccines, oxidative phosphorylation activity and enzymatic activity, and the resolution of shortcomings such as isolation and purification methods, storage conditions and pharmacokinetics and biodistribution patterns during drug delivery will facilitate the clinical application of EVs.

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“…For example, Zieren et al performed a multi-omic analysis on RCC and benign kidney cell lines. They identified 34 proteins as a candidate for pRCC biomarkers in EVs, and 20 proteins and 8 mRNA for ccRCC [ 90 ]. The results of this basic research pushed them to verification of their hypothesis in a human study.…”

Section: Evs As Rcc Biomarker and Prognostic Factormentioning

confidence: 99%

Extracellular Vesicles—A New Potential Player in the Immunology of Renal Cell Carcinoma

Kleibert

Czystowska-Kuźmicz

2022

JPM

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The incidence of renal cell carcinoma (RCC) has doubled in the developed world within the last fifty years, and now it is responsible for 2–3% of diagnosed cancers. The delay in diagnosis and the not fully understood pathogenesis are the main challenges that have to be overcome. It seems that extracellular vesicles (EVs) are one of the key players in tumor development since they ensure a proper microenvironment for the tumor cells. The stimulation of angiogenesis and immunosuppression is mediated by molecules contained in EVs. It was shown that EVs derived from cancer cells can inhibit T cell proliferation, natural killer lymphocyte activation, and dendritic cell maturation by this mechanism. Moreover, EVs may be a biomarker for the response to anti-cancer treatment. In this review, we sum up the knowledge about the role of EVs in RCC pathogenesis and show their future perspectives in this field.

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Defining candidate mRNA and protein EV biomarkers to discriminate ccRCC and pRCC from non-malignant renal cells in vitro

Cited by 8 publications

References 54 publications

Identification of novel snoRNA-based biomarkers for clear cell renal cell carcinoma from urine-derived extracellular vesicles

Identification of novel snoRNA-based biomarkers for clear cell renal cell carcinoma from urine-derived extracellular vesicles

Biological Features of Extracellular Vesicles and Challenges

Extracellular Vesicles—A New Potential Player in the Immunology of Renal Cell Carcinoma

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