Clinical utility of circulating non-coding RNAs — an update

Abstract

Over the past decade, the amount of research and the number of publications on associations between circulating small and long non-coding RNAs (ncRNAs) and cancer have grown exponentially. Particular focus has been placed on the development of diagnostic and prognostic biomarkers to enable efficient patient management — from early detection of cancer to monitoring for disease recurrence or progression after treatment. Owing to their high abundance and stability, circulating ncRNAs have potential utility as non-invasive, blood-based biomarkers that can provide information on tumour biology and the effects of treatments, such as targeted therapies and immunotherapies. Increasing evidence highlights the roles of ncRNAs in cell-to-cell communication, with a number of ncRNAs having the capacity to regulate gene expression outside of the cell of origin through extracellular vesicle-mediated transfer to recipient cells, with implications for cancer progression and therapy resistance. Moreover, ‘foreign’ microRNAs (miRNAs) encoded by non-human genomes (so-called xeno-miRNAs), such as viral miRNAs, have been shown to be present in human body fluids and can be used as biomarkers. Herein, we review the latest developments in the use of circulating ncRNAs as diagnostic and prognostic biomarkers and discuss their roles in cell-to-cell communication in the context of cancer. We provide a compendium of miRNAs and long ncRNAs that have been reported in the literature to be present in human body fluids and that have the potential to be used as diagnostic and prognostic cancer biomarkers.

Key points

  • Non-coding RNAs (ncRNAs) have important roles in regulating the expression of genes that control fundamental biological functions; altered levels of ncRNAs are frequently detected in cancer cells compared with nonmalignant cells.

  • ncRNAs can be secreted into extracellular space as cell-free RNAs either encapsulated inside macrovesicles (such as extracellular vesicles) or in association with proteins (as RNA–protein complexes) or high-density lipoproteins (HDLs), and can subsequently be detected in blood samples as circulating ncRNAs.

  • Altered levels of circulating ncRNAs are found in body fluids, including serum, plasma, urine, and saliva, from patients with cancer compared with individuals without cancer and have potential clinical applications as diagnostic and prognostic blood-based biomarkers.

  • Circulating ncRNAs can mediate cell-to-cell communication and regulate gene expression in recipient cells, thereby acting similarly to hormones (mediating communication between cells within an individual) or as exogenous messengers (participating in inter-individual and cross-species molecular communication).

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Fig. 1: Mechanisms of action of non-coding RNAs.
Fig. 2: Extraction, detection, and normalization strategies for non-coding RNAs in body fluids.

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Acknowledgements

Work in G.A.C.’s laboratory is supported by US National Institutes of Health, National Center for Advancing Translational Sciences (NIH–NCATS) grant UH3TR00943-01 through the NIH Common Fund, Office of Strategic Coordination (OSC); by NIH National Cancer Institute (NCI) grant 1 R01 CA182905-01; by a U54 grant (University of Puerto Rico and The University of Texas MD Anderson Cancer Center (UPR–MDACC) Partnership for Excellence in Cancer Research 2016 Pilot Project); by a Team (US Department of Defense) grant (CA160445P1); by a Ladies Leukemia League grant; by a Chronic Lymphoblastic Leukemia Moonshot Flagship project grant; by a Sister Institution Network Fund (SINF) 2017 grant; and by the Estate of C. G. Johnson Jr. Work in K.P.’s laboratory is supported by the European Community’s Seventh Framework Program (FP7) under grant agreement Innovative Medicines Initiative (IMI) contract no. 115749 CANCER-ID (European Union’s FP7 and EFPIA companies’ in kind contribution); by European Research Council Advanced Investigator grant 269081 DISSECT; by European Research Council Proof-of-Concept grant no. 754453 CTCapture_2.0; by German Research Foundation (DFG) grant PA 341/19-2; and by Deutsche Krebshilfe grant 70112507. We also thank M. Dragomir for his critical review of this manucript.

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Nature Reviews Clinical Oncology thanks O. Slaby, J. Ellinger, L. Castellano, and the other, anonymous reviewer for their contribution to the peer review of this work.

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Anfossi, S., Babayan, A., Pantel, K. et al. Clinical utility of circulating non-coding RNAs — an update. Nat Rev Clin Oncol 15, 541–563 (2018). https://doi.org/10.1038/s41571-018-0035-x

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