Extracellular RNAs: development as biomarkers of human disease

Abstract

Ten ongoing studies designed to test the possibility that extracellular RNAs may serve as biomarkers in human disease are described. These studies, funded by the NIH Common Fund Extracellular RNA Communication Program, examine diverse extracellular body fluids, including plasma, serum, urine and cerebrospinal fluid. The disorders studied include hepatic and gastric cancer, cardiovascular disease, chronic kidney disease, neurodegenerative disease, brain tumours, intracranial haemorrhage, multiple sclerosis and placental disorders. Progress to date and the plans for future studies are outlined.

Diverse Long RNAs Are Differentially Sorted into Extracellular Vesicles Secreted by Colorectal Cancer Cells

“…Potentially, miRNAs are more tightly regulated as a subtype of RNA because they are exported largely intact whereas the range of long RNAs may encompass both intact and fragmented RNAs. This is consistent with the fact that miRNAs are more frequently being examined as potential biomarkers in various extracellular fluids, but as sequencing of such fluids continues, specific long RNAs might be identified that are subject to tightly regulated export and therefore more likely to serve as useful biomarkers of disease (Freedman et al, 2016; Matsumura et al, 2015; Quinn et al, 2015). …”

“…This potentially allows secretion of proteins and RNAs that could inhibit local growth and simultaneously ‘educate’ distant tissues for metastasis (Peinado et al, 2012). Circulating RNAs encased in vesicles or protein complexes are often altered in cancer and bear tumor-type-specific ‘signatures,’ making them attractive candidates as clinical biomarkers for disease diagnosis and prognosis (Quinn et al, 2015). …”

High-Definition Medicine

“…Circulating DNA methylation profiles can further refine tissue-specific cell death signatures (Lehmann-Werman et al, 2016), and circulating RNA profiles can allow the assessment of the state of tissues, such as the brain, which are otherwise inaccessible (Koh et al, 2014). These capabilities allow for the detection of organ specific disease processes such as early detection of organ transplant rejection (De Vlaminck et al, 2015), and a variety of other tissue-specific degenerative conditions, such as neurodegeneration (Quinn et al, 2015). Thus, longitudinal profiling of circulating nucleotides has the potential to be utilized as a more general health surveillance tool, where changes from baseline levels of circulating DNA from each tissue source indicate either tissue specific neoplastic or tissue specific degenerative processes.…”

Sources and Functions of Extracellular Small RNAs in Human Circulation

“…The interest in ex-sRNAs, especially in extracellular miRNAs, as clinical biomarkers for distinct pathologies has grown tremendously over the past decade, since they present numerous essential attributes which make them qualify as potentially ideal candidates for biomarkers including (i) their key regulatory functions (7, 152) and dysregulation in disease (7, 120, 152, 157); (ii) their cell type- and tissue-specific expression patterns (108, 163, 210); (iii) their relative ease of sampling and measurement (21, 40, 50, 52, 126, 205) and (iv) their stability (40, 52, 126, 176, 190, 237). …”

“…They are known to play key functions in regulating gene expression intracellularly and specific miRNAs are known to be dysregulated in certain diseases. Because these dysregulated sRNAs can be reflected in the overall ex-sRNA complement (7, 152), they have been proposed as potentially important biomarkers for a panoply of different diseases (102, 111, 126, 152, 210). Apart from miRNAs, it has only recently become clear that other ex-sRNAs, such as tRNA halves (tRHs), tRNA fragments (tRFs), rRNA fragments (rRFs), yRNA fragments (yRFs), piwi-interacting RNAs (piRNAs) and circular RNAs (circRNA) may also be suitable biomarkers for human diseases (16, 51, 52, 175, 196) (Table 1).…”