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Happel et al. J Cancer Metastasis Treat 2020;6:32 I http://dx.doi.org/10.20517/2394-4722.2020.71 Page 15 of 18

The expectation is to develop liquid biopsy-based analytical assays using circulating exRNAs specific for the
tumour type and to identify clinically relevant biomarkers useful as a diagnostic, prognostic or treatment
response markers for cancer patients to fully appreciate its clinical potential as cancer biomarkers.

FUTURE PERSPECTIVES
The potential for the use of EVs, exosomes, and exRNAs in cancer biomarker development are starting to
yield clinical utilities for diagnosing cancer, and as indicators of progression and/or treatment response.
EVs derived from cancer cells appear to modulate the function and may induce epigenetic changes
in distant recipient cells. Results from several studies as indicated in this review have already shown a
prominent role of exRNAs associated with exosomes in instituting these changes. EVs can retain the
molecular signature of the cell of origin, and its exRNA cargo has tremendous diagnostic potential. Since
the identification of exRNAs in various human bio-fluids, an increasing number of studies have positioned
exRNA as a new type of non-invasive biomarker with wide-ranging clinical potential.

While significant advances have been made, the use of exosomes and exRNAs as cancer biomarkers faces
remaining challenges that slows down its full potential from being realized. The NIH-led ERCC has
supported research into the important roles of exRNAs in biological processes and its potential in molecular
diagnosis, and to advance the technologies of exRNA identification and isolation from different types of
bio-fluid. The ERCC has played critical roles in unmasking the mechanism of exRNA biogenesis, delivery
and function; in defining a reference catalogue of exRNA in normal individual body fluids; in developing
the clinical utility of exRNA as biomarkers of disease or as therapeutic molecules. The ERCC have also led
the field in addressing major challenges in the field and providing valuable tools and technologies in this
emerging field.

Although a few exRNA biomarkers have been discovered individually for cancer diagnosis, a systematic
identification of novel exRNA biomarkers will need to be further pursued through better isolation of
homogeneous populations of exosomes and comprehensive analyses of their cargo. Currently, there are
only limited mature exRNA biomarkers that could guide clinical decision making. Large cohorts with
matched clinical information, including survival time, disease recurrence, response for drug usage or other
information can be catalytic in the identification of novel exRNA biomarkers. Sufficient clinical cohorts are
also required to validate the performance of biomarkers for early-diagnosis, prognosis and drug usage for
precision oncology.

In the future, it is also possible to target exRNAs as cancer therapeutic methods. The secretion and
circulation of EVs that contain regulatory exRNAs can be blocked to prevent cancer from progressing and
metastasis developing. In addition, exosomes could be used as a transmitter of specific regulatory elements
into target cells, inhibiting the development of tumour. Some regulatory exRNAs that play roles in pivotal
processes in tumour development could be repressed or sequestered to lower their abundance and inhibit
their functions. In summary, exRNA is useful not only for liquid biopsies to diagnose various cancer types,
but it also provides potential avenues for therapy.

DECLARATIONS
Authors’ contributions
Conception and preparation of the manuscript: Happel C, Ganguly A, Tagle DA

Availability of data and materials
Not applicable.