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Page 4 of 18 Happel et al. J Cancer Metastasis Treat 2020;6:32 I http://dx.doi.org/10.20517/2394-4722.2020.71

Figure 2. A schematic diagram showing the biogenesis pathway of microvesicles and exosomes. Microvesicles are formed by direct
budding from the plasma membrane and are capable of encapsulating multiple forms of molecular cargo including proteins and nucleic
acids. The biogenesis of exosomes begins with internalization of the cell membrane leading to the formation of early endosomes.
Intraluminal vesicles (ILVs) are formed by the inward invagination of endosomal membranes, resulting in the formation of multivesicular
bodies (MVBs). During this process, cytosolic constituents, including nucleic acids and proteins, can be sorted into ILVs. Upon fusion
of MVBs with the plasma membrane, ILVs are released as exosomes into the extracellular milieu. Exosomes can include many different
types of exRNA as listed in Table 1. ER: endoplasmic reticulum; MLV: multivesicular body; ILV: intraluminal vesicle; miRNA: microRNA;
piRNA: piwi-interacting RNA; tRF: tRNA-derived RNA fragments; snoRNA: small nucleolar RNA; lncRNA: long non-coding RNA

Non-vesicle associated carriers include ribonucleoprotein (RNP) and lipoprotein (LPP) complexes. These
non-membrane bound exRNA carriers have been shown to be present in human plasma and serum [14,15] .
The LPP family of complexes are classically regarded as carriers of lipids and can be further broken
down into high-density lipoproteins (HDLs), low-density lipoproteins (LDLs), very LDLs (VLDLs), and
chylomicrons based on their mass density. Recent studies have revealed that lipoproteins, such as HDLs
and LDLs, can transport miRNAs and deliver them to recipient cells where they carry out their functional
roles [16,17] . One of the main interests in exRNA research is focused on their ability to mediate intercellular
communication and act as signalling molecules in normal cell homeostasis, or as a consequence of
pathological development. The exRNAs demonstrated potential as cancer biomarkers due to their function.
[18]
There are published reports to support the use of exRNA for both cancer diagnosis and prognosis .

This article focuses on exosome-derived exRNAs obtained non-invasively from liquid biopsy as potential
biomarkers for the early detection and monitoring of cancers. Developing biomarkers based on exRNA is