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Page 2 Asao et al. Extracell Vesicles Circ Nucleic Acids 2023;4:461-85 https://dx.doi.org/10.20517/evcna.2023.37

least, the progress in EVP analysis technologies that have facilitated these discoveries is discussed, which may
further propel EVP research in the future.

Keywords: Extracellular vesicles and particles, cancer, pre-metastatic niche, organotropism, biomarkers, treatment

INTRODUCTION
EVPs are nano-sized structures secreted by all cell types that serve as critical mediators of intercellular
[1]
communication . They participate in a wide array of physiological processes, such as immune responses,
neural signaling, and tissue regeneration, as well as pathologies, including cancer, inflammation, infectious
diseases, neurological disorders, cardiovascular diseases, and autoimmune disorders. The groundbreaking
research into the mechanisms that govern vesicle trafficking, which is crucial for understanding EVP
[2]
biogenesis, earned the 2013 Nobel Prize in Physiology or Medicine .

Over the past decade, EVP research has made remarkable leaps, which can be attributed to the solid
foundation laid by these studies [Figure 1]. Advances have been achieved in several areas, encompassing the
discovery of new EVP fractions facilitated by technological innovations, comprehensive characterization of
EVP cargo, such as proteins, nucleic acids, and metabolites, and a better grasp of their involvement in
various diseases. Particularly noteworthy is elucidating the roles of EVPs in cancer development, such as in
pre-metastatic niche (PMN) formation, the creation of a favorable environment within distant organs that
supports cancer cell colonization, as well as metastatic organotropism and progression. More recently, EVPs
have been shown to play critical roles in mediating the systemic effects of cancer, leading to vascular
dysfunction, coagulation, metabolic alterations, and immune suppression. These findings have greatly
enhanced our knowledge in the field and led to the recognition of EVP cargo as biomarkers of cancer, its
progression and response to treatment, as well as the exploration of the therapeutic applications of EVPs.

This review aims to provide a comprehensive overview of the research conducted on the pleiotropic roles of
EVPs in cancer over the past decade, highlighting the most significant discoveries and their implications for
the future of cancer diagnosis and treatment.

EVP HETEROGENEITY
EVPs are highly heterogeneous and include a wide variety of particles, ranging from about 10 nm to over
1 μm in diameter. Since their discovery in the 1980s, research on extracellular vesicles has revealed that all
cell types release a variety of EVPs. Conventionally, extracellular vesicles have been largely categorized as
exosomes and microvesicles (MVs) based on size and biogenesis pathways .
[3]

EVPs carry various cargo, such as proteins, nucleic acids (RNA, DNA), lipids, and metabolites, and can
exert various functions. Recent advances in technology have led to the discovery of novel EVP populations,
as well as the reclassification of conventional EVPs [4-13] . In particular, small EVPs were recently re-classified
based on their size and structure as large exosomes (Exo-L; 90-120 nm), small exosome (Exo-S; 60-90 nm),
non-membranous nanoparticles termed exomeres (35-50 nm) and supermeres (25-35 nm) [12-14] . Exomeres
and supermeres are nanoparticles that lack an external membrane structure and are therefore classified as
new populations called extracellular nanoparticles (ENPs). Each of these EVP subsets has a distinct protein,
nucleic acid, lipid, and proteoglycan composition, suggesting that they have distinct functions. Exomeres
are rich in metabolic enzymes, particularly those involved in glycolysis, and may play a role in metabolic
programs, coagulation, and responses to low oxygen. Moreover, cancer-derived supermeres promote lactate
secretion and drug resistance, and decrease hepatic lipids and glycogen, suggesting that ENPs may be