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Page 2 of 8 Panfoli et al. J Cancer Metastasis Treat 2020;6:35 I http://dx.doi.org/10.20517/2394-4722.2020.50

INTRODUCTION
[1-4]
Exosomes (Exo) are nanovesicles secreted by virtually any cell and found in all human body fluids . They
[4-6]
play important roles in intercellular communication both in physiology and disease . After being released
into the extracellular space, Exo can enter the circulation and ultimately be taken up by recipient cells
[7,8]
to which they can convey their protein, nucleic acid and lipid cargo in turn modulating their activity .
By proteomic and biochemical analyses, we have reported a novel characteristic of human Exo, i.e.,
they can consume oxygen to aerobically synthesize ATP [9-11] . Proteomic and statistical analyses of both
human mesenchymal stem cell (MSC) and urinary Exo showed enrichment of proteins related to aerobic
metabolism, including the redox complexes I, IV, and V in their membranes [9-11] . Such aerobic metabolic
capacity appears consistent with the Exo need to maintain their cup-shaped structure and functionality in
the face of a prolonged permanence in the circulation [10-12] and with their ability to rescue bioenergetics of
damaged cells [13,14] .

Research in the field of cancer is benefiting from the growing understanding of the biogenesis and
functions of Exo released from cancer cells [15-18] . However, the role of Exo in the pathophysiology of cancer
[19]
is multifaceted . Cancer cell-derived Exo have long been known to be involved in processes such as
cancer progression, metastasis, immune escape, angiogenesis and therapy resistance [20,21] . Exo function as
signalling molecules between the tumour microenvironment, i.e., the complex of both cancer and stromal
cells, and the rest of the body . Tumour-derived Exo can drive the metastatic process by targeting specific
[16]
[17]
organs setting a pre-metastatic environment . The tumour environment reacts by amplifying oncogenic
[22]
pathways in which Exo signalling is proposed to play a role .
Nonetheless, Exo also contain biomarkers, and can be considered biomarkers themselves [23,24] . For example,
urinary Exo deriving from every cell of the urinary tract and kidney, may represent a promising reservoir of
cancer biomarkers to assess disease progression in urologic cancers [25,26] . Exo can be noninvasively isolated
from human urine to detect biomarkers, with promising applications in patient stratification, monitoring of
therapy response or use as vehicles for therapeutic delivery .
[27]
Thanks to high throughput mass spectrometry techniques, it can be envisioned that Exo will help in earlier
diagnosis, directing therapeutic targets and assessing therapy resistance upon detection of signature cargo
biomarker biomolecules [1,16] . In the landscape of precision medicine, cancer liquid biopsies, i.e., the analysis
[28]
of circulating cell-free tumour DNA and tumour cells (CTC) , can exploit examining Exo signatures,
when they are derived from biological fluids . Exo can also potentially be used as tumour-targeting
[29]
vehicles for cancer [17,18,21] . There is also the exciting possibility of engineering the content of Exo and
targeting them to tissues of interest [30,31] .

This review focuses on the dual role of Exo in cancer. The good side of Exo is their clinical potential.
The ability of Exo to mediate cell-to-cell communication as stable carriers of molecular messages can
be exploited for cancer diagnosis and therapy, with novel exciting perspectives of translation to the
clinical setting [16,32] . The bad side of Exo is the long-recognized ability of their cargo to modify the cancer
microenvironment promoting cancer progression and metastasis by recruiting target cells, as is the case for
[33]
melanoma .

EXOSOMES
Exo, a subset of extracellular vesicles (EVs) of endocytic origin, actively shed from multivesicular bodies
(MVBs) which carry proteins, RNAs (mRNA, miRNA, transfer RNA, ribosomal RNA, nucleolar RNA, and
noncoding RNA) and DNA fragments [1,3,7,34] . Exo biogenesis involves the formation of early endosomal
vesicles, that develop into late endosomes undergoing inward budding forming intraluminal vesicles