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Asao et al. Extracell Vesicles Circ Nucleic Acids 2023;4:461-85 https://dx.doi.org/10.20517/evcna.2023.37 Page 13

In conclusion, the field of EVPs has come a long way since their initial discovery in the 1980s, when they
were thought to be cellular debris or cellular “garbage disposals”. Over the past few decades, numerous
groundbreaking studies have instead revealed the critical roles that EVPs play in cancer progression and
metastasis. Their involvement in intercellular communication, promotion of angiogenesis, immune
response modulation, EMT, and formation of PMNs has transformed our understanding of cancer
progression.

As our knowledge of the complex interplay between EVPs and cancer metastasis continues to grow, new
therapeutic strategies targeting EVPs and their cargo may emerge, providing novel approaches to combat
cancer progression and metastasis. The ongoing research in this field holds great promise for the
development of innovative cancer treatments and a deeper understanding of the mechanisms driving
metastasis. One key aspect of this research involves the identification and study of biomarkers, which can
help track disease progression and response to therapy. In the next section, we will delve into the role of
biomarkers in cancer research and how they may further advance our understanding of EVPs in metastasis.

EVPS AS CANCER BIOMARKERS
In recent years, the potential of using EVPs as biomarkers for various diseases, including cancer, has gained
significant attention . The use of EVPs as biomarkers for cancer has several advantages over traditional
[139]
[142]
[141]
methods . Firstly, detecting EVPs in bodily fluids, such as blood , urine , or saliva [143,144] , is non-
[140]
invasive, unlike tissue biopsies, rendering large-scale screening of the general population more feasible and
less costly. Additionally, EVPs are very abundant in these bodily fluids [25,141] and provide a more accurate
representation of the tumor microenvironment and systemic changes than single biomarkers , such as
[48]
proteins or miRNAs, or local sampling such as biopsies. As EVPs carry a diverse range of bioactive
molecules, they can better reflect the complexity and heterogeneity of cancer [48,145] . Lastly, the stability of
EVPs in bodily fluids, conferred by their bilayer lipid membrane, offers a significant advantage over other
biomarkers, especially nucleic acid ones, which are often rapidly degraded [3,146] . This stability allows for more
accurate and reliable testing, as well as the potential for monitoring disease progression and response to
therapy.

This potential has not gone unnoticed, and some practical applications have already been approved by the
United States Food and Drug Administration (FDA). For example, Exosome Diagnostics, now Bio-Techne,
has developed a series of diagnostic tests based on the use of exosomes and other EVPs. Their ExoDx
Prostate (IntelliScore) is a urine test that utilizes exosomal RNA to detect three biomarkers [ERG (V-ets
erythroblastosis virus E26 oncogene homologs), PCA3 (prostate cancer antigen 3), and SPDEF (SAM
pointed domain-containing ETS transcription factor)] for the assessment of prostate cancer risk .
[142]
Compared to serum prostate-specific antigen (PSA), which is a gold standard for monitoring prostate
cancer but has low sensitivity and specificity in terms of diagnosing prostate cancer, ExoDx Prostate showed
better performance in detecting high-grade prostate carcinoma. This test demonstrates the real-world utility
of EVPs as biomarkers in current clinical practices.

Recently, Hoshino et al. characterized the complete proteomic profile of EVPs from plasma samples of 16
different cancer types and identified EVP protein cargo overrepresented or downregulated in cancer-
[48]
associated EVPs . These proteins could distinguish between cancer and non-cancer or different types of
cancer with high sensitivity and specificity, demonstrating the potential use of EVPs as liquid biopsy
markers for early cancer detection [48,147] . Notably, the study revealed that cancer-derived proteins were not
the potential cancer biomarkers in blood-circulating EVPs, but that approximately 50% of the cancer-
associated signature proteins were derived from the tumor microenvironment, distant organs and the