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Page 14 Asao et al. Extracell Vesicles Circ Nucleic Acids 2023;4:461-85 https://dx.doi.org/10.20517/evcna.2023.37

immune system. These findings highlight these cancer-associated or induced EVP cargo changes as critical
components of early cancer detection biomarker signatures.

The study also found that EVP protein packaging is heterogeneous across tumor types and reflects tumor
biology. The researchers then identified a combination of EVP proteins that were most likely to distinguish
cancer from non-cancer, which were highly enriched in both pancreatic and lung tumor tissues and
predictive in identifying cancer. Furthermore, plasma-derived EVPs could be used as a liquid biopsy for
cancer detection and to determine tumor type. Additionally, the researchers identified 29 EVP proteins that
had the highest predictive value for distinguishing among four different cancer types: melanoma, colorectal,
pancreatic, and lung cancer. These findings suggest that plasma-derived EVP proteomes represent tumor-
specific signatures capable of distinguishing cancer types, independent of their stage, and can be beneficial
in determining tumor type for a diagnosis in patients with cancer of unknown primary tumor origin.

Additional studies have found correlations between specific EVP contents and clinical outcomes. In patients
with primary colorectal cancer, high expression of serum HSPC111-containing EVPs positively correlated
with liver metastasis , while high expression of circulating transforming growth factor β receptor II
[148]
(TβRII)-containing EVPs was associated with lower survival rates, as well as lower metastasis-free survival
rates. High levels of plasma S100 calcium binding protein A4 (S100A4)-containing EVPs and osteopontin in
[149]
patients with hepatocellular carcinoma are associated with worse survival and disease-free survival .
Patients with high levels of both S100A4 and osteopontin also have a worse prognosis. Finally, in melanoma
patients, high levels of pigment epithelium-derived factor (PEDF)-containing EVPs are associated with
[150]
higher survival rates .
Nucleic acids packaged within EVPs, such as RNA, especially microRNAs, are another class of molecules
that can be used as diagnostic and prognostic biomarkers for various types of cancer [27,52,61,85,86] , providing
valuable information for cancer detection, diagnosis, prognosis, and monitoring. EVP DNA, including
double-stranded DNA fragments representing cancer-specific DNA mutations or abnormal copy number
variations, can be detected in the blood or other bodily fluids of cancer patients and thus can function as a
cancer biomarker [142,151-154] . Moreover, the DNA content of extracellular vesicles can reveal specific genetic
alterations or mutations related to a particular type of cancer, which can help in determining the cancer type
and its origin, especially in cases of cancers of unknown primary origin. One advantage of EVP-DNA is that
it may provide genomic information on distant or occult metastatic sites, or sites that cannot be
biopsied [153,155,156] . Changes in the levels or composition of EVP-DNA can be associated with cancer
progression, aggressiveness, or metastasis. For example, higher concentrations of specific EVP-DNA (such
as mutant KRAS DNA) may be linked to poor prognosis or advanced stages of cancer [157,158] . During cancer
treatment, the levels of specific EVP-DNA can be used to assess the effectiveness of therapy . A decrease
[159]
in cancer-related EVP-DNA could indicate a positive response to treatment, while an increase or lack of
change might suggest resistance or a need to modify the treatment strategy [160-162] .

In recent decades, the field of extracellular vesicles has made significant strides, with the potential of EVPs
as biomarkers for cancer type, stage, and outcomes becoming increasingly evident. Current research focuses
on refining methods for isolating and characterizing EVPs, identifying new and specific biomarkers, and
exploring EVP-based therapies, such as cancer-targeting drug delivery or gene silencing. To fully realize the
potential of extracellular vesicles in cancer detection, prognosis, and therapeutic guidance over the coming
decade, researchers must address several challenges and take crucial steps. Prioritizing studies with larger,
multi-center, diverse cohorts will improve biomarker selection and uncover novel biomarkers for various
cancer types and patient populations. Developing accessible and standardized methods for EVP isolation