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Page 10 Asao et al. Extracell Vesicles Circ Nucleic Acids 2023;4:461-85 https://dx.doi.org/10.20517/evcna.2023.37

microenvironment, facilitating prostate cancer cell colonization and bone metastasis. Additionally,
miR-181c modulates breast cancer cell organotropism to the brain by targeting PDPK1 in brain endothelial
[81]
cells, destroying BBB . Finally, miR-122 fosters a metabolic symbiosis in the lung and brain by
downregulating pyruvate kinase muscle isozyme M2 (PKM2), supporting metastatic tumor cell growth and
survival . Together, these mechanisms enable cancer cell metastasis to specific organs, where they can
[84]
colonize and form secondary tumors. Of note, while some studies have suggested that cancer is associated
with an overall reduction in microRNAs in cancer cells and tumor microenvironment, recent research has
shown that certain microRNAs are packaged at high levels in EVPs derived from tumor cells [27,52,61,85,86] .

In conducting experimental studies, particularly those related to metastasis, administration of EVPs
[87]
warrants thoughtful consideration, especially regarding dosing . Established protocols involve injecting
5-10 ug of EVPs intravenously every other day over a span of three weeks [25,26,50,51,81-84] . This approach
generates a concentration of EVPs in the blood within the physiological range of blood EVP concentrations
in tumor-bearing mice with cancer adequate. However, the production and release rates of EVPs can vary
considerably depending on the cancer type, its stage, and the general condition of the tumor
[48]
microenvironment . Given the enormous heterogeneity across different cancer types and the dynamic
progression of tumors, it is challenging to determine a universally applicable “per day, per cell” rate of EVP
production in vivo . Moreover, the functional impact of EVPs is not merely dictated by their quantity, but
[48]
also by the molecular cargo they carry, such as proteins like integrins and non-coding RNAs like
microRNAs [48,88] . Thus, additional research, including comparative studies of EVP production rates across
different tumor types and stages, will be vital to adjust EVP dosing in order to faithfully reflect the in vivo
situation. Furthermore, the translation of these findings into human clinical applications will require careful
dose escalation and rigorous safety testing .
[87]

In summary, while both microRNAs and integrins in tumor-derived EVPs contribute to cancer
organotropism, they do so through fundamentally different mechanisms: microRNAs act by modulating
gene expression within recipient cells, whereas integrins mediate EVP-cell interactions and organ-specific
homing.

In conclusion, research on the role of EVPs in the formation of PMN has greatly advanced our
understanding of metastasis organotropism and provided support for Paget’s “seed and soil” hypothesis. By
identifying specific proteins, nucleic acids, and pathways involved in this process, new therapeutic strategies
may be developed to target and inhibit the formation of PMN, ultimately improving patient outcomes in
various types of cancer.

Vasculature
The involvement of EVPs in tumor angiogenesis and vascular remodeling was first recognized in the early
2000s. The first studies demonstrating that tumor-derived EVPs could transfer proangiogenic factors to
endothelial cells, promoting blood vessel formation and supporting tumor growth at distant sites were
published over a decade ago, when our laboratory demonstrated that melanoma-derived EVPs contribute to
metastatic invasion by carrying messenger proteins that direct BMDCs towards a pro-metastatic phenotype,
promoting proangiogenic events and modifying ECM at pre-metastatic sites . Moreover, a subsequent
[25]
study by Zhou et al. showed that EVP miR-105 targets the tight junction protein zonula occludens-1
(ZO-1), enabling the colonization of distant locations by cancer cells . EVPs derived from highly
[52]
metastatic breast cancer cell lines showed significantly higher miR-105 levels, which were associated with
increased endothelial permeability and destruction of vascular sprouts at distant sites. These findings
underscore the critical role of tumor-derived EVPs in vascular processes, such as angiogenesis, vascular