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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 5

cells are engrafted into a primary host and subsequently isolated and engrafted into secondary hosts) in
mice, suggesting the long-term impact of EVPs-mediated reprogramming is crucial for pathological
[25]
process . EVP cargo is only to a certain extent reflective of the cell of origin, and many molecules are
enriched and thus selectively packaged. For instance, it is known that integrin molecules are differentially
packaged into EVPs derived from various cancers . Although the exact mechanism leading to selective
[26]
packaging remains still unknown, recent studies have shed light on how nucleic acids, such as miRNA and
DNA, are loaded into EVPs [27,28] .

In summary, EVPs play a crucial role in intercellular communication and have emerged as an indispensable
means of information transfer, both physiologically and pathologically, alongside soluble factors.

METASTASIS: LOCAL AND DISTANT EFFECTS OF EVPS
Local effects of EVPs
EVPs play a significant role in both local and systemic effects of cancer progression and metastasis [29,30] .
Locally, they mediate intercellular communication within the tumor microenvironment, transferring
oncogenic proteins [25,31,32] , lipids, and nucleic acids to recipient cells, such as cancer cells , cancer-associated
[33]
fibroblasts (CAFs), macrophages [34,35] , and endothelial cells . A key discovery linking EVPs to metastasis
[36]
emerged in 2012 when researchers found that CAF-derived EVPs could promote metastasis by transferring
their contents to cancer cells , establishing a new paradigm in the field and opening the door to further
[37]
investigations into the specific mechanisms through which EVPs contribute to cancer progression. In
particular, the CD81 tetraspanin, present in CAF-derived EVPs, is a key factor in inducing breast cancer cell
motility and promoting metastasis in vivo , through activation of the planar cell polarity (PCP) pathway,
[37]
[38]
which is intimately connected with the Wnt signaling pathway . Wnt signaling is a highly conserved
cellular signaling system that plays essential roles in regulating cell proliferation, differentiation, and
migration, as well as PCP [39,40] . The interplay between Wnt signaling and PCP regulation also influences the
formation and function of invadopodia [41-43] , finger-like protrusions that facilitate tumor cell invasion [41-44] .
These invadopodia have been shown to be crucial for exosome secretion , further emphasizing the
[45]
importance of Wnt signaling and PCP regulation in the context of cancer metastasis. Additionally, several
other tetraspanins present in EVPs also contribute to metastasis through various signaling pathways , such
[46]
as the integrin, epidermal growth factor receptor (EGFR), focal adhesion kinase (FAK), phosphoinositide 3-
kinase (PI3K)/protein kinase B (Akt), and mitogen-activated protein kinase (MAPK) pathways [46-48] .
Numerous other landmark studies revealed the functions of other EVP-associated proteins and their
potential roles in cancer progression [25,26,37,49-51] .

Subsequent research focused on how EVPs contribute to metastasis through various mechanisms, such as
promoting angiogenesis [25,52] , modulating immune responses [53-56] , and inducing epithelial-to-mesenchymal
transition (EMT) [57-59] . Moreover, EVPs could transfer oncogenic proteins and nucleic acids, including
microRNAs and long non-coding RNAs, to recipient cells, modulating their gene expression and
influencing their proliferation, migration, and invasion capabilities, ultimately contributing to metastatic
potential [33,52,60-63] . This process, known as EVP-mediated horizontal transfer, enabled cancer cells to
communicate with and alter the behavior of neighboring cells in the tumor microenvironment, contributing
to the metastatic process.

Building on these foundational findings, additional landmark studies have continued to reveal the local
effects of EVPs on cancer-promoting processes, such as extracellular matrix (ECM) remodeling,
inflammation, and rewiring of oncogenic pathways, further elucidating the multifaceted roles of EVPs in
cancer progression and metastasis. For example, a study by Nabet et al. demonstrated that dynamic