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Page 6 Asao et al. Extracell Vesicles Circ Nucleic Acids 2023;4:461-85 https://dx.doi.org/10.20517/evcna.2023.37

feedback between tumor and stroma subverts normal inflammatory responses by triggering the release of
EVPs containing unshielded RNAs that activate pattern recognition receptors, thereby promoting tumor
[64]
growth and metastasis . Inflammatory pathways, normally activated in response to viral RNAs, were
induced in cancer by deregulated release of exposed endogenous 5’-triphosphorylated double-stranded
RNA in tumor stroma EVPs . These unshielded non-coding RNAs enriched in EVPs from tumor-
[64]
activated stromal cells acted as damage-associated molecular patterns (DAMPs) signals, triggering a
feedback loop that activated the pattern recognition receptor retinoic acid-inducible gene I (RIG-I) and
interferon-stimulated genes in breast cancer and innate immune cells . In light of these findings, further
[64]
investigation is warranted to elucidate the complex interplay between tumor-elicited systemic interferon
responses induced by EVP DAMP proteins, and nucleic acids (DNA and RNA), as well as to determine the
context-dependent roles of these responses in promoting or inhibiting tumorigenesis and metastasis,
potentially considering factors such as the timing and duration of interferon activation both locally and
systemically.

Additionally, recent studies have focused on the impact of ECM stiffness on EVP secretion and cargo, as
ECM stiffening can trigger tumor growth, invasiveness, and chemoresistance, leading to a direct correlation
between tumor aggressiveness and metastatic potential . Wu et al. have shed light on the mechanisms
[65]
linking ECM stiffness with EVP secretion, demonstrating that ECM stiffness activates FAK/PI3K/Akt
signaling, promoting Rab8-induced small extracellular vesicle secretion, and thus cancer growth .
[65]
Moreover, stiff ECM enhanced the secretion of EVPs and altered their cargo, specifically in the context of
hepatocellular carcinoma (HCC), which is strongly associated with increased collagen deposition and tissue
stiffness .
[65]

Finally, EVPs can also rewire oncogenic signaling locally within the primary tumor as well as metastasis.
Astrocyte-derived EVPs containing microRNA-19a induce the loss of phosphatase and tensin homolog
(PTEN) expression in tumor cells, promoting metastasis . PTEN loss in brain metastases was found to be
[63]
reversible and induced by the brain microenvironment, rather than originating from PTEN-low cells in the
primary tumor. The pathway linking PTEN loss to the promotion of brain metastasis involved nuclear
factor-κB signaling and C-C motif chemokine 2 (CCL2)-induced myeloid cell recruitment, indicating
reciprocal crosstalk between tumor cells and the brain microenvironment. Finally, in the case of head and
neck cancers with mutant p53, EVPs secreted by cancer cells lack a specific miRNA called miR-34a, which is
a tumor suppressor. The absence of miR-34a in these EVPs drives the formation of new neurons in the
[66]
tumor microenvironment, contributing to tumor growth and decreased survival time . Specifically, it
enables sympathetic neurons to fuel tumor proliferation via noradrenaline release while allowing
[67]
parasympathetic neurons to spur cancer cell invasion and migration via acetylcholine . This
groundbreaking discovery has opened up new avenues of research to better understand the mechanisms
through which EVPs can influence the formation of brain metastases and identify potential therapeutic
targets to prevent or treat such metastases.

Distant effects of EVPs
As EVPs readily circulate via all bodily fluids, they have a widespread and long-range impact on various
organ systems. Tumor-derived EVPs play a critical role in establishing PMN in distant organs, as they
modify the behavior of recipient cells and alter vascular function, coagulation, metabolism, immunity, and
the nervous system, thereby promoting cancer cell colonization and metastasis [Figure 2]. Notably, EVPs
can traverse and permeabilize the blood-brain barrier, allowing cancer cells to infiltrate the brain-an area
typically regarded as immune-privileged.