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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 9

Figure 3. Extracellular vesicles and particles (EVPs) determine metastatic organotropism. Specific molecules expressed on EVPs
interact with cells or the extracellular matrix of specific organs to deliver biomolecules to distant organs. This causes changes in the
microenvironment, leading to pre-metastatic niche (PMN) formation and facilitating distant metastasis to specific organs. For example,
tumor-derived EVPs expressing integrin αvβ5 are taken up by the liver and promote liver PMN formation. Similarly, integrin α6β1 and α6
β4 expressed on tumor-derived EVPs are taken up by the lung and promote lung metastasis. Integrin α2β1 on cancer-associated
fibroblast-derived EVPs also promotes lung metastasis. Integrin α5, miR-940, and miR-141-3p are involved in bone metastasis, CEMIP
and miR-181c in brain metastasis, and integrin αv in lymph node metastasis, as reported. CDH11: cadherin 11; CEMIP: cell migration
inducing hyaluronidase 1.

the knockdown of integrin β4 on lung tropic cells and their EVPs was sufficient to reduce the lung
metastatic capacity of breast cancer cells. Moreover, EVP integrins, specifically α5, can also mediate breast
cancer cell homing to the bone and communication with osteoblasts . By promoting osteogenic
[51]
differentiation of osteoblasts, EVPs containing α5 integrin may create a more hospitable environment for
cancer cells to grow and spread.

In salivary adenoid cystic carcinoma (SACC), integrin α2β1 mediates the uptake of CAF-derived EVPs by
lung fibroblasts and activates the TGF-β pathway, resulting in the lung fibroblast activation and expression
of PMN proteins, such as fibroblast activation protein, α-smooth muscle actin, and periostin . Blocking
[50]
integrin α2β1 with an inhibitor has been shown to attenuate CAF-EVP uptake by lung fibroblasts, inhibit
activation of fibroblasts, and suppress lung PMN formation and subsequent lung metastasis in SACC
animal models. These findings suggest that integrin α2β1 plays a crucial role in the formation of lung PMNs.
In summary, integrins play a central role in EVP trafficking, homing, and organotropism in the context of
metastatic cancer. These discoveries provide opportunities for therapeutic targeting in multiple cancers,
enabling the development of organ-specific treatments to prevent metastasis.

EVP microRNAs also play a pivotal role in the process of cancer cell organotropism . MicroRNAs are
[79]
small non-coding RNAs that regulate gene expression post-transcriptionally, thereby controlling cellular
[80]
processes such as proliferation, migration, and differentiation . Consequently, the specific miRNA cargo
carried by EVPs dictates the organotropism of cancer cells, guiding their migration and invasion to
preferred metastatic sites . For example, miR-141-3p and miR-940 have been implicated in promoting
[82]
[83]
[81]
bone metastasis in prostate cancer through their effects on osteoblast and osteoclast activity, as well as bone
resorption. Prostate cancer-derived EVPs containing miR-141-3p are taken up by osteoblasts, where they
suppress the expression of the target gene DLC1, a Rho GTPase-activating protein . This suppression leads
[82]
to enhanced osteoblast activity, promoting a favorable environment for prostate cancer cell colonization in
bone. Similarly, cancer-secreted EVPs containing miR-940 are internalized by osteoblasts, targeting Rho
[83]
GTPase activating protein 1 (ARHGAP1) and reticulophagy regulator family member 2 (FAM134A) . The
downregulation of these genes promotes an osteoblastic phenotype in the bone metastatic