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Page 8 Asao et al. Extracell Vesicles Circ Nucleic Acids 2023;4:461-85 https://dx.doi.org/10.20517/evcna.2023.37

[72]
which can directly promote liver PMN formation organs . Moreover, pancreatic ductal adenocarcinoma is
a CAF-rich tumor, and CAF-derived EVPs play a significant role in promoting the formation of PMN at
[50]
distant metastatic sites such as the lung through the release of EVPs . Thus, EVPs orchestrate PMN
formation in a cancer-type specific manner, targeting those organs that are the most common sites of
metastasis through direct and indirect mechanisms.

The role of EVPs in breaching the blood-brain barrier (BBB) has also gained attention in the context of
metastasis. In 2019, Rodrigues et al. demonstrated that breast cancer-derived EVPs could cross the BBB and
[75]
promote brain metastasis . Mechanistically, breast cancer-derived EVPs carrying cell migration-inducing
and hyaluronan-binding protein (CEMIP) reach the brain, where they are taken up by endothelial cells and
microglia, remodeling the peri-vascular niche and inducing neuroinflammation, both processes that
[75]
support tumor cell survival in the hostile brain environment and ultimately lead to brain metastasis .
Similarly, cancer-derived EVPs containing small nuclear RNAs are taken up by alveolar epithelial cells in
the lung, which upregulate Toll-like receptor expression, enhancing neutrophil recruitment and
subsequently promoting lung metastasis . EVPs also play critical roles in lymph node metastasis, as
[74]
malignant melanoma-derived EVPs containing nerve growth factor receptors spread in the lymphatic
system and are taken up by lymphatic endothelial cells, promoting lymphangiogenesis and tumor
[73]
colonization .
In summary, the past decade has brought a clear understanding that cancer-related EVPs deliver various
biomolecules to target cells, adjusting the microenvironment of the future organ of metastasis before
metastasis occurs, and promoting cancer cell engraftment, revolutionizing our understanding of cancer
metastasis by shifting the focus away from cell-intrinsic mechanisms of metastasis and towards systemic
interactions with the microenvironment of various organs.

Organotropism
The concept of metastatic organotropism, which can be traced back to the late 19th century, was first
proposed by Stephen Paget in his 1889 “seed and soil” hypothesis. Paget attempted to explain the non-
random pattern of metastatic cancer dissemination by suggesting that the tumor cells, or “seeds,” have a
preferential affinity for specific organs, or “soil” . This hypothesis laid the groundwork for understanding
[76]
the complex and highly regulated process of metastasis, which is now a critical factor in cancer patient
staging and prognosis . Importantly, while tumor-derived EVPs can be detected in various bodily fluids
[77]
and interact with a wide range of cell types, they are not uniformly taken up in all organs [12,26,78] . The selective
uptake of tumor-derived EVPs by specific organs results from a combination of factors, such as EVP cargo,
the composition of the tumor-derived EVP membrane, the recipient cell’s surface receptors, and the
presence of specific proteins and ligands on both the vesicle and target cell surfaces [12,26,78] . In addition, the
physiological state and microenvironment of the recipient organ can impact the ability of tumor-derived
EVPs to interact with and be internalized by cells, resulting in a heterogeneous distribution and uptake
across different organs. Thus, the selective uptake of tumor-derived EVPs aligns with Paget’s “seed and soil”
hypothesis, as it emphasizes the critical role of organ-specific factors and interactions in determining the
successful establishment and propagation of metastatic cancer cells within a particular organ [Figure 3].

In 2015, a study by Hoshino et al. was the first to provide support for Paget’s hypothesis, demonstrating that
tumor-derived EVPs could be home to future metastatic niches in specific organs . For example, EVPs
[26]
carrying integrin αvβ5 were found to target the liver, while EVPs expressing α6β1 and α6β4 integrins
preferentially homed to the lungs . Furthermore, EVP education with lung tropic breast cancer derived-
[26]
EVPs was found to be sufficient to allow otherwise bone metastatic cells to grow in the lung. Additionally,