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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 11

[89]
remodeling, and metastasis .

Coagulation
The link between cancer and coagulation disorders has been recognized since the 19th century [90,91] .
However, it was not until the 1980s that researchers began to uncover the role of tumor-derived EVPs in
promoting thrombosis [92,93] . Tumor cell-derived microvesicles carrying tissue factor (TF), a potent initiator
of the coagulation cascade, lead to thrombin generation, fibrin deposition, and clot formation [94-101] . Recent
studies have also revealed that small EVPs can also promote cancer-associated thrombosis by inducing the
[102]
formation of neutrophil extracellular traps (NETs) , which provide structural support to clot formation,
promote thrombin activation, and directly activate platelets have been shown to induce platelet aggregation
[103]
via NETs . As such, levels of plasma citrullinated histone 3, characteristic of NET formation, are
particularly elevated in cancer patients and correlated with thrombotic events . More research is needed
[103]
to understand how EVPs contribute to clotting in cancer, with the potential to identify new therapeutic
interventions by targeting extracellular vesicle-mediated coagulation in cancer patients.

Metabolism
[104]
The role of EVPs in modulating cancer metabolism began to emerge in the late 2010s , as researchers
discovered that CAF-derived EVPs could reprogram the metabolic phenotype of tumor cells . These EVPs
[104]
can transfer oncogenic molecules, such as miRNAs and proteins, to stromal and immune cells, modulating
their metabolism to support tumor growth and survival [105-110] . For example, Cao et al. provide insights into
the role of breast cancer-derived EVPs and miR-122 in systemic glucose and insulin dysregulation, by
demonstrating that breast cancer-derived EVPs impair insulin secretion and glucose homeostasis .
[111]
Additionally, it reveals that miR-122, which is highly secreted by breast cancer cells, plays a key role in
[111]
suppressing glycolysis and insulin granule exocytosis in pancreatic β-cells . The suppression of glycolysis
and insulin granule exocytosis in pancreatic β-cells carries substantial consequences for breast cancer
patients. Its suppression can lead to an energy imbalance that affects both healthy and cancerous cells [112,113] .
Furthermore, the impaired release of insulin due to hindered insulin granule exocytosis disrupts glucose
uptake regulation by cells [111,114,115] . This disruption can result in dysregulated glucose and insulin levels,
potentially causing insulin resistance, increased inflammation, and promoting cancer progression [116-119] .
Additionally, imbalanced glucose and insulin levels may give rise to metabolic complications, such as
diabetes, which negatively impact a patient's overall health and well-being [120-122] . This can, in turn, influence
the effectiveness of cancer treatments and the patient's quality of life [123-125] .

Moreover, EVPs have been shown to facilitate the transfer of metabolites between tumor cells, enabling
metabolic heterogeneity and promoting treatment resistance. Current research is focused on developing
therapies that target the metabolic reprogramming mediated by EVPs to improve cancer treatment
outcomes. Interestingly, Wang et al. recently reported that tumor-derived EVPs containing fatty acids,
particularly palmitic acid, are taken up by Kupffer cells in metastasis-free livers of tumor-bearing mice and
cancer patients, inducing tumor necrosis factor α (TNFα) secretion and dysregulating liver metabolism by
altering the expression of cytochrome c-encoding genes . This metabolic reprogramming of the liver
[126]
induced fatty liver generation and enhanced the adverse events of chemotherapy, such as myelosuppression
and cardiotoxicity. Interestingly, Exo-S and specifically exomeres (and, to a lesser extent, Exo-L) can
dysregulate liver function. This study showed that EVPs systemically affect not only future metastatic sites
but also non-metastatic organs, particularly in the liver, by altering lipid metabolism, thereby decreasing
liver function.