Extracellular vesicles (EVs) are tiny membrane-bound particles released by cells that have attracted attention in recent years. They are highly diverse in size, origin, contents, and function, and their biological properties are very complex. Below is an overview of the biological properties of extracellular vesicles.
Extracellular vesicles are classified, according to their size and origin, into exosomes, microvesicles, apoptotic bodies, and others. Exosomes are generated from intracellular structures called endosomes and are approximately 30–150 nm in size. Microvesicles, by contrast, are generated by budding directly off the cell membrane and are characteristically larger than exosomes, at 100–1000 nm. Apoptotic bodies are released when a cell undergoes programmed cell death (apoptosis) and are larger still, at 1–5 µm.
These extracellular vesicles function as a means of cell-to-cell communication. Extracellular vesicles can carry a wide variety of molecules, including proteins, lipids, RNA (mRNA, miRNA, etc.), and DNA. These molecules are delivered to the cells targeted by the vesicle, where they exert their functions. For example, the miRNA contained in a vesicle can regulate gene expression in the target cell.
Moreover, extracellular vesicles are released not only by healthy cells but also by diseased cells (for example, cancer cells or virus-infected cells). These vesicles may provide clues for diagnosing disease, judging prognosis, and even developing new therapies.
Extracellular vesicles are like “parcels” by which a cell wraps up a part of itself and sends it to other cells, serving to carry biological information. These vesicles contain diverse biological molecules—such as RNA, proteins, and lipids—that reflect the type and state of the cell from which they originate.
Disease diagnosis: Extracellular vesicles reflect the state of the cells that produce them. For example, cancer cells release extracellular vesicles with properties that differ from those of normal cells. By analyzing these properties, it is thought to become possible to determine the presence of cancer, its type, its degree of progression, and so on. In addition, by analyzing extracellular vesicles present in body fluids such as blood and urine, the development of non-invasive diagnostic methods (liquid biopsy) is being advanced.
A concrete example of disease diagnosis using extracellular vesicles is the early detection and identification of the type of cancer.
For example, in lung cancer it is known that exosomes (a type of extracellular vesicle) derived from lung cancer cells are present in the blood. Because these exosomes contain RNA and proteins specific to lung cancer cells, detecting them makes it possible to diagnose lung cancer.
Specific references include the following:
- Sandfeld-Paulsen, B., Aggerholm-Pedersen, N., Baek, R., Jakobsen, K. R., Meldgaard, P., Folkersen, B. H., … & Sorensen, B. S. (2016). Exosomal proteins as prognostic biomarkers in non-small cell lung cancer. Molecular oncology, 10(10), 1595-1602.
- Research on diagnostic methods using exosomes derived from prostate cancer cells is also advancing for the diagnosis of prostate cancer. By combining them with known markers such as prostate-specific antigen (PSA), more accurate diagnosis is expected.
Specific references include the following:
Judging prognosis: Extracellular vesicles are also useful for evaluating disease progression and the effects of treatment. For example, judging the effect of cancer treatment normally requires imaging studies or tissue examinations, which take time and effort. However, analysis of extracellular vesicles is expected to enable rapid and repeatable assessment.
A concrete example in which extracellular vesicles are used to judge prognosis is the prognostic assessment of cancer.
Breast cancer: The pattern of microRNA (miRNA) contained in exosomes has been shown to be a powerful biomarker for predicting the prognosis of breast cancer. Some miRNAs are known to be closely associated with the progression of breast cancer, and by detecting these miRNAs it becomes possible to predict the prognosis of breast cancer.
Specific references include the following:
Lung cancer: It has been reported that the amount of exosomes present in the blood of lung cancer patients is associated with the prognosis of lung cancer. In particular, patients with a high amount of exosomes in their blood tend to have a worse prognosis.
Specific references include the following:
Development of new therapies: Extracellular vesicles not only carry their own information but also have the ability to alter the activity of the cells that receive that information. Taking advantage of this, the development of “biological delivery systems” that carry drugs or genes to specific cells or tissues is being advanced. The development of new immunotherapies that use extracellular vesicles to modulate the immune response is also anticipated.
For example, there is treatment for spinal cord injury (SCI) using MSC exosomes.
As described above, extracellular vesicles, through their diverse properties and functions, have the potential to provide clues for diagnosing disease, judging prognosis, and developing new therapies.
However, research on extracellular vesicles has only just begun, and much remains to be elucidated. Many questions still await clarification, such as the precise mechanism by which extracellular vesicles are generated, the mechanism of information transfer between cells, the types of molecules contained within the vesicles and the mechanism by which they are selected, and how extracellular vesicles are distributed within the body and how they function there.
Research on extracellular vesicles is expected to have a major impact not only on the life sciences but also on diagnostics and the medical field. For example, extracellular vesicles released by cancer cells are known to play an important role in the progression and metastasis of cancer. Understanding the properties of the extracellular vesicles released by cancer cells may lead to the early detection of cancer, the prevention of metastasis, and the development of new therapies. In addition, the development of new therapies that use extracellular vesicles as “delivery vehicles” to carry drugs to specific tissues or cells is also being advanced.
On the other hand, research on extracellular vesicles faces many difficulties. The isolation and purification of extracellular vesicles is highly challenging using common biological methods, owing to their small size and complex biological properties. In addition, because the properties of extracellular vesicles vary greatly with cell type and state, it is also difficult to generalize research results.
Nevertheless, despite these difficulties, research on extracellular vesicles is advancing rapidly. This field is overflowing with new discoveries and technological innovations, including the development of new isolation and purification methods, the development of new technologies to identify the contents and cells of origin of vesicles, and even the development of new medical technologies that exploit the functions of extracellular vesicles themselves.
Extracellular vesicles have the potential to fundamentally change our understanding of the concept of “cell-to-cell communication.” This new perspective—in which a cell sends a part of itself to other cells to convey information—will open up new possibilities not only in the life sciences but also in many fields such as medicine, pharmacology, and even engineering and information science.
Reference papers
- Yáñez-Mó, M., Siljander, P. R. M., Andreu, Z., Zavec, A. B., Borràs, F. E., Buzas, E. I., … & De Wever, O. (2015). Biological properties of extracellular vesicles and their physiological functions. Journal of extracellular vesicles, 4(1), 27066.
- Théry, C., Witwer, K. W., Aikawa, E., Alcaraz, M. J., Anderson, J. D., Andriantsitohaina, R., … & Buzas, E. I. (2018). Minimal information for studies of extracellular vesicles 2018 (MISEV2018): a position statement of the International Society for Extracellular Vesicles and update of the MISEV2014 guidelines. Journal of extracellular vesicles, 7(1), 1535750.
- Kalluri, R., & LeBleu, V. S. (2020). The biology, function, and biomedical applications of exosomes. Science, 367(6478), eaau6977.