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Formation and role of exosomes in cancer

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Abstract

Exosomes offer new insight into cancer biology with both diagnostic and therapeutic implications. Because of their cell-to-cell communication, exosomes influence tumor progression, metastasis, and therapeutic efficacy. They can be isolated from blood and other bodily fluids to reveal disease processes occurring within the body, including cancerous growth. In addition to being a reservoir of cancer biomarkers, they can be re-engineered to reinstate tumor immunity. Tumor exosomes interact with various cells of the microenvironment to confer tumor-advantageous changes that are responsible for stromal activation, induction of the angiogenic switch, increased vascular permeability, and immune escape. Exosomes also contribute to metastasis by aiding in the epithelial-to-mesenchymal transition and formation of the pre-metastatic niche. Furthermore, exosomes protect tumor cells from the cytotoxic effects of chemotherapy drugs and transfer chemoresistance properties to nearby cells. Thus, exosomes are essential to many lethal elements of cancer and it is important to understand their biogenesis and role in cancer.

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Abbreviations

MVE:

Multivesicular endosome

ESCRT:

Endosomal-sorting complexes required for transport

MDSC:

Myeloid-derived suppressor cells

EMT:

Epithelial-to-mesenchymal transition

HIF:

Hypoxia-inducible factor

GM-CSF:

Granulocyte–macrophage colony-stimulating factor

ASC:

Adipose stem cell

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Authors and Affiliations

  1. Department of Biomedical Engineering, University of Virginia, PO Box 800759 Health System, Charlottesville, VA, 22908, USA

    Lindsey T. Brinton & Kimberly A. Kelly

  2. Robert M. Berne Cardiovascular Research Center, University of Virginia School of Medicine, PO Box 801394, Charlottesville, VA, USA

    Lindsey T. Brinton & Kimberly A. Kelly

  3. Department of Chemistry, University of Virginia, PO Box 400319, Charlottesville, VA, 22904, USA

    Hillary S. Sloane

  4. Department of Pharmacology, University of Virginia School of Medicine, PO Box 800735, Charlottesville, VA, 22908, USA

    Mark Kester

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  1. Lindsey T. Brinton
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  3. Mark Kester
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Correspondence to Kimberly A. Kelly.

Appendices

Box 1: historical perspective on exosome formation

In the 1970s, plasma membrane fragments were being isolated from human bodily fluids as well as cultured cells [27, 126, 127]. However, it was not until 1983 that two teams of researchers from the laboratories of Stahl and Johnstone independently discovered what we now term exosomes [128, 129]. The actual title of “exosome” was applied by the Johnstone group to these vesicles in 1987 [130]. Although “exosome” had previously been used by Trams et al. to describe small enzyme-containing vesicles that they observed being released from both normal and cancerous cells in culture that they postulated to have a role in communication, these vesicles do not fit the current definition of exosome [25, 131]. It was later discovered that the intracellular origin of exosomes is multivesicular endosomes (MVEs) that fuse with the plasma membrane and release their contents into the extracellular space; the connection between exosomes and MVEs lead scientists to believe that exosomes were an additional means of waste removal from cells [132, 133]. Indeed, immunological cell waste, including Major Histocompatability Complex (MHC), was found to be discarded via exosomes, but Raposo et al. [134] re-popularized the idea that exosomes were more than garbage receptacles and further postulated that exosomes could function in antigen presentation and stimulate a T cell response. Presently, exosomes are even categorized as a novel mechanism of cell-to-cell communication, particularly between tumor and stromal cells [135, 136]. For a more in-depth look at the history and nomenclature of exosomes, see [131, 137].

Box 2: use of “exosome” in scientific literature

It is important to recognize many different systems of classification of small, secreted vesicles have been used and, thus, terminology cannot necessarily be relied upon. Typically, it is agreed that exosomes are about 50–100 nm; sediment at 100,000–160,000×g or float on a sucrose gradient of 1.13–1.19 g/mL; look like a flattened sphere (transmission electron microscope, TEM), round trilobed structure with a central depression (2nN amplitude modulated—atomic force microscopy, AM–AFM), or round bulging sphere (field emission scanning electron microscope, FESEM). To ensure that research articles are indeed referring to exosomes as now defined, a few precautions should be taken:

  • careful search of the parameters used by the authors to classify the described vesicles

  • analysis of purification methods–since some are more robust than others, many false positive identifications of exosome proteins have arisen from analysis of contaminated samples [119]

  • many papers describe exosomes but incorrectly refer to them as some other type of vesicle, so it may be easy to overlook valuable exosome research

  • while some noted the presence of DNA as a difference between apoptotic vesicles and exosomes, others later concluded that exosomes also contain DNA [22, 138]

  • sometimes LAMP1 or LAMP2 is used to differentiate exosomes from other secretory vesicles; however, because of their lysosomal escape, some exosomes lack these lysosomal proteins [139–141].

For a more detailed analysis, refer to [137], which reviews the inconsistencies in nomenclature for exosomes.

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Brinton, L.T., Sloane, H.S., Kester, M. et al. Formation and role of exosomes in cancer. Cell. Mol. Life Sci. 72, 659–671 (2015). https://doi.org/10.1007/s00018-014-1764-3

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