The evolving translational potential of small extracellular vesicles in cancer

Abstract

Cancer-derived extracellular vesicles (EVs) are regarded as having promising potential to be used as therapeutics and disease biomarkers. Mechanistically, EVs have been shown to function in most, if not all, steps of cancer progression. Cancer EVs, including small EVs (sEVs), contain unique biomolecular cargo, consisting of protein, nucleic acid and lipids. Through progress in the identification of this specific cargo, cancer biomarkers have been identified and developed, opening up novel and interesting opportunities for cancer diagnosis and prognosis. Intriguingly, we still lack a comprehensive understanding of the cancer-specific pathways that govern EV biogenesis in cancer cells. Filling this knowledge gap will rapidly improve cancer EV biomarkers, as it will also allow discrimination of the procancer and anticancer actions of those EVs. Even more promising is uncovering therapeutically targetable, tumour-specific EV pathways and content, which will generate novel classes of cancer therapies. This Review highlights the progress the cancer sEV field has made in the areas of biomarker discovery and validation as well as sEV-based therapeutics, highlights the challenges we are facing and identifies gaps in our knowledge, which currently prevent us from developing the full potential of sEVs in cancer diagnostic and therapy.

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Fig. 1: Small extracellular vesicle uptake, biogenesis, cargo content and biological effects.
Fig. 2: Cancer-derived sEV heterogeneity is multifaceted.
Fig. 3: Evaluation and development of new sEV-based therapeutics.

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Acknowledgements

The authors thank M. Smyth and M. Ernst for their comments and suggestions during the writing process. It is with regret that not all relevant studies could be cited due to space limitations. This Review was supported by Australian National Breast Cancer Foundation (IIRS-18-159) and Australia National Health and Medical Research Council (APP1185907) grants to A.M. R.J.L. is supported by the CSIRO Synthetic Biology Future Science Platform.

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The authors contributed equally to all aspects of the article.

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Correspondence to Andreas Möller.

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A.M. and R.J.L. are listed as inventors on patents owned by the QIMR Berghofer Medical Research Institute on the use of extracellular vesicles as a cancer biomarker.

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Nature Reviews Cancer thanks the anonymous reviewers for their contribution to the peer review of this work.

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Glossary

Biodistribution

The in vivo localization at which an extracellular vesicle accumulates as a result of size or surface content.

Recipient cells

Cells that, in the extracellular vesicle context, take up extracellular vesicles by one or several mechanisms, including for example receptor-mediated uptake, phagocytosis, macropinocytosis or various forms of endocytosis.

Ectosomes

The term used to classify vesicles that are directly formed by budding of the plasma membrane.

sEV cargo

The content of a small extracellular vesicle (sEV), which includes proteins, nucleic acids and lipids, as well as metabolites, derived from the cell of origin and/or artificially engineered into sEVs.

Liquid biopsy

The use of bodily fluids to provide information on the presence (or absence) of certain conditions, including molecular information (for example, genetic alterations), as an alternative and/or addition to obtaining tissue biopsy samples.

Organotropic

Targeted preferentially and/or specifically to a certain individual organ or tissue in the body.

M1 macrophages

Subset of macrophages with a proinflammatory phenotype, including the secretion of IL-6 and tumour necrosis factor.

Chimeric antigen receptor

(CAR). An engineered, artificial cell surface receptor that bestows a specific function on the cell.

Affibody

Small proteins that are engineered antibody equivalents to specifically recognize and bind target sequences, with an intentional use in diagnostic and therapeutic applications.

Optogenetic tools

Optogenetic tools utilise light-sensitive proteins for precise spatial and temporal control of protein activity.

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Möller, A., Lobb, R.J. The evolving translational potential of small extracellular vesicles in cancer. Nat Rev Cancer 20, 697–709 (2020). https://doi.org/10.1038/s41568-020-00299-w

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