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Extracellular vesicles in cancer — implications for future improvements in cancer care

Abstract

The sustained growth, invasion, and metastasis of cancer cells depend upon bidirectional cell–cell communication within complex tissue environments. Such communication predominantly involves the secretion of soluble factors by cancer cells and/or stromal cells within the tumour microenvironment (TME), although these cell types have also been shown to export membrane-encapsulated particles containing regulatory molecules that contribute to cell–cell communication. These particles are known as extracellular vesicles (EVs) and include species of exosomes and shed microvesicles. EVs carry molecules such as oncoproteins and oncopeptides, RNA species (for example, microRNAs, mRNAs, and long non-coding RNAs), lipids, and DNA fragments from donor to recipient cells, initiating profound phenotypic changes in the TME. Emerging evidence suggests that EVs have crucial roles in cancer development, including pre-metastatic niche formation and metastasis. Cancer cells are now recognized to secrete more EVs than their nonmalignant counterparts, and these particles can be isolated from bodily fluids. Thus, EVs have strong potential as blood-based or urine-based biomarkers for the diagnosis, prognostication, and surveillance of cancer. In this Review, we discuss the biophysical properties and physiological functions of EVs, particularly their pro-metastatic effects, and highlight the utility of EVs for the development of cancer diagnostics and therapeutics.

Key points

  • Exosomes and shed microvesicles are two classes of small lipid-encapsulated extracellular vesicles (EVs) that transmit molecular messengers (functional proteins and nucleic acids) between cells to alter the phenotype of recipient cells.

  • Each class of EVs has a distinct mechanism of biogenesis, and within each class, subtypes (subpopulations) exist that can be distinguished by their distinct protein and RNA signatures.

  • The participation of exosomes in signalling between tumour cells and the microenvironment aids the establishment of the pre-metastatic niche and facilitates tumour progression.

  • Circulating exosomes containing tumour-specific molecular signatures (oncoproteins, mRNAs, long non-coding RNAs, and DNA fragments) have clinical utility as next-generation biomarkers for liquid biopsy in cancer diagnosis and management.

  • Standardized isolation protocols for EV subpopulations are required to enable interlaboratory data comparison and for the advancement of their clinical utility.

  • Exosomes have potential as vehicles for the delivery of therapeutic agents and also as anticancer vaccines and could possibly guide changes in clinical practice.

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Fig. 1: EV biogenesis and cargo contents.
Fig. 2: Biodistribution of cancer exosomes in mice and common cancer metastatic sites in humans.
Fig. 3: Exosomes and pre-metastatic niche formation.

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Acknowledgements

R.X., A.R., M.C., W.S., D.W.G., and R.J.S. acknowledge funding support from La Trobe University, Melbourne, Australia. The authors thank D. Dorow for assistance in revising the manuscript; the authors also thank W. Chen for his comments on the status of extracellular vesicle vaccines.

Reviewer information

Nature Reviews Clinical Oncology thanks T. Whiteside and the other, anonymous reviewers for their contribution to the peer review of this work.

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All authors researched the data for the article. R.X., A.R., M.C., W.S., D.W.G., and R.J.S. contributed to discussions of the content. R.X., A.R., and R.J.S. wrote the manuscript. R.X., A.R., W.S., D.W.G., and R.J.S. reviewed and/or edited the manuscript before submission.

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Correspondence to Richard J. Simpson.

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Supplementary information

41571_2018_36_MOESM1_ESM.pdf

Supplementary Figure 1 Physical properties and characteristics of extracellular vesicles. Supplementary Box 1 Clinically relevant approaches for EV isolation Supplementary Box 2 Paget’s ‘seed and soil’ hypothesis — a basic tenet of metastasis

Glossary

Extracellular vesicle

(EV). Lipid membrane-encapsulated particle released by cells into the intercellular space and/or circulation that functions in bidirectional cell–cell communication; EVs comprise at least two major subclasses — exosomes and shed microvesicles — with distinct cargo profiles of proteins, RNAs, DNA, and lipids

Exosomes

A major class of extracellular vesicle (typically 30–150 nm in diameter) of endocytic origin released by all cell types following fusion of multivesicular bodies with the plasma membrane.

Shed microvesicles

(sMVs). A major class of extracellular vesicle (typically, 50–1,300 nm in diameter) formed by direct budding from the plasma membrane; sMVs are also known as microparticles and ectosomes.

Tumour microenvironment

(TME). The area immediately surrounding a tumour that typically comprises nonmalignant lymphoid and/or myeloid cells, fibroblasts, pericytes, endothelial cells, lymphoid vessels, and extracellular matrix (collectively referred to as the stroma). The interaction between stromal cells and tumour cells has a critical role in cancer growth and metastasis.

Pre-metastatic niche

A microenvironment induced by factors released from the primary tumour in a distant organ that supports metastatic cell seeding, survival, and outgrowth.

Popliteal lymph node

A deep lymph node posterior to the knee embedded in the popliteal fossa that is moderately small in size, close to the popliteal vessels and superficial vessels, and functions as part of the lymphatic system of the lower leg and feet.

Active metastatic niches

Microenvironments in a distant organ that are conducive to metastasis but exist independently of the influence of the primary tumour.

Sleepy niches

Specialized microenvironments in which tumour cells survive in a dormant state, thereby extensively delaying the development of overt metastases.

Multiple reaction monitoring

(MRM). A targeted mass spectrometry-based proteomics approach for the detection and precise quantification of a predetermined set of proteins or peptides; can also occur via selected reaction monitoring.

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Xu, R., Rai, A., Chen, M. et al. Extracellular vesicles in cancer — implications for future improvements in cancer care. Nat Rev Clin Oncol 15, 617–638 (2018). https://doi.org/10.1038/s41571-018-0036-9

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