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.
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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Ahmed, K. A. & Xiang, J. Mechanisms of cellular communication through intercellular protein transfer. J. Cell. Mol. Med. 15, 1458–1473 (2011).
Pitt, J. M., Kroemer, G. & Zitvogel, L. Extracellular vesicles: masters of intercellular communication and potential clinical interventions. J. Clin. Invest. 126, 1139–1143 (2016).
Peinado, H., Lavotshkin, S. & Lyden, D. The secreted factors responsible for pre-metastatic niche formation: old sayings and new thoughts. Semin. Cancer Biol. 21, 139–146 (2011).
Xu, R., Greening, D. W., Zhu, H. J., Takahashi, N. & Simpson, R. J. Extracellular vesicle isolation and characterization: toward clinical application. J. Clin. Invest. 126, 1152–1162 (2016).
Colombo, M., Raposo, G. & Thery, C. Biogenesis, secretion, and intercellular interactions of exosomes and other extracellular vesicles. Annu. Rev. Cell Dev. Biol. 30, 255–289 (2014).
Witwer, K. W. et al. Standardization of sample collection, isolation and analysis methods in extracellular vesicle research. J. Extracell. Vesicles 2, 20360 (2013).
Parolini, I. et al. Microenvironmental pH is a key factor for exosome traffic in tumor cells. J. Biol. Chem. 284, 34211–34222 (2009).
Mittelbrunn, M. et al. Unidirectional transfer of microRNA-loaded exosomes from T cells to antigen-presenting cells. Nat. Commun. 2, 282 (2011).
Kucharzewska, P. & Belting, M. Emerging roles of extracellular vesicles in the adaptive response of tumour cells to microenvironmental stress. J. Extracell. Vesicles 2, 20304 (2013).
An, Q., van Bel, A. J. & Huckelhoven, R. Do plant cells secrete exosomes derived from multivesicular bodies? Plant Signal. Behav. 2, 4–7 (2007).
Deatherage, B. L. & Cookson, B. T. Membrane vesicle release in bacteria, eukaryotes, and archaea: a conserved yet underappreciated aspect of microbial life. Infect. Immun. 80, 1948–1957 (2012).
Heijnen, H. F., Schiel, A. E., Fijnheer, R., Geuze, H. J. & Sixma, J. J. Activated platelets release two types of membrane vesicles: microvesicles by surface shedding and exosomes derived from exocytosis of multivesicular bodies and alpha-granules. Blood 94, 3791–3799 (1999).
Greening, D. W., Gopal, S. K., Xu, R., Simpson, R. J. & Chen, W. Exosomes and their roles in immune regulation and cancer. Semin. Cell Dev. Biol. 40, 72–81 (2015).
Robbins, P. D. & Morelli, A. E. Regulation of immune responses by extracellular vesicles. Nat. Rev. Immunol. 14, 195–208 (2014).
Nair, R. et al. Extracellular vesicles derived from preosteoblasts influence embryonic stem cell differentiation. Stem Cells Dev. 23, 1625–1635 (2014).
Teng, X. et al. Mesenchymal stem cell-derived exosomes improve the microenvironment of infarcted myocardium contributing to angiogenesis and anti-inflammation. Cell Physiol. Biochem. 37, 2415–2424 (2015).
Baixauli, F., Lopez-Otin, C. & Mittelbrunn, M. Exosomes and autophagy: coordinated mechanisms for the maintenance of cellular fitness. Front. Immunol. 5, 403 (2014).
Greening, D. W., Nguyen, H. P., Elgass, K., Simpson, R. J. & Salamonsen, L. A. Human endometrial exosomes contain hormone-specific cargo modulating trophoblast adhesive capacity: Insights into endometrial-embryo interactions. Biol. Reprod. 94, 38 (2016).
Simon, C. et al. Extracellular vesicles in human reproduction in health and disease. Endocr. Rev. https://doi.org/10.1210/er.2017-00229 (2018).
Mitchell, M. D. et al. Placental exosomes in normal and complicated pregnancy. Am. J. Obstet. Gynecol. 213 (Suppl.), S173–S181 (2015).
Fruhbeis, C. et al. Neurotransmitter-triggered transfer of exosomes mediates oligodendrocyte-neuron communication. PLoS Biol. 11, e1001604 (2013).
Fruhbeis, C., Frohlich, D., Kuo, W. P. & Kramer-Albers, E. M. Extracellular vesicles as mediators of neuron-glia communication. Front. Cell. Neurosci. 7, 182 (2013).
Budnik, V., Ruiz-Canada, C. & Wendler, F. Extracellular vesicles round off communication in the nervous system. Nat. Rev. Neurosci. 17, 160–172 (2016).
Peinado, H. et al. Pre-metastatic niches: organ-specific homes for metastases. Nat. Rev. Cancer 17, 302–317 (2017).
Maas, S. L. N., Breakefield, X. O. & Weaver, A. M. Extracellular vesicles: unique intercellular delivery vehicles. Trends Cell Biol. 27, 172–188 (2017).
Gopal, S. K. et al. Extracellular vesicles: their role in cancer biology and epithelial-mesenchymal transition. Biochem. J. 474, 21–45 (2017).
Hanahan, D. & Weinberg, R. A. Hallmarks of cancer: the next generation. Cell 144, 646–674 (2011).
Sadeghipour, S. & Mathias, R. A. Herpesviruses hijack host exosomes for viral pathogenesis. Semin. Cell Dev. Biol. 67, 91–100 (2017).
Skog, J. et al. Glioblastoma microvesicles transport RNA and proteins that promote tumour growth and provide diagnostic biomarkers. Nat. Cell Biol. 10, 1470–1476 (2008).
Peinado, H. et al. Melanoma exosomes educate bone marrow progenitor cells toward a pro-metastatic phenotype through MET. Nat. Med. 18, 883–891 (2012).
Tao, S. C., Guo, S. C. & Zhang, C. Q. Platelet-derived extracellular vesicles: an emerging therapeutic approach. Int. J. Biol. Sci. 13, 828–834 (2017).
Atkin-Smith, G. K. & Poon, I. K. H. Disassembly of the dying: mechanisms and functions. Trends Cell Biol. 27, 151–162 (2017).
Xu, R., Greening, D. W., Rai, A., Ji, H. & Simpson, R. J. Highly-purified exosomes and shed microvesicles isolated from the human colon cancer cell line LIM1863 by sequential centrifugal ultrafiltration are biochemically and functionally distinct. Methods 87, 11–21 (2015).
Kowal, J. et al. Proteomic comparison defines novel markers to characterize heterogeneous populations of extracellular vesicle subtypes. Proc. Natl Acad. Sci. USA 113, E968–E977 (2016).
Tkach, M. et al. Qualitative differences in T cell activation by dendritic cell-derived extracellular vesicle subtypes. EMBO J. 36, 3012–3028 (2017).
Tauro, B. J. et al. Two distinct populations of exosomes are released from LIM1863 colon carcinoma cell-derived organoids. Mol. Cell. Proteom. 12, 587–598 (2013).
Willms, E. et al. Cells release subpopulations of exosomes with distinct molecular and biological properties. Sci. Rep. 6, 22519 (2016).
Zhang, H. et al. Identification of distinct nanoparticles and subsets of extracellular vesicles by asymmetric flow field-flow fractionation. Nat. Cell Biol. 20, 332–343 (2018).
Aatonen, M. T. et al. Isolation and characterization of platelet-derived extracellular vesicles. J. Extracell. Vesicles 3, 24692 (2014).
Piper, R. C. & Katzmann, D. J. Biogenesis and function of multivesicular bodies. Annu. Rev. Cell Dev. Biol. 23, 519–547 (2007).
Appelqvist, H., Waster, P., Kagedal, K. & Ollinger, K. The lysosome: from waste bag to potential therapeutic target. J. Mol. Cell. Biol. 5, 214–226 (2013).
Luzio, J. P., Gray, S. R. & Bright, N. A. Endosome-lysosome fusion. Biochem. Soc. Trans. 38, 1413–1416 (2010).
Bucci, C., Thomsen, P., Nicoziani, P., McCarthy, J. & van Deurs, B. Rab7: a key to lysosome biogenesis. Mol. Biol. Cell 11, 467–480 (2000).
Kowal, J., Tkach, M. & Thery, C. Biogenesis and secretion of exosomes. Curr. Opin. Cell Biol. 29, 116–125 (2014).
Bobrie, A., Colombo, M., Raposo, G. & Thery, C. Exosome secretion: molecular mechanisms and roles in immune responses. Traffic 12, 1659–1668 (2011).
Katzmann, D. J., Babst, M. & Emr, S. D. Ubiquitin-dependent sorting into the multivesicular body pathway requires the function of a conserved endosomal protein sorting complex. ESCRT-I. Cell 106, 145–155 (2001).
Hurley, J. H. ESCRTs are everywhere. EMBO J. 34, 2398–2407 (2015).
Henne, W. M., Buchkovich, N. J. & Emr, S. D. The ESCRT pathway. Dev. Cell 21, 77–91 (2011).
Colombo, M. et al. Analysis of ESCRT functions in exosome biogenesis, composition and secretion highlights the heterogeneity of extracellular vesicles. J. Cell Sci. 126, 5553–5565 (2013).
Buschow, S. I., Liefhebber, J. M., Wubbolts, R. & Stoorvogel, W. Exosomes contain ubiquitinated proteins. Blood Cells Mol. Dis. 35, 398–403 (2005).
Clague, M. J., Liu, H. & Urbe, S. Governance of endocytic trafficking and signaling by reversible ubiquitylation. Dev. Cell 23, 457–467 (2012).
Hurley, J. H. & Odorizzi, G. Get on the exosome bus with ALIX. Nat. Cell Biol. 14, 654–655 (2012).
Trajkovic, K. et al. Ceramide triggers budding of exosome vesicles into multivesicular endosomes. Science 319, 1244–1247 (2008).
Ghossoub, R. et al. Syntenin-ALIX exosome biogenesis and budding into multivesicular bodies are controlled by ARF6 and PLD2. Nat. Commun. 5, 3477 (2014).
Baietti, M. F. et al. Syndecan-syntenin-ALIX regulates the biogenesis of exosomes. Nat. Cell Biol. 14, 677–685 (2012).
Muralidharan-Chari, V. et al. ARF6-regulated shedding of tumor cell-derived plasma membrane microvesicles. Curr. Biol. 19, 1875–1885 (2009).
Li, B., Antonyak, M. A., Zhang, J. & Cerione, R. A. RhoA triggers a specific signaling pathway that generates transforming microvesicles in cancer cells. Oncogene 31, 4740–4749 (2012).
Nabhan, J. F., Hu, R., Oh, R. S., Cohen, S. N. & Lu, Q. Formation and release of arrestin domain-containing protein 1-mediated microvesicles (ARMMs) at plasma membrane by recruitment of TSG101 protein. Proc. Natl Acad. Sci. USA 109, 4146–4151 (2012).
Fujii, K., Hurley, J. H. & Freed, E. O. Beyond Tsg101: the role of Alix in ‘ESCRTing’ HIV-1. Nat. Rev. Microbiol. 5, 912–916 (2007).
Christ, L. et al. ALIX and ESCRT-I/II function as parallel ESCRT-III recruiters in cytokinetic abscission. J. Cell Biol. 212, 499–513 (2016).
Morita, E. et al. Human ESCRT and ALIX proteins interact with proteins of the midbody and function in cytokinesis. EMBO J. 26, 4215–4227 (2007).
Bianco, F. et al. Acid sphingomyelinase activity triggers microparticle release from glial cells. EMBO J. 28, 1043–1054 (2009).
Cocucci, E. & Meldolesi, J. Ectosomes and exosomes: shedding the confusion between extracellular vesicles. Trends Cell Biol. 25, 364–372 (2015).
Abels, E. R. & Breakefield, X. O. Introduction to extracellular vesicles: biogenesis, RNA cargo selection, content, release, and uptake. Cell. Mol. Neurobiol. 36, 301–312 (2016).
Mulcahy, L. A., Pink, R. C. & Carter, D. R. Routes and mechanisms of extracellular vesicle uptake. J. Extracell. Vesicles 3, 24641 (2014).
Tan, A., De La Pena, H. & Seifalian, A. M. The application of exosomes as a nanoscale cancer vaccine. Int. J. Nanomed. 5, 889–900 (2010).
Escudier, B. et al. Vaccination of metastatic melanoma patients with autologous dendritic cell (DC) derived-exosomes: results of the first phase I clinical trial. J. Transl Med. 3, 10 (2005).
Morse, M. A. et al. A phase I study of dexosome immunotherapy in patients with advanced non-small cell lung cancer. J. Transl Med. 3, 9 (2005).
Greening, D. W., Xu, R., Gopal, S. K., Rai, A. & Simpson, R. J. Proteomic insights into extracellular vesicle biology — defining exosomes and shed microvesicles. Expert Rev. Proteom. 14, 69–95 (2017).
Nielsen, M., Thomsen, J. L., Primdahl, S., Dyreborg, U. & Andersen, J. A. Breast cancer and atypia among young and middle-aged women: a study of 110 medicolegal autopsies. Br. J. Cancer 56, 814–819 (1987).
Harach, H. R., Franssila, K. O. & Wasenius, V. M. Occult papillary carcinoma of the thyroid. A “normal” finding in Finland. A systematic autopsy study. Cancer 56, 531–538 (1985).
Manser, R. L., Dodd, M., Byrnes, G., Irving, L. B. & Campbell, D. A. Incidental lung cancers identified at coronial autopsy: implications for overdiagnosis of lung cancer by screening. Respir. Med. 99, 501–507 (2005).
Andea, A., Sarkar, F. & Adsay, V. N. Clinicopathological correlates of pancreatic intraepithelial neoplasia: a comparative analysis of 82 cases with and 152 cases without pancreatic ductal adenocarcinoma. Mod. Pathol. 16, 996–1006 (2003).
Dolberg, D. S. & Bissell, M. J. Inability of Rous sarcoma virus to cause sarcomas in the avian embryo. Nature 309, 552–556 (1984).
Folkman, J. & Kalluri, R. Cancer without disease. Nature 427, 787 (2004).
Bissell, M. J. & Hines, W. C. Why don’t we get more cancer? A proposed role of the microenvironment in restraining cancer progression. Nat. Med. 17, 320–329 (2011).
Quail, D. F. & Joyce, J. A. Microenvironmental regulation of tumor progression and metastasis. Nat. Med. 19, 1423–1437 (2013).
Barcellos-Hoff, M. H., Lyden, D. & Wang, T. C. The evolution of the cancer niche during multistage carcinogenesis. Nat. Rev. Cancer 13, 511–518 (2013).
Hsu, Y. L. et al. Hypoxic lung cancer-secreted exosomal miR-23a increased angiogenesis and vascular permeability by targeting prolyl hydroxylase and tight junction protein ZO-1. Oncogene 36, 4929–4942 (2017).
Webber, J., Steadman, R., Mason, M. D., Tabi, Z. & Clayton, A. Cancer exosomes trigger fibroblast to myofibroblast differentiation. Cancer Res. 70, 9621–9630 (2010).
Webber, J. P. et al. Differentiation of tumour-promoting stromal myofibroblasts by cancer exosomes. Oncogene 34, 290–302 (2015).
Kim, J. W. et al. Fas ligand-positive membranous vesicles isolated from sera of patients with oral cancer induce apoptosis of activated T lymphocytes. Clin. Cancer Res. 11, 1010–1020 (2005).
Wieckowski, E. U. et al. Tumor-derived microvesicles promote regulatory T cell expansion and induce apoptosis in tumor-reactive activated CD8+ T lymphocytes. J. Immunol. 183, 3720–3730 (2009).
Liu, C. et al. Murine mammary carcinoma exosomes promote tumor growth by suppression of NK cell function. J. Immunol. 176, 1375–1385 (2006).
Valadi, H. et al. Exosome-mediated transfer of mRNAs and microRNAs is a novel mechanism of genetic exchange between cells. Nat. Cell Biol. 9, 654–659 (2007).
Zhang, Y. et al. Secreted monocytic miR-150 enhances targeted endothelial cell migration. Mol. Cell 39, 133–144 (2010).
Pegtel, D. M. et al. Functional delivery of viral miRNAs via exosomes. Proc. Natl Acad. Sci. USA 107, 6328–6333 (2010).
Kosaka, N. et al. Secretory mechanisms and intercellular transfer of microRNAs in living cells. J. Biol. Chem. 285, 17442–17452 (2010).
Qu, L. et al. Exosome-transmitted lncARSR promotes sunitinib resistance in renal cancer by acting as a competing endogenous RNA. Cancer Cell 29, 653–668 (2016).
Antonyak, M. A. et al. Cancer cell-derived microvesicles induce transformation by transferring tissue transglutaminase and fibronectin to recipient cells. Proc. Natl Acad. Sci. USA 108, 4852–4857 (2011).
Lugini, L. et al. Exosomes from human colorectal cancer induce a tumor-like behavior in colonic mesenchymal stromal cells. Oncotarget 7, 50086–50098 (2016).
Abd Elmageed, Z. Y. et al. Neoplastic reprogramming of patient-derived adipose stem cells by prostate cancer cell-associated exosomes. Stem Cells 32, 983–997 (2014).
Al-Nedawi, K. et al. Intercellular transfer of the oncogenic receptor EGFRvIII by microvesicles derived from tumour cells. Nat. Cell Biol. 10, 619–624 (2008).
Melo, S. A. et al. Cancer exosomes perform cell-independent microRNA biogenesis and promote tumorigenesis. Cancer Cell 26, 707–721 (2014).
Zhao, H. et al. The key role of extracellular vesicles in the metastatic process. Biochim. Biophys. Acta 1869, 64–77 (2018).
Demory Beckler, M. et al. Proteomic analysis of exosomes from mutant KRAS colon cancer cells identifies intercellular transfer of mutant KRAS. Mol. Cell Proteom. 12, 343–355 (2013).
Nilsson, R. J. et al. Rearranged EML4-ALK fusion transcripts sequester in circulating blood platelets and enable blood-based crizotinib response monitoring in non-small-cell lung cancer. Oncotarget 7, 1066–1075 (2016).
Wei, Y. et al. Exosomal miR-221/222 enhances tamoxifen resistance in recipient ER-positive breast cancer cells. Breast Cancer Res. Treat. 147, 423–431 (2014).
Patel, A. P. et al. Single-cell RNA-seq highlights intratumoral heterogeneity in primary glioblastoma. Science 344, 1396–1401 (2014).
Junttila, M. R. & de Sauvage, F. J. Influence of tumour micro-environment heterogeneity on therapeutic response. Nature 501, 346–354 (2013).
Luga, V. et al. Exosomes mediate stromal mobilization of autocrine Wnt-PCP signaling in breast cancer cell migration. Cell 151, 1542–1556 (2012).
Shimoda, M. et al. Loss of the Timp gene family is sufficient for the acquisition of the CAF-like cell state. Nat. Cell Biol. 16, 889–901 (2014).
Zhang, L. et al. Microenvironment-induced PTEN loss by exosomal microRNA primes brain metastasis outgrowth. Nature 527, 100–104 (2015).
Nabet, B. Y. et al. Exosome RNA unshielding couples stromal activation to pattern recognition receptor signaling in cancer. Cell 170, 352–366.e13 (2017).
Zheng, P. et al. Exosomal transfer of tumor-associated macrophage-derived miR-21 confers cisplatin resistance in gastric cancer cells. J. Exp. Clin. Cancer Res. 36, 53 (2017).
Yokoi, A. et al. Malignant extracellular vesicles carrying MMP1 mRNA facilitate peritoneal dissemination in ovarian cancer. Nat. Commun. 8, 14470 (2017).
Rahman, M. A. et al. Lung cancer exosomes as drivers of epithelial mesenchymal transition. Oncotarget 7, 54852–54866 (2016).
Kalluri, R. The biology and function of exosomes in cancer. J. Clin. Invest. 126, 1208–1215 (2016).
Psaila, B. & Lyden, D. The metastatic niche: adapting the foreign soil. Nat. Rev. Cancer 9, 285–293 (2009).
Kaplan, R. N. et al. VEGFR1-positive haematopoietic bone marrow progenitors initiate the pre-metastatic niche. Nature 438, 820–827 (2005).
Huang, Y. et al. Pulmonary vascular destabilization in the premetastatic phase facilitates lung metastasis. Cancer Res. 69, 7529–7537 (2009).
Hiratsuka, S. et al. Primary tumours modulate innate immune signalling to create pre-metastatic vascular hyperpermeability foci. Nat. Commun. 4, 1853 (2013).
Gupta, G. P. et al. Mediators of vascular remodelling co-opted for sequential steps in lung metastasis. Nature 446, 765–770 (2007).
Liu, Y. et al. Tumor exosomal RNAs promote lung pre-metastatic niche formation by activating alveolar epithelial TLR3 to recruit neutrophils. Cancer Cell 30, 243–256 (2016).
Giles, A. J. et al. Activation of hematopoietic stem/progenitor cells promotes immunosuppression within the pre-metastatic niche. Cancer Res. 76, 1335–1347 (2016).
Gil-Bernabe, A. M. et al. Recruitment of monocytes/macrophages by tissue factor-mediated coagulation is essential for metastatic cell survival and premetastatic niche establishment in mice. Blood 119, 3164–3175 (2012).
Hiratsuka, S. et al. The S100A8-serum amyloid A3-TLR4 paracrine cascade establishes a pre-metastatic phase. Nat. Cell Biol. 10, 1349–1355 (2008).
Shojaei, F. et al. G-CSF-initiated myeloid cell mobilization and angiogenesis mediate tumor refractoriness to anti-VEGF therapy in mouse models. Proc. Natl Acad. Sci. USA 106, 6742–6747 (2009).
Kaplan, R. N., Rafii, S. & Lyden, D. Preparing the “soil”: the premetastatic niche. Cancer Res. 66, 11089–11093 (2006).
Costa-Silva, B. et al. Pancreatic cancer exosomes initiate pre-metastatic niche formation in the liver. Nat. Cell Biol. 17, 816–826 (2015).
Hoshino, A. et al. Tumour exosome integrins determine organotropic metastasis. Nature 527, 329–335 (2015).
Fong, M. Y. et al. Breast-cancer-secreted miR-122 reprograms glucose metabolism in premetastatic niche to promote metastasis. Nat. Cell Biol. 17, 183–194 (2015).
Hood, J. L., San, R. S. & Wickline, S. A. Exosomes released by melanoma cells prepare sentinel lymph nodes for tumor metastasis. Cancer Res. 71, 3792–3801 (2011).
Grange, C. et al. Microvesicles released from human renal cancer stem cells stimulate angiogenesis and formation of lung premetastatic niche. Cancer Res. 71, 5346–5356 (2011).
Balaj, L. et al. Tumour microvesicles contain retrotransposon elements and amplified oncogene sequences. Nat. Commun. 2, 180 (2011).
Carter, C. L., Allen, C. & Henson, D. E. Relation of tumor size, lymph node status, and survival in 24,740 breast cancer cases. Cancer 63, 181–187 (1989).
Pucci, F. et al. SCS macrophages suppress melanoma by restricting tumor-derived vesicle-B cell interactions. Science 352, 242–246 (2016).
Otto, B. et al. Molecular changes in pre-metastatic lymph nodes of esophageal cancer patients. PLoS ONE 9, e102552 (2014).
Mansfield, A. S. et al. Regional immunity in melanoma: immunosuppressive changes precede nodal metastasis. Mod. Pathol. 24, 487–494 (2011).
Matsuura, K. et al. Maturation of dendritic cells and T cell responses in sentinel lymph nodes from patients with breast carcinoma. Cancer 106, 1227–1236 (2006).
Sleeman, J. P. The lymph node pre-metastatic niche. J. Mol. Med. 93, 1173–1184 (2015).
Jung, T. et al. CD44v6 dependence of premetastatic niche preparation by exosomes. Neoplasia 11, 1093–1105 (2009).
Rana, S., Malinowska, K. & Zoller, M. Exosomal tumor microRNA modulates premetastatic organ cells. Neoplasia 15, 281–295 (2013).
Kaur, A. et al. sFRP2 in the aged microenvironment drives melanoma metastasis and therapy resistance. Nature 532, 250–254 (2016).
Yan, L., Cai, Q. & Xu, Y. The ubiquitin-CXCR4 axis plays an important role in acute lung infection-enhanced lung tumor metastasis. Clin. Cancer Res. 19, 4706–4716 (2013).
Bliss, S. A. et al. Mesenchymal stem cell-derived exosomes stimulate cycling quiescence and early breast cancer dormancy in bone marrow. Cancer Res. 76, 5832–5844 (2016).
Gao, H. et al. The BMP inhibitor Coco reactivates breast cancer cells at lung metastatic sites. Cell 150, 764–779 (2012).
Kobayashi, A. et al. Bone morphogenetic protein 7 in dormancy and metastasis of prostate cancer stem-like cells in bone. J. Exp. Med. 208, 2641–2655 (2011).
Ghajar, C. M. et al. The perivascular niche regulates breast tumour dormancy. Nat. Cell Biol. 15, 807–817 (2013).
Ono, M. et al. Exosomes from bone marrow mesenchymal stem cells contain a microRNA that promotes dormancy in metastatic breast cancer cells. Sci. Signal. 7, ra63 (2014).
Fuzery, A. K., Levin, J., Chan, M. M. & Chan, D. W. Translation of proteomic biomarkers into FDA approved cancer diagnostics: issues and challenges. Clin. Proteom. 10, 13 (2013).
Drabovich, A. P., Martinez-Morillo, E. & Diamandis, E. P. Toward an integrated pipeline for protein biomarker development. Biochim. Biophys. Acta 1854, 677–686 (2015).
Pepe, M. S. et al. Early-phase studies of biomarkers: what target sensitivity and specificity values might confer clinical utility? Clin. Chem. 62, 737–742 (2016).
Siravegna, G., Marsoni, S., Siena, S. & Bardelli, A. Integrating liquid biopsies into the management of cancer. Nat. Rev. Clin. Oncol. 14, 531–548 (2017).
Urabe, F., Kosaka, N., Yoshioka, Y., Egawa, S. & Ochiya, T. The small vesicular culprits: the investigation of extracellular vesicles as new targets for cancer treatment. Clin. Transl Med. 6, 45 (2017).
Sugimachi, K. et al. Identification of a bona fide microRNA biomarker in serum exosomes that predicts hepatocellular carcinoma recurrence after liver transplantation. Br. J. Cancer 112, 532–538 (2015).
Jin, X. et al. Evaluation of tumor-derived exosomal miRNA as potential diagnostic biomarkers for early-stage non-small cell lung cancer using next-generation sequencing. Clin. Cancer Res. 23, 5311–5319 (2017).
Huang, S. H., Li, Y., Zhang, J., Rong, J. & Ye, S. Epidermal growth factor receptor-containing exosomes induce tumor-specific regulatory T cells. Cancer Invest. 31, 330–335 (2013).
Reclusa, P. et al. Exosomes as diagnostic and predictive biomarkers in lung cancer. J. Thorac. Dis. 9, S1373–S1382 (2017).
Liu, Q. et al. Circulating exosomal microRNAs as prognostic biomarkers for non-small-cell lung cancer. Oncotarget 8, 13048–13058 (2017).
Nedaeinia, R. et al. Circulating exosomes and exosomal microRNAs as biomarkers in gastrointestinal cancer. Cancer Gene Ther. 24, 48–56 (2017).
Ogata-Kawata, H. et al. Circulating exosomal microRNAs as biomarkers of colon cancer. PLoS ONE 9, e92921 (2014).
Madhavan, B. et al. Combined evaluation of a panel of protein and miRNA serum-exosome biomarkers for pancreatic cancer diagnosis increases sensitivity and specificity. Int. J. Cancer 136, 2616–2627 (2015).
Alegre, E. et al. Study of circulating microRNA-125b levels in serum exosomes in advanced melanoma. Arch. Pathol. Lab. Med. 138, 828–832 (2014).
Ragusa, M. et al. miRNA profiling in vitreous humor, vitreal exosomes and serum from uveal melanoma patients: pathological and diagnostic implications. Cancer Biol. Ther. 16, 1387–1396 (2015).
Fleming, N. H. et al. Serum-based miRNAs in the prediction and detection of recurrence in melanoma patients. Cancer 121, 51–59 (2015).
Logozzi, M. et al. High levels of exosomes expressing CD63 and caveolin-1 in plasma of melanoma patients. PLoS ONE 4, e5219 (2009).
Chen, I. H. et al. Phosphoproteins in extracellular vesicles as candidate markers for breast cancer. Proc. Natl Acad. Sci. USA 114, 3175–3180 (2017).
Zhou, J. et al. Urinary microRNA-30a-5p is a potential biomarker for ovarian serous adenocarcinoma. Oncol. Rep. 33, 2915–2923 (2015).
Valentino, A. et al. Exosomal microRNAs in liquid biopsies: future biomarkers for prostate cancer. Clin. Transl Oncol. 19, 651–657 (2017).
Zitvogel, L. et al. Eradication of established murine tumors using a novel cell-free vaccine: dendritic cell-derived exosomes. Nat. Med. 4, 594–600 (1998).
Melo, S. A. et al. Glypican-1 identifies cancer exosomes and detects early pancreatic cancer. Nature 523, 177–182 (2015).
Lai, X. et al. A microRNA signature in circulating exosomes is superior to exosomal glypican-1 levels for diagnosing pancreatic cancer. Cancer Lett. 393, 86–93 (2017).
Siegel, R. L., Miller, K. D. & Jemal, A. Cancer statistics, 2016. CA Cancer J. Clin. 66, 7–30 (2016).
Su, G. et al. Glypican-1 is frequently overexpressed in human gliomas and enhances FGF-2 signaling in glioma cells. Am. J. Pathol. 168, 2014–2026 (2006).
Matsuda, K. et al. Glypican-1 is overexpressed in human breast cancer and modulates the mitogenic effects of multiple heparin-binding growth factors in breast cancer cells. Cancer Res. 61, 5562–5569 (2001).
Li, J. et al. GPC1 exosome and its regulatory miRNAs are specific markers for the detection and target therapy of colorectal cancer. J. Cell. Mol. Med. 21, 838–847 (2017).
Kleeff, J. et al. The cell-surface heparan sulfate proteoglycan glypican-1 regulates growth factor action in pancreatic carcinoma cells and is overexpressed in human pancreatic cancer. J. Clin. Invest. 102, 1662–1673 (1998).
Picotti, P. & Aebersold, R. Selected reaction monitoring-based proteomics: workflows, potential, pitfalls and future directions. Nat. Methods 9, 555–566 (2012).
Wang, Q. et al. Selected reaction monitoring approach for validating peptide biomarkers. Proc. Natl Acad. Sci. USA 114, 13519–13524 (2017).
Ha, D., Yang, N. & Nadithe, V. Exosomes as therapeutic drug carriers and delivery vehicles across biological membranes: current perspectives and future challenges. Acta Pharm. Sin. B 6, 287–296 (2016).
Barile, L. & Vassalli, G. Exosomes: therapy delivery tools and biomarkers of diseases. Pharmacol. Ther. 174, 63–78 (2017).
Wang, J., Zheng, Y. & Zhao, M. Exosome-based cancer therapy: implication for targeting cancer stem cells. Front. Pharmacol. 7, 533 (2016).
Luan, X. et al. Engineering exosomes as refined biological nanoplatforms for drug delivery. Acta Pharmacol. Sin. 38, 754–763 (2017).
Mizrak, A. et al. Genetically engineered microvesicles carrying suicide mRNA/protein inhibit schwannoma tumor growth. Mol. Ther. 21, 101–108 (2013).
Sun, D. et al. A novel nanoparticle drug delivery system: the anti-inflammatory activity of curcumin is enhanced when encapsulated in exosomes. Mol. Ther. 18, 1606–1614 (2010).
Iessi, E. et al. Acridine orange/exosomes increase the delivery and the effectiveness of acridine orange in human melanoma cells: a new prototype for theranostics of tumors. J. Enzyme Inhib Med. Chem. 32, 648–657 (2017).
Srivastava, A. et al. Nanosomes carrying doxorubicin exhibit potent anticancer activity against human lung cancer cells. Sci. Rep. 6, 38541 (2016).
Kim, M. S. et al. Development of exosome-encapsulated paclitaxel to overcome MDR in cancer cells. Nanomedicine 12, 655–664 (2016).
Kamerkar, S. et al. Exosomes facilitate therapeutic targeting of oncogenic KRAS in pancreatic cancer. Nature 546, 498–503 (2017).
Pascucci, L. et al. Paclitaxel is incorporated by mesenchymal stromal cells and released in exosomes that inhibit in vitro tumor growth: a new approach for drug delivery. J. Control. Release 192, 262–270 (2014).
Rivoltini, L. et al. TNF-related apoptosis-inducing ligand (TRAIL)-armed exosomes deliver proapoptotic signals to tumor site. Clin. Cancer Res. 22, 3499–3512 (2016).
Lou, G. et al. Exosomes derived from miR-122-modified adipose tissue-derived MSCs increase chemosensitivity of hepatocellular carcinoma. J. Hematol. Oncol. 8, 122 (2015).
Alvarez-Erviti, L. et al. Delivery of siRNA to the mouse brain by systemic injection of targeted exosomes. Nat. Biotechnol. 29, 341–345 (2011).
Tian, Y. et al. A doxorubicin delivery platform using engineered natural membrane vesicle exosomes for targeted tumor therapy. Biomaterials 35, 2383–2390 (2014).
Kooijmans, S. A. et al. Display of GPI-anchored anti-EGFR nanobodies on extracellular vesicles promotes tumour cell targeting. J. Extracell. Vesicles 5, 31053 (2016).
Qi, H. et al. Blood exosomes endowed with magnetic and targeting properties for cancer therapy. ACS Nano 10, 3323–3333 (2016).
Munagala, R., Aqil, F., Jeyabalan, J. & Gupta, R. C. Bovine milk-derived exosomes for drug delivery. Cancer Lett. 371, 48–61 (2016).
Mu, J. et al. Interspecies communication between plant and mouse gut host cells through edible plant derived exosome-like nanoparticles. Mol. Nutr. Food Res. 58, 1561–1573 (2014).
Wang, Q. et al. Grapefruit-derived nanovectors use an activated leukocyte trafficking pathway to deliver therapeutic agents to inflammatory tumor sites. Cancer Res. 75, 2520–2529 (2015).
US National Library of Medicine. ClinicalTrials.gov https://clinicaltrials.gov/ct2/show/NCT01939899 (2016).
Lener, T. et al. Applying extracellular vesicles based therapeutics in clinical trials — an ISEV position paper. J. Extracell. Vesicles 4, 30087 (2015).
Webber, J. & Clayton, A. How pure are your vesicles? J. Extracell. Vesicles 2, 19861 (2013).
Belov, L. et al. Surface profiling of extracellular vesicles from plasma or ascites fluid using DotScan antibody microarrays. Methods Mol. Biol. 1619, 263–301 (2017).
Baek, R. & Jorgensen, M. M. Multiplexed phenotyping of small extracellular vesicles using protein microarray (EV array). Methods Mol. Biol. 1545, 117–127 (2017).
Arraud, N. et al. Extracellular vesicles from blood plasma: determination of their morphology, size, phenotype and concentration. J. Thromb. Haemost. 12, 614–627 (2014).
Liang, K. et al. Nanoplasmonic quantification of tumor-derived extracellular vesicles in plasma microsamples for diagnosis and treatment monitoring. Nat. Biomed. Eng. 1, 0021 (2017).
Pritchard, C. C., Cheng, H. H. & Tewari, M. MicroRNA profiling: approaches and considerations. Nat. Rev. Genet. 13, 358–369 (2012).
Yang, S. et al. Detection of mutant KRAS and TP53 DNA in circulating exosomes from healthy individuals and patients with pancreatic cancer. Cancer Biol. Ther. 18, 158–165 (2017).
Li, P., Kaslan, M., Lee, S. H., Yao, J. & Gao, Z. Progress in exosome isolation techniques. Theranostics 7, 789–804 (2017).
Tauro, B. J. et al. Comparison of ultracentrifugation, density gradient separation, and immunoaffinity capture methods for isolating human colon cancer cell line LIM1863-derived exosomes. Methods 56, 293–304 (2012).
Ghosh, A. et al. Rapid isolation of extracellular vesicles from cell culture and biological fluids using a synthetic peptide with specific affinity for heat shock proteins. PLoS ONE 9, e110443 (2014).
Christianson, H. C., Svensson, K. J., van Kuppevelt, T. H., Li, J. P. & Belting, M. Cancer cell exosomes depend on cell-surface heparan sulfate proteoglycans for their internalization and functional activity. Proc. Natl Acad. Sci. USA 110, 17380–17385 (2013).
Balaj, L. et al. Heparin affinity purification of extracellular vesicles. Sci. Rep. 5, 10266 (2015).
Ji, H. et al. Proteome profiling of exosomes derived from human primary and metastatic colorectal cancer cells reveal differential expression of key metastatic factors and signal transduction components. Proteomics 13, 1672–1686 (2013).
Carrasco-Ramirez, P. et al. Podoplanin is a component of extracellular vesicles that reprograms cell-derived exosomal proteins and modulates lymphatic vessel formation. Oncotarget 7, 16070–16089 (2016).
Kahlert, C. et al. Identification of double-stranded genomic DNA spanning all chromosomes with mutated KRAS and p53 DNA in the serum exosomes of patients with pancreatic cancer. J. Biol. Chem. 289, 3869–3875 (2014).
Thakur, B. K. et al. Double-stranded DNA in exosomes: a novel biomarker in cancer detection. Cell Res. 24, 766–769 (2014).
San Lucas, F. A. et al. Minimally invasive genomic and transcriptomic profiling of visceral cancers by next-generation sequencing of circulating exosomes. Ann. Oncol. 27, 635–641 (2016).
Lee, T. H. et al. Barriers to horizontal cell transformation by extracellular vesicles containing oncogenic H-ras. Oncotarget 7, 51991–52002 (2016).
Dijkstra, S. et al. Prostate cancer biomarker profiles in urinary sediments and exosomes. J. Urol. 191, 1132–1138 (2014).
Chen, M. et al. Transcriptome and long noncoding RNA sequencing of three extracellular vesicle subtypes released from the human colon cancer LIM1863 cell line. Sci. Rep. 6, 38397 (2016).
Krug, A. K. et al. Improved EGFR mutation detection using combined exosomal RNA and circulating tumor DNA in NSCLC patient plasma. Ann. Oncol. 29, 700–706 (2018).
Li, Q. et al. Plasma long noncoding RNA protected by exosomes as a potential stable biomarker for gastric cancer. Tumour Biol. 36, 2007–2012 (2015).
Zhang, J. et al. Exosomal long noncoding RNAs are differentially expressed in the cervicovaginal lavage samples of cervical cancer patients. J. Clin. Lab. Anal. 30, 1116–1121 (2016).
Dong, L. et al. Circulating long RNAs in serum extracellular vesicles: their characterization and potential application as biomarkers for diagnosis of colorectal cancer. Cancer Epidemiol. Biomarkers Prev. 25, 1158–1166 (2016).
Viaud, S. et al. Dendritic cell-derived exosomes promote natural killer cell activation and proliferation: a role for NKG2D ligands and IL-15Ralpha. PLoS ONE 4, e4942 (2009).
Viaud, S. et al. Updated technology to produce highly immunogenic dendritic cell-derived exosomes of clinical grade: a critical role of interferon-gamma. J. Immunother. 34, 65–75 (2011).
Besse, B. et al. Dendritic cell-derived exosomes as maintenance immunotherapy after first line chemotherapy in NSCLC. Oncoimmunology 5, e1071008 (2016).
Wolfers, J. et al. Tumor-derived exosomes are a source of shared tumor rejection antigens for CTL cross-priming. Nat. Med. 7, 297–303 (2001).
Andre, F. et al. Malignant effusions and immunogenic tumour-derived exosomes. Lancet 360, 295–305 (2002).
Dai, S. et al. Phase I clinical trial of autologous ascites-derived exosomes combined with GM-CSF for colorectal cancer. Mol. Ther. 16, 782–790 (2008).
US National Library of Medicine. ClinicalTrials.gov https://clinicaltrials.gov/show/NCT01550523 (2013).
Cappello, F. et al. Exosome levels in human body fluids: a tumor marker by themselves? Eur. J. Pharm. Sci. 96, 93–98 (2017).
Menck, K. et al. Characterisation of tumour-derived microvesicles in cancer patients’ blood and correlation with clinical outcome. J. Extracell. Vesicles 6, 1340745 (2017).
De Paoli, S. H. et al. Dissecting the biochemical architecture and morphological release pathways of the human platelet extracellular vesiculome. Cell. Mol. Life Sci. https://doi.org/10.1007/s00018-018-2771-6 (2018).
Fricke, A. et al. Levels of activated platelet-derived microvesicles in patients with soft tissue sarcoma correlate with an increased risk of venous thromboembolism. BMC Cancer 17, 527 (2017).
Vickers, K. C., Palmisano, B. T., Shoucri, B. M., Shamburek, R. D. & Remaley, A. T. MicroRNAs are transported in plasma and delivered to recipient cells by high-density lipoproteins. Nat. Cell Biol. 13, 423–433 (2011).
Arroyo, J. D. et al. Argonaute2 complexes carry a population of circulating microRNAs independent of vesicles in human plasma. Proc. Natl Acad. Sci. USA 108, 5003–5008 (2011).
Mork, M. et al. Prospects and limitations of antibody-mediated clearing of lipoproteins from blood plasma prior to nanoparticle tracking analysis of extracellular vesicles. J. Extracell. Vesicles 6, 1308779 (2017).
Mathivanan, S., Fahner, C. J., Reid, G. E. & Simpson, R. J. ExoCarta 2012: database of exosomal proteins, RNA and lipids. Nucleic Acids Res. 40, D1241–D1244 (2012).
Kalra, H. et al. Vesiclepedia: a compendium for extracellular vesicles with continuous community annotation. PLoS Biol. 10, e1001450 (2012).
Smyth, T. et al. Biodistribution and delivery efficiency of unmodified tumor-derived exosomes. J. Control. Release 199, 145–155 (2015).
Plebanek, M. P. et al. Pre-metastatic cancer exosomes induce immune surveillance by patrolling monocytes at the metastatic niche. Nat. Commun. 8, 1319 (2017).
Zhang, H. et al. Exosome-delivered EGFR regulates liver microenvironment to promote gastric cancer liver metastasis. Nat. Commun. 8, 15016 (2017).
Sharghi-Namini, S., Tan, E., Ong, L. L., Ge, R. & Asada, H. H. Dll4-containing exosomes induce capillary sprout retraction in a 3D microenvironment. Sci. Rep. 4, 4031 (2014).
Tominaga, N. et al. Brain metastatic cancer cells release microRNA-181c-containing extracellular vesicles capable of destructing blood-brain barrier. Nat. Commun. 6, 6716 (2015).
Umezu, T. et al. Exosomal miR-135b shed from hypoxic multiple myeloma cells enhances angiogenesis by targeting factor-inhibiting HIF-1. Blood 124, 3748–3757 (2014).
Zomer, A. et al. In vivo imaging reveals extracellular vesicle-mediated phenocopying of metastatic behavior. Cell 161, 1046–1057 (2015).
Allenson, K. et al. High prevalence of mutant KRAS in circulating exosome-derived DNA from early-stage pancreatic cancer patients. Ann. Oncol. 28, 741–747 (2017).
Del, Re,M. et al. The detection of androgen receptor splice variant 7 in plasma-derived exosomal RNA strongly predicts resistance to hormonal therapy in metastatic prostate cancer patients. Eur. Urol. 71, 680–687 (2017).
McKiernan, J. et al. A novel urine exosome gene expression assay to predict high-grade prostate cancer at initial biopsy. JAMA Oncol. 2, 882–889 (2016).
Liu, T. et al. Exosomal long noncoding RNA CRNDE-h as a novel serum-based biomarker for diagnosis and prognosis of colorectal cancer. Oncotarget 7, 85551–85563 (2016).
Cazzoli, R. et al. microRNAs derived from circulating exosomes as noninvasive biomarkers for screening and diagnosing lung cancer. J. Thorac. Oncol. 8, 1156–1162 (2013).
Skotland, T. et al. Molecular lipid species in urinary exosomes as potential prostate cancer biomarkers. Eur. J. Cancer 70, 122–132 (2017).
Saari, H. et al. Microvesicle- and exosome-mediated drug delivery enhances the cytotoxicity of Paclitaxel in autologous prostate cancer cells. J. Control. Release 220, 727–737 (2015).
Kim, M. S. et al. Engineering macrophage-derived exosomes for targeted paclitaxel delivery to pulmonary metastases: in vitro and in vivo evaluations. Nanomedicine 14, 195–204 (2018).
Hadla, M. et al. Exosomes increase the therapeutic index of doxorubicin in breast and ovarian cancer mouse models. Nanomedicine 11, 2431–2441 (2016).
Jang, S. C. et al. Bioinspired exosome-mimetic nanovesicles for targeted delivery of chemotherapeutics to malignant tumors. ACS Nano 7, 7698–7710 (2013).
Yang, T. et al. Exosome delivered anticancer drugs across the blood-brain barrier for brain cancer therapy in Danio rerio. Pharm. Res. 32, 2003–2014 (2015).
US National Library of Medicine. ClinicalTrials.gov https://clinicaltrials.gov/ct2/show/NCT02657460 (2016).
US National Library of Medicine. ClinicalTrials.gov https://clinicaltrials.gov/ct2/show/NCT03230708 (2017).
Ma, J. et al. Reversing drug resistance of soft tumor-repopulating cells by tumor cell-derived chemotherapeutic microparticles. Cell Res. 26, 713–727 (2016).
Yang, T. et al. Delivery of small interfering RNA to inhibit vascular endothelial growth factor in zebrafish using natural brain endothelia cell-secreted exosome nanovesicles for the treatment of brain cancer. AAPS J. 19, 475–486 (2017).
Ohno, S. et al. Systemically injected exosomes targeted to EGFR deliver antitumor microRNA to breast cancer cells. Mol. Ther. 21, 185–191 (2013).
Munoz, J. L. et al. Delivery of functional anti-miR-9 by mesenchymal stem cell-derived exosomes to glioblastoma multiforme cells conferred chemosensitivity. Mol. Ther. Nucleic Acids 2, e126 (2013).
Aspe, J. R. et al. Enhancement of Gemcitabine sensitivity in pancreatic adenocarcinoma by novel exosome-mediated delivery of the Survivin-T34A mutant. J. Extracell. Vesicles 3, 23244 (2014).
Cho, J. A. et al. Exosomes: a new delivery system for tumor antigens in cancer immunotherapy. Int. J. Cancer 114, 613–622 (2005).
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.
Nature Reviews Clinical Oncology thanks T. Whiteside and the other, anonymous reviewers for their contribution to the peer review of this work.
The authors declare no competing interests.
Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.
National Cancer Institute: https://www.cancer.gov/
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
- 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
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