Extracellular Vesicles As Disease Biomarkers ?

Mercedes Tkach1,2, Joanna Kowal1,2, Clotilde Thery1,2
1Institut Curie Section recherche, Paris, France; 
2INSERM U932, Paris, France

Eukaryotic cells release different types of membrane vesicles into their extracellular environment that mediates communication with the surrounding cells. Among them, exosomes are small (30-100 nm) vesicles formed by inward budding inside the lumen of endosomes, which then fuse with the plasma membrane to release extracellularly their internal vesicles. Once released, exosomes can either bind to surface receptors and/or be internalized, or directly fuse with a target cell. Their cargo, including specific proteins, lipids and nucleic acids, can induce various forms of intracellular signalling, thus modifying the physiological state of the recipient cell in a very complex way.
The function of exosome secretion in the context of tumor development has been extensively studied in the past years. On the one hand, exosomes secreted by tumor cells can be captured by dendritic cells and induce anti-tumor immune responses. On the contrary, it has been shown that they can also actively suppress tumor-specific immune responses. Moreover, it has also been demonstrated that tumor derived exosomes can transfer angiogenic proteins or oncogenes from one cell to another, thus promoting tumorigenesis and metastasis.
Exosomes were found in several body fluids. In particular, numerous studies show that cancer patients have higher concentrations of circulating exosomes, a feature that correlates with disease progression. As these exosomes can carry tumor molecules, there has been an increasing interest in the study of circulating exosomes as a source of biomarkers in cancer patients. This was further sparked upon the discovery of mRNA and miRNA in exosomes. These nucleic acids are specifically loaded into the lumen of exosomes and can be then transferred to other cells regulating their gene expression. Several groups have detected an altered RNA cargo in body fluid-derived exosomes from patients with different diseases, strongly encouraging the use of exosomes as biomarkers for diagnosis and prognosis.
However, we want to stress that the actual nature of the vesicles analyzed is not always clearly demonstrated. Depending on the specific intracellular site of vesicle formation, their constitutive components differ from one type of vesicles to another and so the functions and the utility as biomarkers may be different. We have already shown that the vesicles obtained with the classical differential ultracentrifugation method are heterogeneous in their size, density, composition and biogenesis. More recently, we analyzed these vesicles in detail, using novel strategies to separate them and performed a side-by-side comparison of their protein composition. This allowed us to identify novel markers specific for the different vesicles secreted by a cell. In our opinion, this type of analysis should be done in different cell types in order to determine if all, or some, or none of these vesicles could be relevant as disease biomarkers.

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