Exosomes as a new frontier of cancer liquid biopsy

Abstract

Liquid biopsy, characterized by minimally invasive detection through biofluids such as blood, saliva, and urine, has emerged as a revolutionary strategy for cancer diagnosis and prognosis prediction. Exosomes are a subset of extracellular vesicles (EVs) that shuttle molecular cargoes from donor cells to recipient cells and play a crucial role in mediating intercellular communication. Increasing studies suggest that exosomes have a great promise to serve as novel biomarkers in liquid biopsy, since large quantities of exosomes are enriched in body fluids and are involved in numerous physiological and pathological processes. However, the further clinical application of exosomes has been greatly restrained by the lack of high-quality separation and component analysis methods. This review aims to provide a comprehensive overview on the conventional and novel technologies for exosome isolation, characterization and content detection. Additionally, the roles of exosomes serving as potential biomarkers in liquid biopsy for the diagnosis, treatment monitoring, and prognosis prediction of cancer are summarized. Finally, the prospects and challenges of applying exosome-based liquid biopsy to precision medicine are evaluated.

Keywords: Biomarker; Cancer; Exosome; Liquid biopsy; Precision medicine.

Fig. 1

Exosomes as a new target for liquid biopsy. Exosomes are enriched in body fluids and are critically involved in tumorigenesis, tumor progression and metastasis. Compared with CTC and ctDNA, exosomes show superior characteristics such as living-cell secreted vesicles, large amounts and stable circulation. Traditional and advanced technologies have been used to separate exosomes from various body fluids and to detect exosomal cargoes. The detection of specific molecules of exosome may provide a new strategy for cancer diagnosis, progression monitoring, and prognosis prediction

Fig. 2

The biogenesis, contents, and internalization of exosomes. Exosomes are vesicles derived from the fusion of multivesicular bodies with plasma membranes. Cytoplasmic contents of donor cells such as nucleic acids and proteins are sorted into exosomes and are delivered to recipient cells through the manner of endocytosis, phagocytosis, direct fusion or direct binding (receptor-ligand interaction)

Fig. 3

New technologies for the isolation of exosomes. A Immunoaffinity/ immunomagnetic enrichment. Copyright 2020 by Yang [58], 2017 by Kang [59], 2018 by Cai [60], 2020 by Sun [61]. B Physical feature-based separation. Copyright 2017 by Liu [62], 2019 by Sunkara V [63], 2019 by Hattori [64]. C Lipid mediated-separation. Copyright 2018 by Xu [65], 2021 by Jiang [66]. D Acoustic-based isolation / Thermophoretic enrichment. Copyright 2021 by Tayebi [67], 2019 by Liu [68], 2021 by Tian [69]

Fig. 4

Technologies for the characterization of exosomes. A Transmission electron microscopy. Copyright 2020 by Li [99]. B Cryo-electron microscopy. Copyright 2018 by Tian [97]. C Scanning electron microscopy. Copyright 2010 by Sharma [96]. D Atomic force microscopy. Copyright 2010 by Sharma [96]. E Dynamic light scattering. F Nanoparticle Tracking Analysis. G Tunable resistive pulse sensing

Fig. 5

New methods to detect the contents of exosomes. A Colorimetric detection. Copyright 2018 by Chen [110], 2020 by Di [112]. B Fluorescent detection. Copyright 2014 by He [36], 2018 by Jin [113]. C Electrochemical detection. Copyright 2020 by Cao [114]. 2020 by Kashefi-Kheyrabadi L [115]. D SPR/SERS detection. Copyright 2014 by Hyungsoon Im [116], 2020 by Dong [117]. E Single exosome detection. Copyright 2019 by Wang [118], 2019 by He [119]. F ddPCR. Copyright 2020 by Sun [61], 2021 by Liu [120]. G Molecular beacon., Copyright 2016 by Ji HyeLee [121], 2015 by Ji HyeLee [122]. H LSPR detection. Copyright 2021 by Wu [123]

Fig. 6

The application of exosomes in cancer liquid biopsy. Cancer-derived exosomes are enriched in differentially expressed proteins and nucleic acids, and have been tested as new biomarkers for the early diagnosis, stage classification, and prognosis prediction of different cancers, highlighting their important value in cancer liquid biopsy and precision medicine