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Review
. 2022 Jul 10;14(14):3350.
doi: 10.3390/cancers14143350.

Circulating Exosome Cargoes Contain Functionally Diverse Cancer Biomarkers: From Biogenesis and Function to Purification and Potential Translational Utility

Megan I Mitchell  1 , Junfeng Ma  2 , Claire L Carter  1 , Olivier Loudig  1
Affiliations
Review

Circulating Exosome Cargoes Contain Functionally Diverse Cancer Biomarkers: From Biogenesis and Function to Purification and Potential Translational Utility

Megan I Mitchell et al. Cancers (Basel). .

Abstract

Although diagnostic and therapeutic treatments of cancer have tremendously improved over the past two decades, the indolent nature of its symptoms has made early detection challenging. Thus, inter-disciplinary (genomic, transcriptomic, proteomic, and lipidomic) research efforts have been focused on the non-invasive identification of unique "silver bullet" cancer biomarkers for the design of ultra-sensitive molecular diagnostic assays. Circulating tumor biomarkers, such as CTCs and ctDNAs, which are released by tumors in the circulation, have already demonstrated their clinical utility for the non-invasive detection of certain solid tumors. Considering that exosomes are actively produced by all cells, including tumor cells, and can be found in the circulation, they have been extensively assessed for their potential as a source of circulating cell-specific biomarkers. Exosomes are particularly appealing because they represent a stable and encapsulated reservoir of active biological compounds that may be useful for the non-invasive detection of cancer. T biogenesis of these extracellular vesicles is profoundly altered during carcinogenesis, but because they harbor unique or uniquely combined surface proteins, cancer biomarker studies have been focused on their purification from biofluids, for the analysis of their RNA, DNA, protein, and lipid cargoes. In this review, we evaluate the biogenesis of normal and cancer exosomes, provide extensive information on the state of the art, the current purification methods, and the technologies employed for genomic, transcriptomic, proteomic, and lipidomic evaluation of their cargoes. Our thorough examination of the literature highlights the current limitations and promising future of exosomes as a liquid biopsy for the identification of circulating tumor biomarkers.

Keywords: circulating biomarkers; early cancer detection; exosomes; extracellular vesicles; lipidomics; proteomics; transcriptomics.

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Conflict of interest statement

The authors declare no conflict of interest.

Figures

Figure 1
Figure 1
Exosomes and pre-metastatic niche formation. Exosomes released from primary tumors into the circulatory system specifically home to distant target organs (step 1). Upon their arrival, tumor-derived exosomes actively prepare the pre-metastatic niche through myofibroblast activation, induction of angiogenesis, and ECM remodeling (step 2). Local invasion of the primary tumor by cancer cells is followed by their intravasation into the tumor vasculature. These cancer cells survive and travel within the circulatory system, and upon their arrest in capillaries at distant sites, they extravasate into the parenchyma of target organs to commence metastatic colonization (step 3).
Figure 2
Figure 2
An estimate of the use of exosome isolation techniques over the past 10 years. Pie chart representation of the percentage utilization of each exosome isolation technique extracted from 173 publications spanning the years 2012–2022.
Figure 3
Figure 3
Exosome biogenesis. Exosomes originate from multivesicular bodies (MVBs) (also referred to as late endosomes). The inward budding of the late endosomal membrane around selectively packaged cargo results in the formation of exosomes. The selective packaging of proteins (e.g., tetraspanins, cytoplasmic proteins, and enzymes), nucleic acids (e.g., DNA, RNA, and miRNAs), and lipids (e.g., cholesterol) into exosomes is cell-type dependent and reflects the metabolic status of originating cells. Fusion of MVBs with either lysosomes or the plasma membrane results in either degradation or the release of exosomes into the extracellular matrix, respectively.
Figure 4
Figure 4
Endosomal sorting complexes required for transport (ESCRT)-dependent MVB formation. ESCRT-dependent MVB formation control the internalization of ubiquitinated proteins into the intraluminal vesicles (ILVs) of MVBs. The ESCRT complex is comprised of a series of sub-complexes which function uniformly during ILV production. ESCRT-0, -I, -II, and -III complexes function consecutively in a stepwise manner to control the selective sorting of ubiquitinated proteins into exosomes.
Figure 5
Figure 5
Syndecan–syntenin–ALIX couples to ESCRT-dependent MVB formation in healthy versus cancer cells. Syntenin-1 interacts directly with syndecans and ALIX, the interaction of ALIX with Snf7 of the ESCRT-III complex forms the syndecan–syntenin–ALIX pathway which is directly linked to exosome biogenesis. In cancer, several proteins in this pathway are altered, leading to enhanced exosome production. Alterations leading to the upregulation of either the syndecans, ALIX, and/or CD90 all result in enhanced exosome production, whereas any alterations leading to the downregulation of the ESCRT-III protein Vsp4 A/B and/or CD63 results in the increased production of exosomes seen in cancer cells.
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