Using exosomes for identifying and monitoring diseases

In healthcare, early and correct identification of disease is important for obtaining appropriate treatment. An emerging and exciting field of research in diagnostics is studying exosomes and their contents.

Exosomes are a class of extracellular vesicle involved in the transportation of material from cell to cell. Ranging from approximately 50 to 150 nm in diameter, exosomes are natural nanoparticle biovehicles, carrying a diverse range of payloads including proteins, metabolites, and nucleic acids. As a result, exosomes play an important role in modulating microenvironments in both local and distant tissues (1). Exosomal proteins and nucleic acids are currently the subject of biomarker discovery research and are showing their potential for use in clinical diagnosis and disease monitoring.

In this blog, we review some of the current efforts to identify exosomal biomarkers of disease, describe how these biomarkers can be developed into valuable diagnostic tools, and consider future prospects for exosomes in research and clinical practice.

The role of exosomes in cancer progression

Tumor cells generally produce more exosomes than normal cells (2), and research shows that exosome derived from cancer cells play active roles in tumorigenesis, metastasis, and response to therapy through a combination of autocrine and paracrine signaling. Exosomes facilitate cancer progression by transferring RNA, miRNA, proteins, DNA, and metabolites between cancer cells and between cancer cells and the tumor stroma.

The material transferred by exosomes acts as stimuli for the recipient cells, modifying intracellular and extracellular signaling pathways, which create and maintain a microenvironment where cancer can thrive.

Material from cancerous cells transported by exosomes can activate receptors or change RNA expression in the neighboring cancer cells to alter their biological phenotypes. Such changes have been found to promote tumor aggressiveness, drug resistance, and angiogenesis among other things, thereby actively facilitating disease progression (3).

Exosomes as novel biomarkers of cancer

Exosomal molecules are especially well-suited as diagnostic biomarkers because they remain stable for long periods and are easily detected in body fluids, such as blood, urine, saliva, and cerebrospinal fluid. As a result, exosomes are noninvasive options for biomarker extraction by liquid biopsy.

However, no simple “one-size fits all” exists with cancer biomarkers. Applying exosome biomarkers to cancer diagnosis requires high sensitivity and specificity because cancer heterogeneity means exosome biomarkers are usually highly specific.

Thus, exosome biomarkers for cancer are not easy to identify, but researchers have already had some successes.

Glyplican-1 in pancreatic cancer

One exosomal protein found in serum, the cell surface protein glypican-1 (GPC1), is a strong biomarker for pancreatic cancer (4). In fact, GPC1 detection is more sensitive than the commonly tested pancreatic cancer biomarker, CA19-9, because GPC1 detection can distinguish between pancreatic cancer patients and patients with benign pancreatic disease.

RNA screening test for prostate cancer

Another example of an effective exosomal biomarker for cancer in clinical use is the urine exosome gene expression assay for prostate cancer (5). This assay detects RNA expression of several genes with known roles in prostate cancer.

As a screening tool, the urine exosome gene expression assay result, combined with standard clinical data, can accurately identify patients with prostate cancer at multiple stages of disease, reducing the number of biopsies needed.

Read more about liquid biopsies for cancer diagnosis here

Other exosome biomarker applications

Aside from potential applications in cancer diagnosis, the simplicity of extracting exosomes from liquid biopsy has prompted research into their use as biomarkers of various other pathologies.

A prime example of this is exosomal amyloid peptides and tau protein, which are known to accumulate in the brain plaques of Alzheimer’s disease (AD) patients. Both are detectable at elevated levels in exosomes from cerebrospinal fluid of AD patents; even those with very mild symptoms (6).

Identifying AD and other neurodegenerative diseases early is vital to slowing disease progression with appropriate treatment, and liquid biopsy of exosomal proteins shows great potential as an early diagnostic tool.

Another interesting avenue is the prospect of using exosome biomarkers to monitor prenatal physiology and pathophysiology, potentially enabling clinicians to detect pregnancy complications and fetal developmental disorders.

Maternal peripheral blood contains a variety of factors that reflect the health of the fetus, and several exosomal miRNAs have been identified for a range of fetal conditions including gestational hypertension, diabetes, premature delivery, Down syndrome, congenital heart defects, and neural tube defects (7).

Given the current lack of biomarkers with early predictive value for congenital conditions, exosomal biomarkers represent a valuable noninvasive tool for early diagnosis of pregnancy-related conditions.

Future challenges and prospects of exosomes

Despite exosome biomarkers showing promise in research settings, only a few have broken through as clinical diagnostic tools. This fact shows that we’re still in the preliminary discovery and development stage of using exosomes in diagnostics and that challenges still need to be understood and overcome.

One of the main obstacles is the difficulty of isolating exosomes and their contents. Traditionally, exosomal isolation meant using ultracentrifugation, a time-consuming and laborious process that requires expensive equipment, which is less suited to clinical diagnostics.

Now though, exosomal proteins and nucleic acids can be isolated by in-house precipitation using commercial reagents. For example, the Sera-Xtracta™ Cell-Free DNA Kit from Cytiva enables the rapid isolation of cell-free DNA from easily accessible biofluids such as plasma, serum, and urine.

With the demand for a less invasive approach to diagnostics using liquid biopsies, exosomal biomarker research is set to accelerate. As such, technical advancements in their isolation and kits for isolating other exosomal payloads, which make exosome biomarker research more viable and cost-efficient, are around the corner.

In the future, a deeper understanding of the mechanisms behind exosome and extracellular vesicle roles in pathophysiology will enable researchers to expand their applications in the clinic and as diagnostic tools. Because exosomes are also found in a range of pathological microorganisms including bacteria, eukaryotic parasites, and fungal pathogens, many other diagnostic possibilities can be explored.

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