Exosomal Non Coding RNAs (ncRNAs): Potential Tumor Biomarkers in Early Diagnosis

Exosomal ncRNAs have become one of the most promising categories of biomarkers for cancer detection. Exosomes, tiny capsules released by almost all cells, carry hundreds of biomolecules, including ncRNAs, which indicate the molecular position of their progenitor cells. Exosome-borne ncRNAs have opened up novel pathways to diagnosis for cancer by providing non-invasive, highly specific and cost-effective ways to measure biomarkers in body fluids.

What is Non Coding RNA?

Non-coding RNAs (ncRNAs) are non-coding RNA molecules that regulate gene expression at transcriptional, post-transcriptional and epigenetic levels. In contrast to messenger RNA (mRNA), which encodes proteins, ncRNAs regulate cell differentiation, apoptosis and proliferation, which are all essential for the biology of cancer. ncRNAs are classified in two general classes, small ncRNAs and long-lngRNAs. Microscopic ncRNAs, such as microRNAs (miRNAs), are involved in gene silencing and cell signalling, while lncRNAs are involved in chromatin remodelling, transcriptional control and cell signalling. These ncRNAs are present in exosomes and have proved invaluable for cancer biomarker-finding, especially in liquid biopsy.

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What are Exosomes?

Exosomes are extracellular vesicles, typically ranging from 30 to 150 nm in diameter, that are released into the extracellular environment by various cell types. These vesicles are formed inside the cell by inward budding of multivesicular bodies (MVBs), which then fuse with the plasma membrane to release the exosomes. Exosomes contain a variety of bioactive molecules, including proteins, lipids, and nucleic acids, such as RNA, DNA, and microRNAs, which are reflective of the molecular composition of their parent cells.

The illustration of a cell secreting exosomes.

Exosomes play critical roles in intercellular communication by transferring these bioactive molecules between cells, influencing various physiological and pathological processes, including immune response modulation, tumor progression, and metastasis. Their ability to cross biological barriers, including the blood-brain barrier, and their presence in all bodily fluids, including blood, urine, saliva, and cerebrospinal fluid, makes exosomes an ideal candidate for non-invasive biomarker discovery.

Exosome RNA

Exosomes play crucial roles in intercellular communication by transferring bioactive molecules, such as proteins, lipids, and nucleic acids, between cells. The RNA content of exosomes is reflective of the cellular state of the donor cell, providing insights into both normal physiological conditions and pathological states, such as cancer. Exosomal RNA, including both coding and non-coding RNA, is particularly stable, protected from degradation by RNases due to the lipid bilayer membrane encapsulating it. This stability, combined with their presence in easily accessible body fluids, makes exosomal RNAs ideal candidates for biomarker discovery in early cancer detection.

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Exosomal Non-Coding RNAs (ncRNAs)

Exosomal ncRNAs are non-coding RNA molecules encapsulated within exosomes. These include microRNAs (miRNAs), long non-coding RNAs (lncRNAs), circular RNAs (circRNAs), and other smaller RNA species. These ncRNAs are involved in regulating a variety of cellular processes, including cancer cell proliferation, migration, and metastasis, making them excellent candidates for use as tumor biomarkers. Their specific presence in exosomes offers several advantages in clinical diagnostics. Exosomal ncRNAs reflect not only the gene expression patterns of the originating tumor cells but also the broader tumor microenvironment, offering a more comprehensive picture of the disease state. As such, exosomal ncRNAs have shown great potential as biomarkers for early cancer diagnosis, prognosis, and therapeutic monitoring.

Types of Exosomal Non-Coding RNAs (ncRNAs)

Exosomal miRNAs

These are small RNA molecules, typically 20-24 nucleotides in length, that regulate gene expression by binding to complementary sequences on target mRNAs, leading to mRNA degradation or translation repression. miRNAs have been extensively studied in exosomes and have been found to be involved in regulating tumor initiation, progression, and metastasis. For example, exosomal miR-21 and miR-223 have been shown to be upregulated in various cancers, including breast cancer and gastric cancer.

Exosomal lncRNAs

These are longer RNA molecules (over 200 nucleotides) that do not encode proteins but have regulatory roles in gene expression. Exosomal lncRNAs, such as MALAT1, HOTAIR, and PCA3, are implicated in tumorigenesis and metastasis. The upregulation of lncRNAs like MALAT1 has been associated with poor prognosis in lung and breast cancers.

Exosomal circRNAs

These are a class of non-coding RNAs with a covalently closed loop structure, which confer resistance to exonuclease degradation. Exosomal circRNAs, such as circHIPK3, have been found to be differentially expressed in cancer and may serve as stable biomarkers in early detection.

Exosomal Piwi-Interacting RNAs (piRNAs)

Though less well understood, piRNAs in exosomes are emerging as potential regulators of tumor biology. These RNA species interact with Piwi proteins to regulate gene expression and suppress transposon activity, which could be crucial in maintaining genomic stability in cancer cells.

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Advantages of Exosomal ncRNAs as Tumor Biomarkers

Exosomal ncRNAs offer several advantages over traditional tumor biomarkers, making them highly attractive for early cancer detection:

• High Stability: Exosomal ncRNAs are highly stable in body fluids due to their encapsulation within exosomes, which protect them from enzymatic degradation. This stability is particularly advantageous for non-invasive cancer diagnostics, as it allows for reliable RNA detection in a variety of samples, including plasma, serum, saliva, and urine.
• Non-Invasive Collection: Exosomes are present in almost all body fluids, offering a non-invasive means of collecting diagnostic samples. Liquid biopsy, which involves the analysis of exosomal ncRNAs from plasma or serum, provides a less invasive alternative to tissue biopsies, reducing patient discomfort and risk.
• Tumor Specificity: Exosomal ncRNAs reflect the molecular characteristics of tumor cells, making them highly specific to cancer. Certain ncRNAs, such as miR-21 and MALAT1, have been shown to be upregulated in various types of cancers, including breast, lung, and colorectal cancers, offering the potential for early detection.
• Real-Time Monitoring: Exosomal ncRNAs offer the ability to monitor changes in tumor dynamics over time, making them ideal for monitoring treatment responses and detecting recurrence. The ability to track these changes in real-time is invaluable for personalized treatment strategies.
• Potential for Multicancer Detection: Certain exosomal ncRNAs may be useful for detecting multiple cancer types, allowing for the development of broader diagnostic panels. For example, miR-21 has been shown to be elevated in multiple cancers, making it a promising candidate for a universal cancer biomarker.

Exosomal Non Coding RNAs Detection

The detection of exosomal ncRNAs in clinical samples requires highly sensitive and specific techniques. Several methods have been developed to isolate, extract, and analyze exosomal RNA content.

Exosome Separation

Exosome separation from biological fluids can be achieved using a variety of methods, including ultracentrifugation, size exclusion chromatography, and immunocapture techniques. Ultracentrifugation is the gold standard for exosome isolation, but it is labor-intensive and may result in the co-isolation of non-exosomal contaminants. Size exclusion chromatography offers a more efficient and scalable approach for exosome isolation, while immunocapture methods, such as those using anti-CD63 antibodies, are highly specific but require the availability of exosome-specific markers.

Exosome RNA Extraction

Once exosomes are isolated, RNA extraction is typically performed using commercial RNA isolation kits optimized for low-abundance RNA species. Methods such as phenol-chloroform extraction, silica column-based extraction, and magnetic bead-based RNA isolation are commonly used. The high stability of exosomal RNA allows for the use of less invasive collection methods, such as saliva or urine samples, further enhancing the potential for liquid biopsy applications.

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Challenges of Exosomal Non-Coding RNAs Detection

• Low Abundance of Specific ncRNAs: Some exosomal ncRNAs are present in very low abundance, making their detection challenging. Sensitive amplification methods, such as quantitative PCR (qPCR) and droplet digital PCR (ddPCR), are necessary to detect these low-abundance molecules. However, biases in RNA extraction and amplification methods can affect the accuracy and reproducibility of results.
• Heterogeneity of Exosomal RNA: Exosomes exhibit significant heterogeneity in both their RNA content and their release from different cell types. This variability can complicate the interpretation of exosomal RNA profiles, particularly when attempting to correlate specific ncRNAs with particular cancer types.
• Standardization of Techniques: Currently, there is no universally accepted standard for exosome isolation, RNA extraction, or ncRNA detection. Variations in these techniques can lead to inconsistent results across different studies, hindering the development of reliable diagnostic tools.
• Complexity of ncRNA Profiles: Exosomal ncRNAs exist as complex and diverse populations, and the biological relevance of each species in the context of tumor biology is not yet fully understood. Further research is needed to delineate the precise roles of different ncRNAs and their potential as biomarkers.

Prospective Applications of Exosomal Non Coding RNAs as Tumor Biomarkers

The application of exosomal ncRNAs in early cancer diagnosis has the potential to revolutionize clinical oncology. These molecules can be used not only for detecting cancer at an early stage but also for monitoring disease progression, response to therapy, and recurrence.

• Early Detection of Cancer: The ability to detect cancer in its earliest stages is crucial for improving survival rates. Exosomal ncRNAs offer a promising avenue for detecting cancers before they become clinically apparent. For example, exosomal miR-21 and MALAT1 have shown promise as biomarkers for early-stage breast cancer, while miR-223 has been identified as a potential biomarker for gastric cancer.
• Monitoring Treatment Response: Exosomal ncRNAs can provide real-time insights into how a tumor is responding to treatment, enabling clinicians to make adjustments to therapeutic strategies. The dynamic changes in the levels of specific ncRNAs, such as miR-21, can offer valuable information regarding the efficacy of chemotherapy, immunotherapy, or targeted therapies.
• Detection of Minimal Residual Disease: Exosomal ncRNAs can be used to detect minimal residual disease, which is often associated with cancer recurrence. By monitoring the expression of specific ncRNAs over time, clinicians can identify signs of relapse before they are visible through traditional imaging techniques.

Exosomal ncRNAs represent a cutting-edge frontier in cancer diagnostics. With their stability, specificity, and abundance in bodily fluids, they offer enormous potential for the non-invasive early detection of cancer. Despite the challenges associated with their detection and characterization, advancements in exosome isolation and RNA analysis techniques continue to enhance their clinical utility. As the field progresses, exosomal ncRNAs are poised to become central components of personalized oncology, providing clinicians with powerful tools for early detection, monitoring, and treatment optimization.

Exosomal Non Coding RNAs (ncRNAs): Potential Tumor Biomarkers in Early Diagnosis

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