Circulating microvesicle

Circulating microvesicle

The identification of small, membrane-bound vesicles has opened a new era in the understanding of cell signaling and the process of molecular communication between cells. Human body fluids contain small, membrane-bound exosomes and larger vesicular bodies, collectively referred to as circulating microvesicles (cMVs). cMVs are released by a number of cell types during cellular activation and apoptosis. Although a consistent and precise definition is still lacking, cMVs are generally considered to be a heterogeneous population of small, membrane-covered vesicles whose diameter ranges from 50-1,000 nanometers(nm).[1][2]


Circulating Microvesicle Formation and Purpose

cMVs, which were originally considered cellular debris, are now recognized as a heterogeneous population of membrane-bound vesicles that varies in cellular origin, number, size, and composition.[citation needed]

Process of Formation

Microvesicles and exosomes are formed and released by two slightly different mechanisms. These processes result in the release of intercellular signaling vesicles. Microvesicles are small, plasma-membrane-derived particles that are released into the extracellular environment by the outward budding and fission of the plasma membrane. This budding process involves multiple signaling pathways including the elevation of intracellular calcium and reorganization of the cell's structural scaffolding. The formation and release of microvesicles involves contractile machinery that draws opposing membranes together before pinching off the membrane connection and launching the vesicle into the extracellular space.[1][2][3]

Microvesicle budding takes place at unique locations on the cell membrane that are enriched with specific lipids and proteins reflecting their cellular origin. At these locations, proteins, lipids, and nucleic acids are selectively incorporated into microvesicles and released into the surrounding environment.[2]

Exosomes are preformed, membrane-covered vesicles that are smaller than 150 nm. In contrast to microvesicles, which are formed through a process of membrane budding, or exocytosis, exosomes are initially formed by endocytosis. Exosomes are formed by invagination within a cell to create an intracellular vesicle called an endosome, or an endocytic vesicle. In general, exosomes are formed by segregating the cargo (e.g., lipids, proteins, and nucleic acids) within the endosome. Once formed, the endosome combines with a structure known as a multivesicular body (MVB). The MVB containing segregated endosomes ultimately fuses with the plasma membrane, resulting in exocytosis of the exosomes.[3][4]

Once formed, both microvesicles and exosomes (collectively called cMVs) circulate in the extracellular space near the site of release, where they can be taken up by other cells or gradually deteriorate. In addition, some vesicles migrate significant distances by diffusion, ultimately appearing in biological fluids such as cerebrospinal fluid, blood, and urine.[3]

The Molecular Content of cMVs

The lipid and protein content of cMVs has been analyzed using various biochemical techniques. cMVs display a spectrum of molecules enclosed within the vesicles and their plasma membranes. Both the membrane molecular pattern and the internal contents of the vesicle depend on the cellular origin and the molecular processes triggering their formation. Because cMVs are not intact cells, they do not contain mitochondria, Golgi, endoplasmic reticulum, or a nucleus with its associated DNA.[4][5]

cMV membranes consist mainly of lipids and proteins. Regardless of their cell type of origin, nearly all cMVs contain proteins involved in membrane transport and fusion. They are surrounded by a phopholipid bilayer composed of several different lipid molecules. The protein content of each cMV reflects the origin of the cell from which it was released. For example, those released from antigen-presenting cells (APCs), such as B cells and dendritic cells, are enriched in proteins necessary for adaptive immunity, while cMVs released from tumors contain proapoptotic molecules and oncogenic receptors (e.g. EGFR).[4]

In addition to the proteins specific to the cell type of origin, some proteins are common to most cMVs. For example, nearly all contain the cytoplasmic proteins tubulin, actin and actin-binding proteins, as well as many proteins involved in signal transduction, cell structure and motility, and transcription. Most cMVs contain the so-called "heat-shock proteins" hsp-70 and hsp-90, which can facilitate interactions with cells of the immune system. Finally, tetraspanin proteins, including CD9, CD37, CD63 and CD81 are one of the most abundant protein families found in cMV membranes.[4][5][6][7]

Other than lipids and proteins, recent studies have also shown that cMVs are enriched with nucleic acids (e.g., messenger RNA [mRNA] and microRNA [miRNA]). The identification of RNA molecules in cMVs supports the hypothesis that they are a biological vehicle for the transfer of nucleic acids and subsequently modulate the target cell's protein synthesis. Messenger RNA transported from one cell to another through cMVs can be translated into proteins, conferring new function to the target cell[7]. The discovery that cMVs may shuttle specific mRNA and miRNA suggests that this may be a new mechanism of genetic exchange between cells.[7][8] Recently, it was also shown that exosomes produced by cells exposed to oxidative stress can mediate protective signals, reducing oxidative stress in recipient cells, a process which is proposed to depend on exosomal RNA transfer.[9]

Proteins associated with diseases such as kidney disease and prostate cancer have also been detected in cMVs, suggesting potential clinical utility.[7][10] In fact, biochemical studies on cMVs have generated an expansive list of molecular signatures, demonstrating valuable potential for the diagnostic, prognostic and predictive use of cMVs.[11]

Because the specific proteins, mRNAs, and miRNAs in CMVs are highly variable, it is likely that these molecules are specifically packaged into vesicles using an active sorting mechanism. At this point, it is unclear exactly which mechanisms are involved in packaging soluble proteins and nucleic acids into cMVs.[2][10]

Potential Effects on Neighboring Cells

Once released from their cell of origin. cMVs interact specifically with cells they recognize by binding to cell-type specific, membrane-bound receptors. Because cMVs contain a variety of surface molecules, they provide a mechanism for engaging different cell receptors and exchanging material between cells. This interaction ultimately leads to fusion with the target cell and release of the vesicles' components, thereby transferring bioactive molecules, lipids, genetic material, and proteins. The transfer of cMV components includes specific mRNAs and proteins, contributing to the proteomic properties of target cells.[12] cMVs can also transfer miRNAs that are known to regulate gene expression by altering mRNA turnover.[2][3][5][13]

Recently, many aspects of cancer progression have been linked to the increased release of cMVs. Tumor-associated cMVs have a number of effects on neighboring cells and have been correlated with cancer progression, promotion of angiogenesis, and acquisition of aggressive phenotypes (e.g. promoting malignancy) and multidrug resistance. By harnessing specific bioactive molecules such as proteins, RNAs, and miRNAs , and facilitating the cell-to-cell transfer of their cargo, tumor-associated cMVs can affect a variety of cellular events that significantly impact tumor progression.[1][2]

Promoting Aggressive Tumor Phenotypes

The oncogenic receptor ECGFvIII, which is located in a specific type of aggressive glioma tumor, can be transferred to a non-aggressive population of tumor cells via cMVs. After the oncogenic protein is transferred, the recipient cells become transformed and show characteristic changes in the expression levels of target genes. It is possible that transfer of other mutant oncogenes, such as HER2, may be a general mechanism by which malignant cells cause cancer growth at distant sites.[2][13]

Promoting Angiogenesis

Angiogenesis, which is essential for tumor survival and growth, occurs when endothelial cells proliferate to create a matrix of blood vessels that infiltrate the tumor, supplying the nutrients and oxygen necessary for tumor growth. A number of reports have demonstrated that tumor-associated cMVs release proangiogenic factors that promote endothelial cells proliferation, angiogenesis, and tumor growth. cMVs shed by tumor cells and taken up by endothelial cells also facilitate angiogenic effects by transferring specific mRNAs and miRNAs.[3]

Involvement In Multidrug Resistance

When anticancer drugs such as doxorubicin accumulate in cMVs, the drug's cellular levels decrease. This can ultimately contribute to the process of drug resistance. Similar processes have been demonstrated in cMVs released from cisplatin-insensitive cancer cells. Vesicles from these tumors contained nearly three times more cisplatin than those released from cisplatin-sensitive cells. For example, tumor cells can accumulate drugs into cMVs. Subsequently, the drug-containing cMVs are released from the cell into the extracellular environment, thereby mediating resistance to chemotherapeutic agents and resulting in significantly increased tumor growth, survival, and metastasis.[2][14]

Interference With Antitumor Immunity

cMVs from various tumor types can express specific cell-surface molecules (e.g. FasL or CD95) that induce T-cell apoptosis and reduce the effectiveness of other immune cells. cMVs released from lymphoblastoma cells express the immune-suppressing protein latent membrane protein-1 (LMP-1), which inhibits T-cell proliferation and prevents the removal of circulating tumor cells (CTCs). As a consequence, tumor cells can turn off T-cell responses or eliminate the antitumor immune cells altogether by releasing cMVs.[2]

Impact on Tumor Metastasis

Degradation of the extracellular matrix is a critical step in promoting tumor growth and metastasis. Tumor-derived cmVs often carry protein-degrading enzymes, including matrix metalloproteinase (MMP)-2, MMP-9, and urokinase-type plasminogen activator (uPA). By releasing these proteases, tumor cells can degrade the extracellular matrix and invade surrounding tissues. Likewise, inhibiting MMP-2, MMP-9, and uPA prevents cMVs from facilitating tumor metastasis. Matrix digestion can also facilitate angiogenesis, which is important for tumor growth and is induced by the horizontal transfer of RNAs from microvesicles.[2]

Potential Role in Cancer Detection

Tumor-associated cMVs are abundant in the blood, urine, and other body fluids of patients with cancer, and are likely involved in tumor progression. They offer a unique opportunity to noninvasively access the wealth of biological information related to their cells of origin. The quantity and molecular composition of cMVs released from malignant cells varies considerably compared with those released from normal cells. Thus, the concentration of plasma cMVs with molecular markers indicative of the disease state may be used as an informative blood-based biosignature for diseases such as cancer.[1]

Role of cMVs in Clinical Trials

Analysis of cMVs in investigational drug trials will likely offer promising benefits to cancer patients and clinical scientists. For instance, analysis of tumor-associated cMVs could help investigators track and monitor patients' clinical responses to therapy during the course of a trial. With this information, clinicians would be able to provide their patients with more timely therapeutic decisions. Furthermore, the potential exists for specific subpopulations of tumor-associated cMVs to help clinical researchers determine and define therapeutic responders versus non-responders.[citation needed]

Additionally as already noted, cMVs contain a unique population of biomarkers including proteins, miRNA and mRNA. There is the real potential to use circulating cMVs as a tool to measure, monitor or identify specific biomarkers of interest.[citation needed]

Role of cMVs in Clinical Practice

cMVs express many membrane-bound proteins, some of which can be used as tumor biomarkers. Several tumor markers accessible as proteins in blood or urine have been used to screen and diagnose various types of cancer. In general, tumor markers are produced either by the tumor itself or by the body in response to the presence of cancer or some inflammatory conditions. If a tumor marker level is higher than normal, the patient is examined more closely to look for cancer or other conditions. For example, CA-19.9, CA-125, and CEA have been used to help diagnose pancreatic, ovarian, and gastrointestinal malignancies, respectively. However, although they have proven clinical utility, none of these tumor markers are highly sensitive or specific. Clinical research data suggests that tumor-specific markers exposed on cMVs are useful as a clinical tool to diagnose and monitor disease. Research is also ongoing to determine if tumor-specific markers exposed on cMVs are predictive for therapeutic response.[15][16][17][18]

Relevance in Other Disease Conditions

The release of cMVs has been shown from endothelial cells, vascular smooth muscle cells, platelets, white blood cells (e.g. leukocytes and lymphocytes), and red blood cells. Although some of these cMV populations occur in the blood of health individuals and patients, there are obvious changes in number, cellular origin, and composition in various disease states.[19]

It has become increasingly clear that cMVs play important roles in regulating the cellular processes that lead to disease pathogenesis. Moreover, because cMVs are released following apoptosis or cell activation, they have the potential to induce or amplify disease processes. Some of the inflammatory and pathological conditions that cMVs are involved in include cardiovascular disease, hypertension, neurodegenerative disorders, diabetes, and rheumatic diseases.[3][4]

Circulating Microvesicle Diagnostic Technology

Caris Life Sciences has developed a technology platform for the capture and profiling of circulating microvesicles from the blood. Caris notes their Carisome technology has tremendous potential across a broad array of clinical testing opportunities in the diagnosis, prognosis and therapeutic response (predictive) in complex diseases like cancer. Furthermore, they note the technology also has significant utility in investigational drug trials within the biopharmaceutical industry.[20]

Caris Life Sciences is currently developing a cMV based prostate cancer diagnostic test called Carisome Prostate cMV 1.0.[20]

Video: The Science of Circulating Microvesicles


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