Exosomal MiRNAs in Osteosarcoma: Biogenesis and Biological Functions
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Abstract:
MiRNAs are a group of non-coding RNA molecules that function in mRNA translational inhibition via base-pairing with complementary sequences in target mRNA. In oncology, miRNAs have raised great attention due to their aberrant expression and pivotal roles in the pathogenesis of multiple malignancies including osteosarcoma. MiRNAs can be transported by exosome, the nano-extracellular vesicle with a diameter of 30–150 nm. Recently, a growing number of studies have demonstrated that exosomal miRNAs play a critical role in tumor initiation and progression, by exerting multiple biological functions including metastasis, angiogenesis, drug resistance and immunosuppression. In this review, we aim to depict the biogenesis of exosomal miRNAs and summarize the potential diagnostic and therapeutic functions of exosomal miRNAs in osteosarcoma.Keywords:
Exosome
Exosomes are the most important intercellular communicators. Tetraspanins/their complexes are suggested to be important in exosomal target cell selection. I showed: changes in Tetraspanin8 associations created from internalization persist upto exosomes and, differences in tetraspanin-complexes on exosomes allow for target cell selectivity.Based on the tetraspanin-complex on exosomes, predictions on potential target cells might be possible, allowing tailored exosome generation for drug delivery.
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To understand the physiological functions of exosomes, we have recently used the inhibition of Rab27a, which prevents exosome release but also alters other secretion pathways. Our work demonstrates that the secretion of exosomes by some tumors in vivo can influence the immune microenvironment to promote tumor progression, but also that this phenomenon cannot be generalized to all tumors and all exosomes.
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Exosomes are extracellular nanovesicles that mediate a number of cellular processes, including intracellular signalling. There are many published examples of exosome-exosome dimers; however, their relevance has not been explored. Here, we propose that cells release exosomes to physically interact with incoming exosomes, forming dimers that we hypothesize attenuate incoming exosome-mediated signalling. We discuss experiments to test this hypothesis and potential relevance in health and disease.
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Exosomes are extracellular vesicles (EVs) of nanometric size studied for their role in tumor pathogenesis and progression and as a new source of tumor biomarkers. The clinical studies have provided encouraging but probably unexpected results, including the exosome plasmatic levels’ clinical relevance and well-known biomarkers’ overexpression on the circulating EVs. The technical approach to obtaining EVs includes methods to physically purify EVs and characterize EVs, such as Nanosight Tracking Analysis (NTA), immunocapture-based ELISA, and nano-scale flow cytometry. Based on the above approaches, some clinical investigations have been performed on patients with different tumors, providing exciting and promising results. Here we emphasize data showing that exosome plasmatic levels are consistently higher in tumor patients than in controls and that plasmatic exosomes express well-known tumor markers (e.g., PSA and CEA), proteins with enzymatic activity, and nucleic acids. However, we also know that tumor microenvironment acidity is a key factor in influencing both the amount and the characteristics of the exosome released by tumor cells. In fact, acidity significantly increases exosome release by tumor cells, which correlates with the number of exosomes that circulate through the body of a tumor patient.
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Saliva is a useful biofluid for the early detection of disease, but how distal tumors communicate with the oral cavity and create disease-specific salivary biomarkers remains unclear. Using an in vitro breast cancer model, we demonstrated that breast cancer-derived exosome-like microvesicles are capable of interacting with salivary gland cells, altering the composition of their secreted exosome-like microvesicles. We found that the salivary gland cells secreted exosome-like microvesicles encapsulating both protein and mRNA. We also showed that the interaction with breast cancer-derived exosome-like microvesicles communicated and activated the transcriptional machinery of the salivary gland cells. Thus, the interaction altered the composition of the salivary gland cell-derived exosome-like microvesicles on both the transcriptomically and proteomically.
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Exosomes, as nanoscale biological vesicles, have been shown to have great potential for biomedical applications. However, the low yield of exosomes limits their application. In this review, we focus on methods to increase exosome yield. Two main strategies are used to increase exosome production, one is based on genetic manipulation of the exosome biogenesis and release pathway, and the other is by pretreating parent cells, changing the culture method or adding different components to the medium. By applying these strategies, exosomes can be produced on a large scale to facilitate their practical application in the clinic.
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Exosomes are nanometer-sized vesicles secreted by a diverse range of live cells that probably have physiological roles in modulating cellular immunity. The extracellular factors that regulate the quantity and phenotype of exosomes produced are poorly understood, and the properties of exosomes that dictate their immune functions are not yet clear. We investigated the effect of cellular stress on the exosomes produced by B-lymphoblastoid cell lines. Under steady-state conditions, the exosomes were positive for hsp27, hsc70, hsp70 and hsp90, and other recognised exosome markers such as MHC class I, CD81, and LAMP-2. Exposing cells to heat stress (42 degrees C for up to 3 hours), resulted in a marked increase in these heat shock proteins (hsps), while the expression of other stress proteins such as hsp60 and gp96 remained negative, and other exosome markers remained unchanged. Stress also triggered a small increase in the quantity of exosomes produced [with a ratio of 1.245+/-0.07 to 1 (mean+/-s.e.m., n=20) of 3-hour-stress-exosomes to control-exosomes]. Flow-cytometric analysis of exosome-coated beads and immuno-precipitation of intact exosomes demonstrated that hsps were located within the exosome lumen, and not present at the exosome-surface, suggesting that such exosomes may not interact with target cells through cell-surface hsp-receptors. Functional studies further supported this finding, in that exosomes from control or heat-stressed B cells did not trigger dendritic cell maturation, assessed by analysis of dendritic-cell-surface phenotype, and cytokine secretion profile. Our findings demonstrate that specific alterations in exosome phenotype are a hitherto unknown component of the cellular response to environmental stress and their extracellular function does not involve the direct activation of dendritic cells.
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Exosomes are generated by the multivesicular degradation of plasma membrane fusion, lysosomal, and extracellular release of intracellular vesicles. The exosome ranges from 30 to 150 nm in size. Exosomes are “bioactive vesicles” that promote intercellular communication. Exosomes contain a variety of biologically active substances packaged with proteins, lipids, and nucleic acids. After any microbe infection into the exosomes, the content of the exosomes changes and is released into the bloodstream. Such type of exosome content could be useful for basic research on exosome biology. Tuberculosis (TB) is a serious infectious disease caused by Mycobacterium tuberculosis (Mtb). During the Mtb infection, the exosomes played an important role in the body’s infection and immune response by releasing several exosome components providing new ideas for diagnosis, prevention, and therapeutic treatment of Mtb infection. The detection of the low abundance of the Mtb numbers or secreted peptides in the serum of TB patients is not possible. The best way of findings for diagnosis and treatment of TB could be possible by the exploration of exosome content analysis through various useful technologies. The study and analysis of exosome content would produce a road map for the future early diagnosis, prognosis estimation, efficacy monitoring, research, and application for TB.
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