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MicroRNAs transported by exosomes in body fluids as mediators of intercellular communication in cancer.

Salido-Guadarrama I, Romero-Cordoba S, Peralta-Zaragoza O, Hidalgo-Miranda A, Rodríguez-Dorantes M - Onco Targets Ther (2014)

Bottom Line: Cancer-cell communication is an important and complex process, achieved through a diversity of mechanisms that allows tumor cells to mold and influence their environment.In recent years, evidence has accumulated indicating that cells communicate via the release and delivery of microRNAs (miRNAs) packed into tumor-released (TR) exosomes.In this review, we focus on miRNAs secreted via TR exosomes, which by acting in a paracrine or endocrine manner, facilitate a diversity of signaling mechanisms between cancer cells.

View Article: PubMed Central - PubMed

Affiliation: Oncogenomics Laboratory, National Institute of Genomics Medicine, Mexico City, Mexico.

ABSTRACT
Cancer-cell communication is an important and complex process, achieved through a diversity of mechanisms that allows tumor cells to mold and influence their environment. In recent years, evidence has accumulated indicating that cells communicate via the release and delivery of microRNAs (miRNAs) packed into tumor-released (TR) exosomes. Understanding the role and mode of action of miRNAs from TR exosomes is of paramount importance in the field of cancer biomarker discovery and for the development of new biomedical applications for cancer therapeutics. In this review, we focus on miRNAs secreted via TR exosomes, which by acting in a paracrine or endocrine manner, facilitate a diversity of signaling mechanisms between cancer cells. We address their contribution as signaling molecules, to the establishment, maintenance, and enhancement of the tumor microenvironment and the metastatic niche in cancer. Finally, we address the potential role of these molecules as biomarkers in cancer diagnosis and prognosis and their impact as a biomedical tool in cancer therapeutics.

No MeSH data available.


Related in: MedlinePlus

Molecular approaches for the use of miRNAs derived from TR exosomes as therapeutic tools.Notes: Exosomes are ideal delivery systems that can be manipulated for the administration of specific molecules such as synthetic miRNAs or anti-miRNAs. (A) Synthetic miRNAs may be transfected into an exosome-producing cell (eg, mesenchymal stem cell). Transfected miRNAs are released and delivered to the recipient cell via exosomes. Once they reach the recipient cell, synthetic miRNAs bind and arrest the translation of their canonical target transcripts (1). MiRNAs can also act like ligands to activate membrane surface receptors (2). (B) In a similar strategy, anti-miRNA molecules are transfected into exosome-producing cells, where they reduce the levels of endogenous miRNAs in the donor cell, thus diminishing the amount of miRNAs transferred to the recipient cells. (C) Alternatively, anti-miRNA molecules can be directly transduced into exosomes and delivered to the recipient cell, where they prevent miRNAs from silencing their cognate mRNA. In a similar fashion, siRNA molecules can be employed to downregulate mRNA targets.Abbreviations: miRNA, microRNA; mRNA, messenger RNA; MVB, multivesicular body; RISC, RNA-induced silencing complex; siRNA, short interfering RNA; TLR, toll-like receptor; TR, tumor-released; UTR, untranslated region.
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f3-ott-7-1327: Molecular approaches for the use of miRNAs derived from TR exosomes as therapeutic tools.Notes: Exosomes are ideal delivery systems that can be manipulated for the administration of specific molecules such as synthetic miRNAs or anti-miRNAs. (A) Synthetic miRNAs may be transfected into an exosome-producing cell (eg, mesenchymal stem cell). Transfected miRNAs are released and delivered to the recipient cell via exosomes. Once they reach the recipient cell, synthetic miRNAs bind and arrest the translation of their canonical target transcripts (1). MiRNAs can also act like ligands to activate membrane surface receptors (2). (B) In a similar strategy, anti-miRNA molecules are transfected into exosome-producing cells, where they reduce the levels of endogenous miRNAs in the donor cell, thus diminishing the amount of miRNAs transferred to the recipient cells. (C) Alternatively, anti-miRNA molecules can be directly transduced into exosomes and delivered to the recipient cell, where they prevent miRNAs from silencing their cognate mRNA. In a similar fashion, siRNA molecules can be employed to downregulate mRNA targets.Abbreviations: miRNA, microRNA; mRNA, messenger RNA; MVB, multivesicular body; RISC, RNA-induced silencing complex; siRNA, short interfering RNA; TLR, toll-like receptor; TR, tumor-released; UTR, untranslated region.

Mentions: Because of their small size and ability to cross biological membranes and protect their mRNA, miRNA, and protein cargo from degradation, exosomes are ideal delivery systems that can be manipulated for the transfer of specific molecules such as miRNAs or anti-miRNAs (Figure 3). In an attempt to block miR-9, which is overexpressed in GBM cells and impairs the response to temozolomide, Munoz et al107 refined a method for the delivery of an anti-miR-9 molecule from mesenchymal stem cells (MSCs) via release of exosome-type microvesicles. They demonstrated that anti-miR-9 was transferred from MSCs to GBM cells. The delivery of anti-miR-9 to the resistant GBM cells reversed the expression of the multidrug transporter and sensitized the GBM cells to temozolomide, as shown by increased cell death and caspase activity, thus illustrating a potential role for MSCs in the functional delivery of synthetic anti-miR-9 to reverse chemoresistance of GBM cells.107 To reinforce the evidence that TR exosomes can serve as vehicles for the delivery of synthetic miRNAs or miRNA inhibitors, a proof of concept study tested whether MSC exosomes could be used as a vehicle for delivery of anti-tumor miRNAs. A miR-146b expression plasmid was transfected into MSCs, and exosomes released by the transfected MSCs were harvested. The study found that intra-tumoral injection of exosomes derived from miR-146-expressing MSCs significantly reduced glioma xenograft growth in a rat model of a primary brain tumor.108 Various approaches have made use of TR exosomes as immune modulators.109,110 However, to our knowledge none of these works have specifically demonstrated the participation of the miRNAs contained in the TR exosomes as modulator molecules in the communication process that influences the immune cell response. Nevertheless, it is highly plausible that miRNA cargo from TR exosomes somehow regulates and helps to reprogram the immune response in cancer.111


MicroRNAs transported by exosomes in body fluids as mediators of intercellular communication in cancer.

Salido-Guadarrama I, Romero-Cordoba S, Peralta-Zaragoza O, Hidalgo-Miranda A, Rodríguez-Dorantes M - Onco Targets Ther (2014)

Molecular approaches for the use of miRNAs derived from TR exosomes as therapeutic tools.Notes: Exosomes are ideal delivery systems that can be manipulated for the administration of specific molecules such as synthetic miRNAs or anti-miRNAs. (A) Synthetic miRNAs may be transfected into an exosome-producing cell (eg, mesenchymal stem cell). Transfected miRNAs are released and delivered to the recipient cell via exosomes. Once they reach the recipient cell, synthetic miRNAs bind and arrest the translation of their canonical target transcripts (1). MiRNAs can also act like ligands to activate membrane surface receptors (2). (B) In a similar strategy, anti-miRNA molecules are transfected into exosome-producing cells, where they reduce the levels of endogenous miRNAs in the donor cell, thus diminishing the amount of miRNAs transferred to the recipient cells. (C) Alternatively, anti-miRNA molecules can be directly transduced into exosomes and delivered to the recipient cell, where they prevent miRNAs from silencing their cognate mRNA. In a similar fashion, siRNA molecules can be employed to downregulate mRNA targets.Abbreviations: miRNA, microRNA; mRNA, messenger RNA; MVB, multivesicular body; RISC, RNA-induced silencing complex; siRNA, short interfering RNA; TLR, toll-like receptor; TR, tumor-released; UTR, untranslated region.
© Copyright Policy
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC4114916&req=5

f3-ott-7-1327: Molecular approaches for the use of miRNAs derived from TR exosomes as therapeutic tools.Notes: Exosomes are ideal delivery systems that can be manipulated for the administration of specific molecules such as synthetic miRNAs or anti-miRNAs. (A) Synthetic miRNAs may be transfected into an exosome-producing cell (eg, mesenchymal stem cell). Transfected miRNAs are released and delivered to the recipient cell via exosomes. Once they reach the recipient cell, synthetic miRNAs bind and arrest the translation of their canonical target transcripts (1). MiRNAs can also act like ligands to activate membrane surface receptors (2). (B) In a similar strategy, anti-miRNA molecules are transfected into exosome-producing cells, where they reduce the levels of endogenous miRNAs in the donor cell, thus diminishing the amount of miRNAs transferred to the recipient cells. (C) Alternatively, anti-miRNA molecules can be directly transduced into exosomes and delivered to the recipient cell, where they prevent miRNAs from silencing their cognate mRNA. In a similar fashion, siRNA molecules can be employed to downregulate mRNA targets.Abbreviations: miRNA, microRNA; mRNA, messenger RNA; MVB, multivesicular body; RISC, RNA-induced silencing complex; siRNA, short interfering RNA; TLR, toll-like receptor; TR, tumor-released; UTR, untranslated region.
Mentions: Because of their small size and ability to cross biological membranes and protect their mRNA, miRNA, and protein cargo from degradation, exosomes are ideal delivery systems that can be manipulated for the transfer of specific molecules such as miRNAs or anti-miRNAs (Figure 3). In an attempt to block miR-9, which is overexpressed in GBM cells and impairs the response to temozolomide, Munoz et al107 refined a method for the delivery of an anti-miR-9 molecule from mesenchymal stem cells (MSCs) via release of exosome-type microvesicles. They demonstrated that anti-miR-9 was transferred from MSCs to GBM cells. The delivery of anti-miR-9 to the resistant GBM cells reversed the expression of the multidrug transporter and sensitized the GBM cells to temozolomide, as shown by increased cell death and caspase activity, thus illustrating a potential role for MSCs in the functional delivery of synthetic anti-miR-9 to reverse chemoresistance of GBM cells.107 To reinforce the evidence that TR exosomes can serve as vehicles for the delivery of synthetic miRNAs or miRNA inhibitors, a proof of concept study tested whether MSC exosomes could be used as a vehicle for delivery of anti-tumor miRNAs. A miR-146b expression plasmid was transfected into MSCs, and exosomes released by the transfected MSCs were harvested. The study found that intra-tumoral injection of exosomes derived from miR-146-expressing MSCs significantly reduced glioma xenograft growth in a rat model of a primary brain tumor.108 Various approaches have made use of TR exosomes as immune modulators.109,110 However, to our knowledge none of these works have specifically demonstrated the participation of the miRNAs contained in the TR exosomes as modulator molecules in the communication process that influences the immune cell response. Nevertheless, it is highly plausible that miRNA cargo from TR exosomes somehow regulates and helps to reprogram the immune response in cancer.111

Bottom Line: Cancer-cell communication is an important and complex process, achieved through a diversity of mechanisms that allows tumor cells to mold and influence their environment.In recent years, evidence has accumulated indicating that cells communicate via the release and delivery of microRNAs (miRNAs) packed into tumor-released (TR) exosomes.In this review, we focus on miRNAs secreted via TR exosomes, which by acting in a paracrine or endocrine manner, facilitate a diversity of signaling mechanisms between cancer cells.

View Article: PubMed Central - PubMed

Affiliation: Oncogenomics Laboratory, National Institute of Genomics Medicine, Mexico City, Mexico.

ABSTRACT
Cancer-cell communication is an important and complex process, achieved through a diversity of mechanisms that allows tumor cells to mold and influence their environment. In recent years, evidence has accumulated indicating that cells communicate via the release and delivery of microRNAs (miRNAs) packed into tumor-released (TR) exosomes. Understanding the role and mode of action of miRNAs from TR exosomes is of paramount importance in the field of cancer biomarker discovery and for the development of new biomedical applications for cancer therapeutics. In this review, we focus on miRNAs secreted via TR exosomes, which by acting in a paracrine or endocrine manner, facilitate a diversity of signaling mechanisms between cancer cells. We address their contribution as signaling molecules, to the establishment, maintenance, and enhancement of the tumor microenvironment and the metastatic niche in cancer. Finally, we address the potential role of these molecules as biomarkers in cancer diagnosis and prognosis and their impact as a biomedical tool in cancer therapeutics.

No MeSH data available.


Related in: MedlinePlus