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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

Biogenesis, packaging, secretion, and uptake of miRNA transported in exosomes.Notes: Cancer cells can secrete exosomes, which act in different ways: (1) by acting in a paracrine fashion on recipient neighboring cells, into which miRNAs may carry out their canonical mechanism of post-transcriptional repression or may activate membrane surface receptors (ie, TLRs) to favor tumor growth and invasiveness; and (2) by exerting their function in an endocrine manner by entering the circulation and reaching tissues at distant organs, where they are taken up by recipient cells and condition the formation of a metastatic niche. Green arrows indicate direction of the exosome trafficking. Black arrows indicate direction of canonic miRNA silencing action.Abbreviations: AGO2, argonaut; RISC, RNA-induced silencing complex; miRNA, microRNA; mRNA, messenger RNA; TLR, toll-like receptor.
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f2-ott-7-1327: Biogenesis, packaging, secretion, and uptake of miRNA transported in exosomes.Notes: Cancer cells can secrete exosomes, which act in different ways: (1) by acting in a paracrine fashion on recipient neighboring cells, into which miRNAs may carry out their canonical mechanism of post-transcriptional repression or may activate membrane surface receptors (ie, TLRs) to favor tumor growth and invasiveness; and (2) by exerting their function in an endocrine manner by entering the circulation and reaching tissues at distant organs, where they are taken up by recipient cells and condition the formation of a metastatic niche. Green arrows indicate direction of the exosome trafficking. Black arrows indicate direction of canonic miRNA silencing action.Abbreviations: AGO2, argonaut; RISC, RNA-induced silencing complex; miRNA, microRNA; mRNA, messenger RNA; TLR, toll-like receptor.

Mentions: Our understanding of intercellular communication is mainly based on the secretion of soluble factors, such as growth factors and neurotransmitters, cytokines, and chemokines, and their specific recognition by cell-surface receptors. However, evidence indicating that cells also communicate via the direct exchange of DNA59–61 and RNA3,62 has been growing over the past several years. In 1988, Benner proposed that RNA is involved in cell-to-cell communication as a short-distance and fast-acting messenger.63 It has recently been reported that exosomes secreted by mast cell lines contain both mRNA and miRNA.3 Several studies have demonstrated that miRNAs are present in a cell-free form in human and mouse serum.34,64–66 These reports reinforced the idea that RNA could function in long-distance communication between cells. In fact, miRNAs have been found in various body fluids, including serum, plasma, saliva, tears, urine, amniotic fluid, colostrum, breast milk, bronchial lavage, cerebrospinal fluid, peritoneal fluid, pleural fluid, and seminal fluid.67 Despite increasing efforts, little is known about the mechanisms that explain the origin and stability of circulating miRNAs in those body fluids.4,68 It is known that miRNAs can be passively released from broken cells and apoptotic bodies68,69 and actively secreted as RNA-protein complexes.70,71 However, an advantage of exosomes as RNA delivery vehicles is that, unlike soluble factors, exosomes are protected from the environment by their lipid bilayer and are more likely to reach their target cells.35 In fact, exosomal miRNAs are more stable and resistant to degradation during prolonged storage and freeze–thaw cycles than cellular miRNAs.7,72,73 Another advantage is that exosomes can deliver multiple messages simultaneously, which make them an attractive way of exchanging specific subsets of mRNA, miRNA, or proteins between donor and recipient cells, despite the distance between one and the other. There is increasing evidence that miRNAs are selectively packaged into exosomes.66,74–76 Therefore, exosomal transport of mRNAs and miRNAs from tumor cells to neighboring cells or cells located at distant organs could have a functional role in the process of tumorigenesis (Figure 2).62,77


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)

Biogenesis, packaging, secretion, and uptake of miRNA transported in exosomes.Notes: Cancer cells can secrete exosomes, which act in different ways: (1) by acting in a paracrine fashion on recipient neighboring cells, into which miRNAs may carry out their canonical mechanism of post-transcriptional repression or may activate membrane surface receptors (ie, TLRs) to favor tumor growth and invasiveness; and (2) by exerting their function in an endocrine manner by entering the circulation and reaching tissues at distant organs, where they are taken up by recipient cells and condition the formation of a metastatic niche. Green arrows indicate direction of the exosome trafficking. Black arrows indicate direction of canonic miRNA silencing action.Abbreviations: AGO2, argonaut; RISC, RNA-induced silencing complex; miRNA, microRNA; mRNA, messenger RNA; TLR, toll-like receptor.
© Copyright Policy
Related In: Results  -  Collection

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

f2-ott-7-1327: Biogenesis, packaging, secretion, and uptake of miRNA transported in exosomes.Notes: Cancer cells can secrete exosomes, which act in different ways: (1) by acting in a paracrine fashion on recipient neighboring cells, into which miRNAs may carry out their canonical mechanism of post-transcriptional repression or may activate membrane surface receptors (ie, TLRs) to favor tumor growth and invasiveness; and (2) by exerting their function in an endocrine manner by entering the circulation and reaching tissues at distant organs, where they are taken up by recipient cells and condition the formation of a metastatic niche. Green arrows indicate direction of the exosome trafficking. Black arrows indicate direction of canonic miRNA silencing action.Abbreviations: AGO2, argonaut; RISC, RNA-induced silencing complex; miRNA, microRNA; mRNA, messenger RNA; TLR, toll-like receptor.
Mentions: Our understanding of intercellular communication is mainly based on the secretion of soluble factors, such as growth factors and neurotransmitters, cytokines, and chemokines, and their specific recognition by cell-surface receptors. However, evidence indicating that cells also communicate via the direct exchange of DNA59–61 and RNA3,62 has been growing over the past several years. In 1988, Benner proposed that RNA is involved in cell-to-cell communication as a short-distance and fast-acting messenger.63 It has recently been reported that exosomes secreted by mast cell lines contain both mRNA and miRNA.3 Several studies have demonstrated that miRNAs are present in a cell-free form in human and mouse serum.34,64–66 These reports reinforced the idea that RNA could function in long-distance communication between cells. In fact, miRNAs have been found in various body fluids, including serum, plasma, saliva, tears, urine, amniotic fluid, colostrum, breast milk, bronchial lavage, cerebrospinal fluid, peritoneal fluid, pleural fluid, and seminal fluid.67 Despite increasing efforts, little is known about the mechanisms that explain the origin and stability of circulating miRNAs in those body fluids.4,68 It is known that miRNAs can be passively released from broken cells and apoptotic bodies68,69 and actively secreted as RNA-protein complexes.70,71 However, an advantage of exosomes as RNA delivery vehicles is that, unlike soluble factors, exosomes are protected from the environment by their lipid bilayer and are more likely to reach their target cells.35 In fact, exosomal miRNAs are more stable and resistant to degradation during prolonged storage and freeze–thaw cycles than cellular miRNAs.7,72,73 Another advantage is that exosomes can deliver multiple messages simultaneously, which make them an attractive way of exchanging specific subsets of mRNA, miRNA, or proteins between donor and recipient cells, despite the distance between one and the other. There is increasing evidence that miRNAs are selectively packaged into exosomes.66,74–76 Therefore, exosomal transport of mRNAs and miRNAs from tumor cells to neighboring cells or cells located at distant organs could have a functional role in the process of tumorigenesis (Figure 2).62,77

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