Tumour microvesicles contain retrotransposon elements and amplified oncogene sequences

Balaj, Leonora; Lessard, Ryan; Dai, Lixin; Cho, Yoon Jae; Pomeroy, Scott L.; Breakefield, Xandra O.; Skog, Johan

doi:10.1038/ncomms1180

Cited by 1,019 publications

(997 citation statements)

References 53 publications

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“…1). Therefore, we reasoned that H-ras sequences in this material may represent the previously reported single-stranded [8], or double-stranded [18][19][20][21] vesicular DNA.…”

Section: Resultsmentioning

confidence: 98%

“…who reported the presence of single-stranded DNA in tumour-derived EVs [8]. The disparity could be related to a different cellular source, or to the diversity of vesiculation processes involved in various systems.…”

Section: Discussionmentioning

confidence: 99%

“…Indeed, insoluble oncoproteins, such as epidermal growth factor receptor (EGFR/EGFRvIII), KRAS or MET have been found to exit cancer cells as cargo of extracellular vesicles (EVs) [2][3][4], the production of which oncogenes stimulate [2,5]. Similarly, oncogenic transcripts and non-coding RNA are found in the cargo of EVs released by different cancer cells [6][7][8]. Notably, horizontal transfer of oncogenecontaining EVs evokes cellular responses reminiscent of malignant transformation and impacts growth, inflammation and angiogenesis [2][3][4]9,10].…”

Section: Introductionmentioning

confidence: 99%

“…Indeed, oncogenic DNA sequences were found in large vesicular structures known as apoptotic bodies (ABs) formed upon death of cancer cells [17]. EVs emanating from viable cancer cells were also found to contain single and double-stranded DNA [8,[18][19][20][21].…”

Section: Introductionmentioning

confidence: 99%

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Oncogenic ras-driven cancer cell vesiculation leads to emission of double-stranded DNA capable of interacting with target cells

Lee

Chennakrishnaiah

Audemard

et al. 2014

Biochemical and Biophysical Research Communications

172

189

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Cell free DNA is often regarded as a source of genetic cancer biomarkers, but the related mechanisms of DNA release, composition and biological activity remain unclear. Here we show that rat epithelial cell transformation by the human H-ras oncogene leads to an increase in production of small, exosomal-like extracellular vesicles by viable cancer cells. These EVs contain chromatin-associated double-stranded DNA fragments covering the entire host genome, including full-length H-ras. Oncogenic N-ras and SV40LT sequences were also found in EVs emitted from spontaneous mouse brain tumour cells. Disruption of acidic sphingomyelinase and the p53/Rb pathway did not block emission of EV-related oncogenic DNA. Exposure of nontransformed RAT-1 cells to EVs containing mutant H-ras DNA led to the uptake and retention of this material for an extended (30 days) but transient period of time, and stimulated cell proliferation. Thus, our study suggests that H-ras-mediated transformation stimulates vesicular emission of this histone-bound oncogene, which may interact with non-transformed cells.

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“…1). Therefore, we reasoned that H-ras sequences in this material may represent the previously reported single-stranded [8], or double-stranded [18][19][20][21] vesicular DNA.…”

Section: Resultsmentioning

confidence: 98%

Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

See 2 more Smart Citations

Oncogenic ras-driven cancer cell vesiculation leads to emission of double-stranded DNA capable of interacting with target cells

Lee

Chennakrishnaiah

Audemard

et al. 2014

Biochemical and Biophysical Research Communications

172

189

View full text Add to dashboard Cite

show abstract

“…Membrane-bound exosomes and microvesicles that can circulate between cells within the brain and between cells in the brain and those in the periphery (and vice versa) are emerging as carriers for lncRNAs [91][92][93]. It has been suggested that these extracellular vehicles carry the bulk of RNA circulating in the periphery, and they are very relevant to disease.…”

Section: Establishing Paradigms For Lncrna-related Pathologymentioning

confidence: 99%

Long Non-coding RNAs: Novel Targets for Nervous System Disease Diagnosis and Therapy

2013

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The human genome encodes tens of thousands of long non-coding RNAs (lncRNAs), a novel and important class of genes. Our knowledge of lncRNAs has grown exponentially since their discovery within the last decade. lncRNAs are expressed in a highly cell-and tissue-specific manner, and are particularly abundant within the nervous system. lncRNAs are subject to post-transcriptional processing and inter-and intra-cellular transport. lncRNAs act via a spectrum of molecular mechanisms leveraging their ability to engage in both sequence-specific and conformational interactions with diverse partners (DNA, RNA, and proteins). Because of their size, lncRNAs act in a modular fashion, bringing different macromolecules together within the three-dimensional context of the cell. lncRNAs thus coordinate the execution of transcriptional, post-transcriptional, and epigenetic processes and critical biological programs (growth and development, establishment of cell identity, and deployment of stress responses). Emerging data reveal that lncRNAs play vital roles in mediating the developmental complexity, cellular diversity, and activitydependent plasticity that are hallmarks of brain. Corresponding studies implicate these factors in brain aging and the pathophysiology of brain disorders, through evolving paradigms including the following: (i) genetic variation in lncRNA genes causes disease and influences susceptibility; (ii) epigenetic deregulation of lncRNAs genes is associated with disease; (iii) genomic context links lncRNA genes to disease genes and pathways; and (iv) lncRNAs are otherwise interconnected with known pathogenic mechanisms. Hence, Electronic supplementary material The online version of this article

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Content release of extracellular vesicles in a cell‐free extract

Bonsergent

Lavieu

2019

FEBS Letters

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Extracellular vesicles (EVs) transfer molecules from donor to acceptor cells. The EV‐content delivery process within the acceptor cell is poorly characterized. We developed a new cell‐free assay to assess EV‐content release in vitro. We found that EV‐cytosolic cargoes are released from EVs when isolated vesicles are incubated with purified plasma membrane sheets at acidic pH, a characteristic of the endolysosomal environment. This process is protein dependent. Our results suggest that EV‐content delivery occurs within the endo/lysosomes of acceptor cells and is triggered by acidification. This process resembles virus content delivery and may require membrane fusion. The assay presented here will facilitate investigations into the core machinery and mechanisms underlying EV content delivery.

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Tumour microvesicles contain retrotransposon elements and amplified oncogene sequences

Cited by 1,019 publications

References 53 publications

Oncogenic ras-driven cancer cell vesiculation leads to emission of double-stranded DNA capable of interacting with target cells

Oncogenic ras-driven cancer cell vesiculation leads to emission of double-stranded DNA capable of interacting with target cells

Long Non-coding RNAs: Novel Targets for Nervous System Disease Diagnosis and Therapy

Content release of extracellular vesicles in a cell‐free extract

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