Large oncosomes mediate intercellular transfer of functional microRNA

Morello, Matteo; Minciacchi, Valentina R.; Candia, Paola de; Yang, Jae Hyuk; Posadas, Edwin M.; Kim, Hyung L.; Griffiths, Duncan; Bhowmick, Neil A.; Chung, Leland W.K.; Gandellini, Paolo; Freeman, Michael R.; Demichelis, Francesca; Vizio, Dolores Di

doi:10.4161/cc.26539

Cited by 194 publications

(182 citation statements)

References 51 publications

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“…LO released from amoeboid cancer cells are abundant in tumor tissues and plasma of patients and mice with metastatic prostate cancer, and are not detected in benign samples (10)(11)(12). LO are also bioactive, as demonstrated by their capacity to degrade extracellular matrices in vitro (10).…”

Section: Introductionmentioning

confidence: 99%

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MYC Mediates Large Oncosome-Induced Fibroblast Reprogramming in Prostate Cancer

et al. 2017

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Communication between cancer cells and the tumor microenvironment results in the modulation of complex signaling networks that facilitate tumor progression. Here, we describe a new mechanism of intercellular communication originating from large oncosomes (LO), which are cancer cell-derived, atypically large (1-10 mm) extracellular vesicles (EV). We demonstrate that, in the context of prostate cancer, LO harbor sustained AKT1 kinase activity, nominating them as active signaling platforms. Active AKT1 was detected in circulating EV from the plasma of metastatic prostate cancer patients and was LO specific. LO internalization induced reprogramming of human normal prostate fibroblasts as reflected by high levels of a-SMA, IL6, and MMP9. In turn, LO-reprogrammed normal prostate fibroblasts stimulated endothelial tube formation in vitro and promoted tumor growth in mice. Activation of stromal MYC was critical for this reprogramming and for the sustained cellular responses elicited by LO, both in vitro and in vivo in an AKT1-dependent manner. Inhibition of LO internalization prevented activation of MYC and impaired the tumor-supporting properties of fibroblasts. Overall, our data show that prostate cancer-derived LO powerfully promote establishment of a tumor-supportive environment by inducing a novel reprogramming of the stroma. This mechanism offers potential alternative options for patient treatment. Cancer Res; 77(9); 2306-17.Ó2017 AACR.

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Section: Introductionmentioning

confidence: 99%

“…LO were incubated with the dye for 3 minutes at room temperature, and the reaction was blocked by BSA 1%. LO were then washed in 5 mL of PBS to remove any unbound dye, concentrated by filtration as previously described (12), and collected in PBS.…”

Section: Pkh26 Stainingmentioning

confidence: 99%

MYC Mediates Large Oncosome-Induced Fibroblast Reprogramming in Prostate Cancer

et al. 2017

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“…In terms of size-based separation, there is evidence that in cancer studies, characteristic vesicles may be discarded in standard stepped centrifugation protocols. These large vesicles, dubbed "large oncosomes," approach the size of platelets and are both rich in potential biomarkers and preferentially released by cancer cells (62 ). Finally, assuming efficiency of EV isolation, can enough RNA be reliably extracted from a small minority of total EVs in clinically relevant fluid volumes to support representative RNA profiling?…”

Section: Ev Subpopulationsmentioning

confidence: 99%

Circulating MicroRNA Biomarker Studies: Pitfalls and Potential Solutions

2015

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BACKGROUND Circulating microRNAs have been proposed as disease biomarkers that may aid in risk assessment, diagnosis, prognosis, and monitoring of treatment response. The perceived opportunity has loomed particularly large in neoplastic disease, where alterations in cancer cells are thought to be reflected in the extracellular space as affected cells release upregulated miRNAs or fail to release apparently downregulated species. Despite the promise of miRNA biomarkers, evaluation of the diagnostic specificity and reproducibility of reported markers suggests that realizing this promise remains a work in progress. CONTENTS This review examines issues of diagnostic specificity and reproducibility that have afflicted circulating miRNA studies. Surveying the breast cancer literature as an example, few miRNAs are reported consistently. Furthermore, it is posited that the assumptions underlying models of direct contributions of diseased tissue to biofluid miRNA profiles may not hold. Suggestions for improving diagnostic specificity and reliability are provided. SUMMARY To maximize the likelihood of return on investment as miRNAs continue to be evaluated as specific and clinically useful markers, a focus is needed on miRNAs found in specific carriers, such as extracellular vesicles. Alternative sampling techniques should be developed, and nonblood biofluids should be considered. Careful optimization and standardization of preanalytical and analytical methods is needed to ensure that future results, positive or negative, are reliable.

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“…Indeed, HCV replication requires the hepatocyte-specific miRNA miR-122 for efficient replication (13), and an miR-122 antagonist was shown to have potent antiviral effects in a human trial (14). Whereas conventional wisdom predicts that extracellular miRNAs found circulating in the plasma are the result of cell lysis, extracellular miRNAs have been shown to be selectively secreted by donor cells and can regulate genes in target cells in animal and tissue culture models (15)(16)(17)(18)(19)(20)(21)(22)(23)(24)(25). We hypothesized that acute HCV infection leads to regulated changes in the abundance of circulating microRNAs.…”

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confidence: 99%

Acute Hepatitis C Virus Infection Induces Consistent Changes in Circulating MicroRNAs That Are Associated with Nonlytic Hepatocyte Release

El-Diwany

Wasilewski

Witwer

et al. 2015

J Virol

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Plasma microRNAs (miRNAs) change in abundance in response to disease and have been associated with liver fibrosis severity in chronic hepatitis C virus (HCV) infection. However, the early dynamics of miRNA release during acute HCV infection are poorly understood. In addition, circulating miRNA signatures have been difficult to reproduce among separate populations. We studied plasma miRNA abundance during acute HCV infection to identify an miRNA signature of early infection. We measured 754 plasma miRNAs by quantitative PCR array in a discovery cohort of 22 individuals before and during acute HCV infection and after spontaneous resolution (n ‫؍‬ 11) or persistence (n ‫؍‬ 11) to identify a plasma miRNA signature. The discovery cohort derived from the Baltimore Before and After Acute Study of Hepatitis. During acute HCV infection, increases in miR-122 (P < 0.01) and miR-885-5p (P corrected < 0.05) and a decrease in miR-494 (P corrected < 0.05) were observed at the earliest time points after virus detection. Changes in miR-122 and miR-885-5p were sustained in persistent (P < 0.001) but not resolved HCV infection. The circulating miRNA signature of acute HCV infection was confirmed in a separate validation cohort that was derived from the San Francisco-based You Find Out (UFO) Study (n ‫؍‬ 28). As further confirmation, cellular changes of signature miRNAs were examined in a tissue culture model of HCV in hepatoma cells: HCV infection induced extracellular release of miR-122 and miR-885-5p despite unperturbed intracellular levels. In contrast, miR-494 accumulated intracellularly (P < 0.05). Collectively, these data are inconsistent with necrolytic release of hepatocyte miRNAs into the plasma during acute HCV infection of humans. IMPORTANCEMicroRNAs are small noncoding RNA molecules that emerging research shows can transmit regulatory signals between cells in health and disease. HCV infects 2% of humans worldwide, and chronic HCV infection is a major cause of severe liver disease. We profiled plasma miRNAs in injection drug users before, during, and (in the people with resolution) after HCV infection. We discovered miRNA signatures of acute and persistent viremia and confirmed these findings two ways: (i) in a separate cohort of people with newly acquired HCV infection and (ii) in an HCV cell culture system. Our results demonstrate that acute HCV infection induces early changes in the abundance of specific plasma miRNAs that may affect the host response to HCV infection. H epatitis C virus (HCV) is a single-stranded positive-sense hepatotropic RNA virus that infects over 170 million people worldwide. Acute HCV infection progresses to chronic infection in ϳ75% of cases (1-3). Little is understood about early hostpathogen interactions due to a lack of representative animal models and the difficulty in studying acute HCV, which is largely asymptomatic.MicroRNAs (miRNAs) are 18-to 25-nucleotide noncoding RNA molecules with widespread gene network regulatory capacity. miRNAs are readily detectable in cell-free compo...

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Large oncosomes mediate intercellular transfer of functional microRNA

Cited by 194 publications

References 51 publications

MYC Mediates Large Oncosome-Induced Fibroblast Reprogramming in Prostate Cancer

MYC Mediates Large Oncosome-Induced Fibroblast Reprogramming in Prostate Cancer

Circulating MicroRNA Biomarker Studies: Pitfalls and Potential Solutions

Acute Hepatitis C Virus Infection Induces Consistent Changes in Circulating MicroRNAs That Are Associated with Nonlytic Hepatocyte Release

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