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New Data Show Cancer Exosomes Can Perform microRNA Biogenesis, Drive Tumors

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NEW YORK (GenomeWeb) — A team led by MD Anderson Cancer Center researchers this month published new data demonstrating that breast cancer-derived exosomes are capable of cell-independent microRNA biogenesis and are able to promote tumorigenesis in a Dicer-dependent manner.

The findings not only point to the potential of cancer exosomes as disease biomarkers, but also suggest that they might be used as "natural nanoparticles" that can both generate and deliver therapeutic miRNAs, Raghu Kalluri, an MD Anderson researcher and senior author of the report, said.

Exosomes are nanovesicles that are excreted by all cell types, including cancer cells, and have been shown to often carry miRNAs. Given his lab's interest in how the tumor microenvironment can affect disease progression, Kalluri and his team set out to conduct a general characterization of cancer-derived exosomes in order to see whether any of the material had either pro- or anti-oncogenic activity.

"That non-biased way of approaching [the effort] led us to look at every component in exosomes, including microRNAs," he told Gene Silencing News this week.

The scientists began by isolating exosomes from four different breast cancers, as well as non-cancerous mammary epithelial cells as controls, dubbed normosomes, and then conducted an analysis of the global miRNA content within them. Both the cancerous and control populations included cells from humans and mice.

Overall, they observed a low correlation between the levels of miRNA expression in normosomes and cancer exosomes, but generally higher correlation levels among normosomes and among cancer exosomes despite species differences, according to their paper, which appeared in Cancer Cell. There was an overall enrichment of miRNAs in cancer exosomes versus normosomes, with enrichment particularly high in exosomes from metastatic cancer cells.

Interestingly, cancer exosomes cultured for 72 hours displayed higher levels of miRNAs compared to those cultured for 24 hours while no such differences were observed in normosomes. Among these were miR-10a and -10b, miR-21, miR-27a, miR-155, and miR-373 — all of which, the investigators noted in their study, have been extensively implicated in cancer progression.

This observation pointed to the possibility of miRNA biogenesis, so Kalluri and his colleagues then looked at whether miRNA precursors (pre-miRNAs) could be found within the exosomes. As expected, they identified pre-miRNAs corresponding to all of the mature miRNAs they had found. More tellingly, the levels of these pre-miRNAs were significantly downregulated after the cancer exosomes were cultured for 72 hours compared with those cultured for 24 hours.

Further, the increase in mature miRNA levels was inversely proportional to the decrease in pre-miRNA levels, Kalluri pointed out.

Further experimentation revealed the presence of several RISC-loading proteins (RLPs) required for proper miRNA functioning — Dicer, and TAR RNA binding protein (TRBP), and Argonaute 2 —in cancer exosomes but not normosomes.

Notably, the researchers were able to direct pre-miRNA processing in cancer exosomes by electroporating synthetic pre-miR-10b and -21, as well as the C. elegans precursors pre-cel-1 pre-miRNA, into them. In line with previous observations, pre-miRNAs levels decreased and mature miRNA levels increased as the exosomes were cultured over 72 hours.

In recent years, there has been a growing body of evidence linking exosomes to cancer progression. One report demonstrated that melanoma-derived exosomes play a role in metastasis, and another that exosomes derived from fibroblasts play a role in the migration of breast cancer cells. Exosomes derived from cancer cells have been found to have a protumorigenic role associated with the transfer of mRNA and proangiogenic proteins, as well as contribute to the horizontal transfer of oncogenes.

In this latest study, Kalluri and his collaborators also showed that cancer exosomes can mediate rapid and efficient mRNA silencing, thereby reprogramming the transcriptome of target cells, but not in the absence of Dicer.

They further found that exosomes from the sera of breast cancer patients, but not healthy individuals, contained Dicer and processed pre-miRNAs into mature miRNAs. When these cancer exosomes were combined with human breast epithelial cells and were injected orthotopically into the mammary tissue of mice, they induced tumor formation. Exosomes from sera of healthy donors had no tumorigenic effect.

To Kalluri, the findings suggest that exosomes might prove useful as cancer biomarkers. "Only cancer exosomes contain Dicer," he explained. "So if we isolate exosomes from circulation in an individual [and] you see Dicer, that's a pretty good indication that that person has cancer."

And while the discovery that miRNA biogenesis can occur outside of a cell is intriguing from a basic science point of view, he added, it may also have clinical implications, with exosomes being co-opted as a sort of biological factory where miRNAs can be created and then delivered to areas of the body where they could have a therapeutic effect.

Still, Kalluri cautioned that the data are preliminary and that work is underway in his lab to extend the findings to other cancer types.

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