Researchers supported by the Common Fund’s Extracellular RNA Communication program are gaining new insight into the potential for some types of extracellular RNA called microRNA (miRNA) to influence cancer progression. The research suggests that cancer cell exosomes, vesicles that are secreted by cells and present in many biological fluids, and the associated mature miRNA they carry are involved in tumor formation. Since only cancer exosomes contain certain proteins, these could serve as important diagnostic markers that may be more useful in detection of cancers compared to some current diagnostic approaches such as imaging. This important distinction may also give insight into the design of novel cancer therapeutics.Though the functional roles of miRNAs remain largely unknown, researchers are beginning to understand their importance in influencing transcription and tumor progression in target cells. In this study, researchers found that breast cancer cells secrete exosomes packed with the necessary proteins to process miRNAs into their mature form, while exosomes from normal non-cancerous cells lacked this ability. The scientists also showed that when cancer exosomes were combined with normal human breast cells and injected into the mammary tissue of mice, the injected cells became cancerous and formed tumors. Conversely, exosomes from sera of healthy donors had no tumorigenic effect. This research suggests a new cell-independent mechanism by which secreted exosomes from cancerous cells are able to process miRNA that can influence and signal non-cancerous cells to become cancerous, demonstrating that RNA released from one part of the body may have the potential to influence cells in distant parts of the body.
Read the article in Cancer Cell
Research supported by the Common Fund’s Extracellular RNA Communication program is laying the foundation for using extracellular RNAs (exRNAs) in saliva to diagnose a variety of diseases, such as cancer, diabetes, autoimmune disorders, and potentially many more. Dr. David Wong and colleagues have conducted the most comprehensive analysis of human exRNAs in saliva to date, and have made several interesting discoveries. One surprising finding is the discovery of approximately 400 circular RNAs in saliva. Circular RNAs were only recently discovered to exist within cells and tissues, and this study marks the first discovery of circular RNAs in any body fluid. The researchers also discovered that saliva contains a significant number of piwi-interacting RNAs (piRNAs), whose functions are largely unknown. In contrast, blood and other body fluids contain very few piRNAs, suggesting that the salivary piRNAs did not originate from RNAs in the blood, and may have originated instead from skin or stem cells within the oral cavity. MicroRNAs (miRNAs), which play important roles in gene regulation, were also found in saliva, and show similar variability between individuals in the saliva samples compared to miRNAs from blood samples or within cells. This result suggests salivary miRNAs may have potential as stable biomarkers that can distinguish between individuals, with the advantage of being easily accessible compared to other body fluids. Together, this research is the first step for future studies on the biological functions of exRNAs in saliva, and opens the door to using salivary exRNAs as non-invasive biomarkers for a number of diseases.
Bahn JH, Zhang Q, Li F, Chan T-M, Lin X, Kim Y, Wong D, and Xiao X. The Landscape of MicroRNA, Piwi-Interacting RNA, and Circular RNA in Human Saliva. Clinical Chemistry, November 2014.
Researchers in the Common Fund’s Extracellular RNA Communication program have discovered a potential treatment for multiple sclerosis (MS), a devastating neurological disorder characterized by muscle weakness, vision problems, difficulty with balance and coordination, and sometimes paralysis. Dr. Richard Kraig and colleagues from the University of Chicago are investigating the therapeutic potential of exosomes, small particles containing biologically active molecules such as RNA and proteins, which are released from cells to travel throughout the body and affect other cells at a distance. Dr. Kraig’s research shows immune cells can be stimulated to produce exosomes that promote formation of myelin to restore the protective insulation around nerve fibers that is damaged in MS. These exosomes contain small pieces of genetic material called microRNAs. Some microRNAs in the exosomes influence immature brain cells to develop into myelin-making cells called oligodendrocytes. Other microRNAs protect against inflammation, thought to contribute to myelin damage in MS. Treatment with exosomes containing these microRNAs increases myelin in both healthy rodent brains and in rat models of demyelination that mimic MS. Importantly, a nasal spray containing exosomes with microRNAs was found to increase myelin in rat brains, suggesting that this type of treatment may be easily administered. In related research, Dr. Kraig and colleagues found that microRNAs in exosomes from young animals and animals living in environmentally enriched conditions also promote myelination, suggesting multiple factors may influence production of microRNA-containing exosomes with therapeutic potential. Further studies will be needed to determine whether exosomal microRNAs can be used to treat patients with MS, but these early studies are a promising first step in developing microRNA-based therapeutics for MS and possibly many other neurological diseases and conditions.
Pusic AD, Pusic KM, Clayton BLL, and Kraig RP. IFNγ-stimulated dendritic cell exosomes as a potential therapeutic for remyelination. Journal of Immunology, Jan. 15, 2014; 266(1-2): 12-23. PMID: 24275061.
Pusic AD and Kraig RP. Youth and environmental enrichment generate serum exosomes containing miR-219 that promote CNS myelination. Glia, Feb. 2014; 62(2): 284-299. PMID: 24339157.
Read about this story in the news:
Naturally Occurring Packets Show Promise for Protecting Nerve Fibers in the Brain
Remyelination: Are Exosomes Containing microRNA the Answer?
NIH Common Fund Issues First Awards in Extracellular RNA Communication!
The NIH is supporting 24 collaborative, multidisciplinary awards to explore a novel cell communication process.