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OSU Team Reports on Link between Secreted microRNAs and Pro-Metastatic Inflammatory Response

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Building on studies examining the roles of microRNAs in cancer cell-derived circulating microvesicles, a team of researcher from Ohio State University this month reported on the discovery that two such miRNAs trigger a pro-metastatic inflammatory response by binding to toll-like receptors.

According to Carlo Croce, the senior author of the study, which appeared in the Proceedings of the National Academy of Sciences, the finding may not only have implications for the treatment of cancers, but other diseases as well.

“Since the induction of the inflammatory cytokines contribute to the invasion of the cancer, we could [potentially] target specific steps in the pathway … to inhibit that inflammation and the spread of the malignancy,” he told Gene Silencing News this week.

While the work detailed in PNAS focused on miR-21 and -29a in the context of lung cancer, Croce noted that his lab is currently conducting experiments examining the impact of other miRNAs on TLRs in different cancers including breast and colorectal, adding that “it seems that a similar mechanism occurs in those cancers.”

At the same time, Croce believes that the findings may extend to a variety of other conditions such as cardiovascular disease.

For example, atherosclerosis is characterized by chronic inflammation in artery walls, triggered by the buildup of fatty substances, “and it could be that the inflammation is dictated by a similar phenomenon,” he said.

“I believe that this is not a cancer-specific mechanism,” he said.

In light of research demonstrating that secreted miRNAs within exosomes could be transferred between cells, regulating gene expression in the receiving cell, Croce and his colleagues were investigating whether tumor-secreted exosomes contained the small, non-coding RNAs, and found that nine were expressed at high levels in two lung cancer cell lines, as well as in HEK293 cells.

However, three miRNAs in particular — miR-21, -27b, and -29a — were expressed at high levels only in the cancer cells, “suggesting a cancer-specific pattern of secreted miRNAs,” the researchers wrote in PNAS.

“When we were in the middle of that work, we [noticed that] the microRNAs were inducing the expression of certain cytokines, and asked, 'How do they do that?'” Croce explained, which led the team to start thinking about toll-like receptors.

Toll-like receptors, namely murine TLR7 and human TLR8, have been shown to recognize and bind viral single-stranded RNA sequences on dendritic cells and B lymphocytes, resulting in cell activation and cytokine production, the investigators stated in PNAS.

Through a series of in vitroexperiments, the researchers found that cancer cells secrete miR-29a in exosomes, and that the miRNA co-localizes with both TLR7 and TLR8 in macrophages at the “tumor-normal tissue interface.”

Further work showed that miR-29a and -21 secreted by tumor cells in exosomes can bind to and activate TLR7 and TLR8 in immune cells, resulting in TLR-mediated activation of NFkB and the secretion of pro-metastatic inflammatory cytokines.

“It has been shown previously that tumor secretion of the extracellular matrix proteoglycan versican induces a pro-inflammatory response by activating TLR2/TLR6 complexes in myeloid cells,” the researchers wrote. “We now show that tumor-secreted miRNAs also participate in the pro-tumoral inflammatory process by activating the TLR8 response on immune cells. As a result, tumor cells tend to generate more lung multiplicities when this paracrine loop is intact.”

Although the cell lines used in the study are not a model of lung cancer metastasis, and further studies are needed to “address the relevance of these findings in mice bearing primary tumors that are prone to form spontaneous metastases, our data identify a mechanism of action of miRNAs as agonists of a specific receptor family and suggest that this mechanism is involved in the tumor micro-environment interaction,” the researchers wrote.

“That is important because we don't have a lot of information about how … cancer cells interact with the cells of the micro-environment,” Croce said. “I think that, in view of our paper, it looks like the micro-environment is dictated by the phenomenon.

“It could have enormous implications in cancer,” he added.

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