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Chicago Team Finds miRNAs Convert Fibroblasts around Ovarian Tumors to Promote Cancer

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Three microRNAs have been implicated in the transformation of normal fibroblasts into cancer-promoting cells and could be potential drug targets in ovarian cancer, a study by University of Chicago and Northwestern University researchers has suggested.

According to the group, which published its report in Cancer Discovery this month, ovarian cancer cells cause dysregulation of these three miRNAs — miR-31, miR-214, and miR-155 — in adjacent fibroblast cells, transforming them into what researchers call cancer-associated fibroblasts, or CAFs, which then promote tumor growth and invasiveness.

In a release highlighting the study, one of the lead authors, the University of Chicago's Ernst Lengyel, said the results suggest these miRNAs are clearly involved in activating fibroblasts' transformation to cancer promoters. Because of this, the molecules may be a "novel and appealing treatment target."

According to Lengyel, the group believes it might be possible to "modify microRNA expression in cancer-associated fibroblasts for therapeutic benefit." Making the tissue around cancer cells less hospitable may be a "new way to fight this disease," he said.

While it has been clear for a long time that cancer cells influence the stromal environment around them to ease their spread, the mechanism for this transformation has been unclear. According to the Chicago team, its new results suggest these three miRNAs influence at least some of this shift.

In the study, the group used arrays and then qRT-PCR to measure miRNA expression in CAFs compared to normal fibroblasts using two experimental setups.

In one approach, the group compared miRNA levels in CAFs isolated from six human subjects with metastatic ovarian cancer to normal fibroblasts from an area of tissue at least one inch away from the patients' tumors. In a second approach, the group took normal fibroblasts from subjects without cancer and cultured some of them in vitro using ovarian cancer cell lines, comparing the original and co-cultured cells to each other.

Overall, the group found 19 miRNAs up-regulated and 15 miRNAs down-regulated in the co-cultured cells induced into becoming CAFs compared to their normal counterparts. Of these, one was also up-regulated and four down-regulated in CAF versus normal fibroblast samples from the six human subjects.

The group chose the most significantly up- and down-regulated miRNAs — miR-155 and miR-214, respectively — and the second most down-regulated miRNA, miR-31, to test further.

To demonstrate that the three miRNAs have a causal role in the shift from normal fibroblasts to CAFs, the researchers transfected normal fibroblast samples with antagonists against miR31 and miR-214, and precursors for miR155. The manipulation of these miRNAs enhanced the colony formation of co-cultured ovarian cancer cells. According to the group, this showed that deregulating the expression of the three miRNAs can convert normal fibroblasts to CAFs.

In a reverse experiment, when the group transfected CAFs with pre-miR-31, pre-miR-214, and a miR-155 inhibitor, the change reduced the migration of the fibroblasts and the invasion and colony formation of co-cultured cancer cells.

According to the researchers, studying each miRNA individually further revealed that mi-214 was involved with regulating fibroblast migration and cancer cell invasiveness. Meanwhile, mR-155 predominantly affected cancer invasiveness and miR-31 mostly affected colony formation.

When the researchers injected either the miR-induced CAFs they had created or the isolated CAFs along with cancer cells into mice, both significantly enhanced the growth of tumor cells compared to an injection of cancer cells with normal fibroblast tissue.

The researchers also compared changes in gene expression between patients' normal fibroblasts and CAFs, and between the isolated normal cells and the cultured, induced CAFs. The group found that one gene product, CCL5, is likely a direct target of miR-214.

Interestingly, when the mice injected with CAFs and tumor cells were given an anti-CCL5 antibody, it blocked cancer growth. "This indicates that the CCL5 secreted by miR-CAFs is a key tumor-promoting factor," the authors wrote.

Overall, the results suggest that the down-regulation of miR-214 and miR-31, and the up-regulation of miR-155, can reprogram normal fibroblasts into CAFs. Affecting CCL5 may be one way the dysregulation of these miRNAs — miR-214 in particular — affects tumor growth and invasiveness.

According to the researchers, targeting these miRNAs to manipulate the tumor environment to be less hospitable for cancer cells might be a promising therapeutic strategy.

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