Manipulation of microRNAs may reverse conversion of normal ovarian cells into cancer cells

Several new targets for ovarian cancer have been identified by unraveling the mechanism that ovarian cancer cells use to change normal cells around them into cells that promote tumor growth. Ovarian cancer cells induce nearby cells to alter their production of three microRNAs.

MicroRNAs can modify a cell's function by changing gene expression. In this case, microRNAs convert normal, healthy fibroblasts into cancer-associated fibroblasts (CAFs).

Fibroblasts are the primary cellular component of connective tissue. They provide the structural framework for other tissues and aid in wound healing. The CAFs pump out chemical signals telling cancer cells to multiply, invade healthy tissues, and travel to distant sites in the abdomen. Importantly, by reversing the microRNA signals, the researchers were able to cause CAFs to revert to normal fibroblasts.

“These cancer-supporting cells provide a novel and appealing treatment target,” said one of the lead authors of the study, Ernst Lengyel, MD, PhD, professor in the department of obstetrics and gynecology at the University of Chicago. “Cancer cells mutate rapidly, which enables them to develop drug resistance. But cancer-associated fibroblasts are genetically stable,” he said. “Their harmful behavior is driven by the microRNAs. Inhibiting those signals is a new way to fight this disease. It disrupts the cancer's support system and is unlikely to evolve resistance.”

“With ovarian cancer,” Lengyel added, “we desperately need new treatments. There have been no new approaches introduced into the clinic for years, and thus no major improvements in patient survival.”

The researchers found that cancer cells caused normal fibroblasts to reduce production of two microRNAs, miR-31 and miR-214, and to increase production of miR-155. Since microRNAs usually block gene expression, reduced levels lead to increased expression of several of their target genes. Many of those genes are involved in the production of the chemical signals associated with CAFs.

The most highly upregulated such signal, known as CCL5, is a key tumor-promoting factor, the authors show. When human ovarian cancer cells and CAFs were co-injected into mice, the tumor cells soon replaced normal ovarian structures. Antibodies that neutralized CCL5 inhibited this augmented growth.

“One strength of our study is that we used tumor cells and CAFs from patients, rather than cell lines,” said Lengyel, a gynecologic oncologist who specializes in the surgical treatment of women with ovarian cancer. “Our model system is as close as possible to the real situation.”

“Therapeutic approaches targeting microRNAs in cancer cells are under development,” added Peter. “Our work suggests that it might be possible to modify microRNA expression in cancer-associated fibroblasts for therapeutic benefit.”

This research was published in Cancer Discovery (2012; doi:10.1158/2159-8290.CD-12-0206).
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