"Wild idea" opens possible new boundaries to ovarian cancer prevention
A laboratory study published in Clinical Cancer Research provides a new perspective on how ovarian cancer is developed and suggests how it can be avoided.
The research is the first to demonstrate that with age occurs the normal ovarian stiffening called fibrosis. It also indicates that this cycle may be prevented by the diabetes medication metformin.
"Fibrosis happens when body tissues are repeatedly injured and inflamed, leaving behind hard collagen fibers that pile up over time, like a scar on the skin," said Dr. Curtis McCloskey, the lead author, "Cancer cells tend to like growing in these fibrotic tissues.
Dr. McCloskey performed the research while he was a PhD student in Dr. Barbara Vanderhyden's lab at The Ottawa Hospital and the University of Ottawa. He is now a postdoctoral fellow at the Princess Margaret Cancer Centre.
Ovarian cancer is the fifth most common cancer in women, with a 5-year survival rate of 45 percent among the worst. People with a family history of ovarian cancer or a BRCA gene mutation are the most susceptible. There is no accurate early cancer screening study. Birth control pills that reduce the risk of ovarian cancer by half or remove ovaries and fallopian pipes are the only options for prevention.
The team found that ovarian fibrosis is a common part of aging, usually after menopause. Dr. McCloskey was shocked during his research to find an ovary by a 69-year-old woman without fibrosis. Medical records revealed that she took metformin, a type 2 diabetes drug. A Taiwanese study previously showed an 82% decrease in ovarian cancer levels in patients with metformin Type 2 diabetes.
The group conducted a series of trials to explore the relations between ovarian fibrosis, aging and metformin.
First of all, they wanted to know what caused the fibrosis. They thought that the answer might lie in ovulation. Whenever an ovary releases an egg it is inflamed and induces a monthly wound process and regeneration.
The group used a drug that prevents mice from ovulating to test this theory. The mice treated did not develop age-long ovarian fibrosis, which indicated that ovulation could be linked to fibrosis development. More detailed studies are required, however, to validate this result.
Additionally, the group analyzed 27 ovaries removed from women between the ages of 21 and 82. Most postmenopausal women's ovaries are fibrotic. While only five ovaries came from women who took metformin after menopause, none of these five had fibrosis.
Combined, these findings suggest that a new alternative to targeted ovarian fibrosis could be to reduce the risk of ovarian cancer and to make it more appropriate to use metformin to avoid ovarian cancer.
"This study was about putting two and two together," said Dr. Vanderhyden, a senior scientist at The Ottawa Hospital and professor and Corinne Boyer Chair in Ovarian Cancer Research at the University of Ottawa. "Now we're doing more research to learn how fibrosis develops in the ovaries, and how metformin stops it from happening."
The findings will need to be confirmed in more mouse models and human ovaries before clinical trials can start. A non-invasive test that can measure fibrosis in the ovary would also need to be created.
"We hope that someday metformin may prove to be an effective preventative treatment for younger women who are at high risk of ovarian cancer, but who can't remove their ovaries because they still want to have children," said Dr. Vanderhyden.
Reference: "Metformin abrogates age-associated ovarian fibrosis." Curtis W. McCloskey, David P. Cook, Brendan S. Kelly, Feryel Azzi, Christian H. Allen, Amanda Forsyth6, Jeremy Upham, Katey J. Rayner, Douglas A. Gray, Robert W. Boyd, Sangeeta Murugkar, Bryan Lo, Dominique Trudel, Mary K. Senterman, Barbara C. Vanderhyden. Clinical Cancer Research. Oct 9,2019
Funders: Research at The Ottawa Hospital is possible because of generous donations to The Ottawa Hospital Foundation. In particular, this study was possible because of donations from the late educator Margaret Craig, who wished to fund innovative, high-risk research in ovarian cancer. The study was also supported by the Canadian Institutes of Health Research.
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