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Finding a Way to Attack Fibroids Through Their Extracellular Matrix

Finding a Way to Attack Fibroids Through Their Extracellular Matrix

The uterus is one of the body’s most plastic organs. During a full-term pregnancy, its volume increases over 1000-fold as it grows from the size of a fist to the size of a watermelon. Then, once pregnancy ends, the process reverses as the uterus shrinks back to its original size.

To accommodate this plasticity, myometrial cells must undergo significant hyperplasia and then return to a quiescent state. It is possible that this extreme plasticity makes the uterus vulnerable, leading to one of gynecology’s most common and challenging conditions: uterine fibroids. These noncancerous uterine tumors affect the majority of women over their lifetime—up to 70 percent of whites and 80 percent of blacks by age 50—causing, for some, extreme pain, fertility issues and bleeding severe enough to require blood transfusions.

Despite the pervasive and serious nature of this problem, few good treatments for fibroids exist, says James Segars, director of the Division of Reproductive Sciences and Women’s Health Research in Johns Hopkins’ Department of Gynecology and Obstetrics. For example, even though hysterectomy offers a permanent solution, it’s major surgery that isn’t an option for women who aren’t finished having children. Fibroid embolization, on the other hand, is less invasive, but this treatment leaves the possibility of fibroid regrowth and a return of symptoms.

That’s why Segars and his colleagues are working on new treatments that attack this problem in a completely different way, based on their long-term research into why fibroids form.

Although no one knows exactly why fibroids arise and grow, Segars and his team have gradually gathered clues through a decade of laboratory research. One of their key studies showed that a bevy of genes are dysregulated in cells that compose fibroids, but those most affected appear to be responsible for excreting the extracellular matrix. Other affected genes include those involved in mechanical signaling.

Functions of these two sets of genes are intimately intertwined in creating fibroids, Segars explains. When there’s an excess of extracellular matrix, the cells become under mechanical stress. Because their intrinsic mechanical signaling is abnormal, they multiply, leading to even more accumulation of extracellular matrix.

“It’s like they’re in an open feedback loop similar to the hyperplasia of pregnancy,” Segars says.

Attacking aspects of this process could lead to new treatments for fibroids, he adds. He and his team are working on a novel enzymatic treatment that could be injected into fibroids, dissolving the abnormal extracellular matrix and, thus, causing the fibroids to shrink or disappear.

“Many women don’t realize that the extreme pain and bleeding that they’ve had since the start of their periods isn’t normal,” Segars says. “We want to offer them a better option to discover how great normal can be.”

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