Aspirin's target, the COX-2 enzyme, linked to cancer of the uterus

July 16, 2002

A researcher at the University of Illinois at Chicago College of Medicine has discovered a link between cancer of the uterus and the COX-2 enzyme, a compound first implicated in the painful inflammation associated with arthritis and more recently in the spread of colon cancer.

Nationally, cancer of the uterus is the most common cancer of the female reproductive system, accounting for 6 percent of all cancers in U.S. women.

In a laboratory study, Dr. Serdar Bulun, director of reproductive endocrinology and infertility and a member of the UIC Cancer Center, cultured malignant epithelial cells from the lining of the uterus alongside normal cells from the same kind of tissue.

In the interaction between normal and malignant cells, the malignant tissue induced the normal tissue to increase production of the enzyme cyclooxydase-2 (COX-2). Levels of certain prostaglandins also rose, hormone-like substances synthesized by COX-2.

As Bulun and other researchers have shown, COX-2 and its product prostaglandins set off a cascade of molecular events, including an abnormal increase in estrogen, that leads to tumor growth.

"The findings suggest that everyday drugs like aspirin or ibuprofen -- nonsteroidal anti-inflammatory drugs that block the COX-2 enzyme -- might be tried as treatments for uterine cancer in combination with other therapies," Bulun said.

Results of the study will be published in the July 17 issue of the Journal of Biological Chemistry.

The prostaglandins synthesized by COX-2 are mediators of inflammation, the body's response to injury characterized by increased blood flow to the tissue, increased temperature, redness, accumulation of immune cells and pain.

Bulun has found increased levels of COX-2 and its product prostaglandins in endometriosis, a painful, inflammatory disease in which endometrial tissue from the lining of the uterus attaches to other organs, including the ovaries, fallopian tubes, and sometimes the gut and rectum, causing internal bleeding, chronic pelvic pain and even infertility.

COX-2 and prostaglandins are also involved in the spread of tumors, such as in colon cancer. They reduce the rate of cell death, increase the invasiveness of the malignancies and promote the growth of blood vessels that deliver nourishment to the lesions. Currently, drugs that inhibit COX-2 are prescribed in the treatment of precancerous polyps in the colon and colon cancer, where cells have increased levels of the enzyme.

In previous research, Bulun found that the prostaglandins manufactured by COX-2 stimulate the production of estrogen. Cancer of the uterus, as well as certain kinds of breast cancer and endometriosis, depends on estrogen for fuel, and estrogen itself drives the manufacture of prostaglandins.

"You see how crafty this cancer is," Bulun said. "By encouraging the production of COX-2, it sets in motion a continuous cycle whereby the tumor can thrive and grow."

In two additional articles published in the July issue of the Journal of Clinical Endocrinology and Metabolism, Bulun demonstrates that two other molecules also increase production of COX-2. One molecule, called vascular endothelial growth factor, is involved in promoting the growth of blood vessels that feed the growing pathological tissue. The other molecule, interleukin-1beta, is a small molecule associated with the immune system, which deploys cells to sites where foreign tissue has invaded.

"These findings suggest that cancer of the uterus finds multiple ways of ensuring its survival," Bulun said.
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University of Illinois at Chicago

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