Enzyme called COX-2 may promote the development of ovarian tumors

Fox Chase Cancer Center scientists have identified how an enzyme called COX-2 may promote the development of ovarian tumors, adding further insight into the mechanism of COX-2 inhibitors and the prevention of this highly lethal disease. The data was presented today at the 95th Annual Meeting of the American Association for Cancer Research in Orlando, Fla.

"We have found that the over-expression of COX-2 correlates with the loss of the basement membrane in ovarian epithelium cells, thus promoting cancer," said Mike (Xiang-Xi) Xu, Ph.D., who heads the Fox Chase team in this research. "A COX-2 inhibitor may reduce the loss of basement membrane and thus decrease cancer risk."

Previous research had shown that COX-2 inhibitors such as aspirin and other non-steroidal anti-inflammatory drugs (NSAIDs) slow the growth of tumors, particularly of the breast and colon, but only now are researchers beginning to understand how COX-2 inhibitors work in thwarting cancer. In the ovaries and other tissues, basement membrane provides a scaffold to which cells called epithelial cells adhere in an organized fashion, Xu explained. When there is no basement membrane, the epithelial cells become disorganized and unregulated and may undergo transformation from a normal to cancerous state. Xu added that basement membrane is also lost during ovulation, which may help explain the association between frequent ovulation and higher ovarian cancer risk.

Ovarian cancer claims the lives of over 14,000 women each year in the United States, making it the most lethal of all gynecologic malignancies. A strong family history of ovarian or breast cancer is evident in about 5 to 10 percent of ovarian cancer cases. While an average woman's risk of getting ovarian cancer is only about 1.4 percent over her lifetime, the risk increases to between 15 and 60 percent if two or more first-degree relatives (parents, siblings or children) have developed ovarian, breast or a certain type of bowel cancer.

The important role of inheritance has led many women with a family history of breast or ovarian cancer to have their breasts and ovaries removed as a means of preventing the development of cancer. Xu and his colleagues studied the tissues removed during prophylactic oophorectomy (removal of the ovaries) for clues about the precancerous changes that go on in the cells.

One of the cell proteins they analyzed was COX-2, a physiologically important enzyme that plays a role in ovulation as well as in antibacterial, immunologic and inflammatory processes. COX-2 has also been shown to stimulate tumor cell division and angiogenesis (new blood vessel formation) and to inhibit a type of programmed cell death called apoptosis, which helps control the growth of tumors. Xu's analysis of the ovarian tissue specimens showed that as the level of COX-2 increases, it appears to promote the loss of basement membrane.

Treatment with COX-2 inhibitors may prevent the development of cancer cells. In fact, the National Cancer Institute will launch a human clinical trial of COX-2 inhibitors. Mary B. Daly, M.D., Ph.D., director of Fox Chase's Cancer Control Program, is heading the multi-center trial, which will include Fox Chase as one of its sites. Fox Chase has one of four Specialized Programs of Research Excellence (SPORE) in Ovarian Cancer, established by the NCI in 1999.

Understanding what happens in ovarian cells before they become cancerous is important not only because it may lead to preventive therapies but also because it may lead to the identification of markers of the disease that will be useful for diagnosis and for assessing treatment results. One of the reasons for the high death rate among women who develop ovarian cancer is that diagnosis often is delayed until late stages of the disease.

In addition to Xu and Daly, the Fox Chase research team includes Isabelle H. Roland, Wan-Lin Yang, Ph.D., Dong-Hua Yang, M.D., Ph.D., Robert F. Ozols, M.D., Ph.D., Thomas C. Hamilton, Ph.D., Henry T. Lynch, Ph.D., and Andrew K. Godwin, Ph.D. The Fox Chase SPORE grant and an additional NCI grant supported the research.

Fox Chase Cancer Center, one of the nation's first comprehensive cancer centers designated by the National Cancer Institute in 1974, conducts basic, clinical, population and translational research; programs of prevention, detection and treatment of cancer; and community outreach. For more information about Fox Chase activities, visit the Center's web site at www.fccc.edu.