Researchers develop first mouse model of epithelial ovarian cancer

Fox Chase Cancer Center researchers and their colleagues have developed a mouse model of the most prevalent and deadly form of human ovarian cancer — epithelial ovarian cancer. The mouse model provides a better opportunity to study the cause of ovarian cancer, examine the genes involved and test preventive, diagnostic and treatment approaches that could be applied to human ovarian cancer.

“These transgenic mice offer us a valuable scientific tool that never before has been available to ovarian cancer researchers,” explained Fox Chase Cancer Center’s Denise C. Connolly, Ph.D., corresponding author of the study, which appears in the March 15, 2003, issue of Cancer Research, a journal of the American Association for Cancer Research.

The mice engineered by Connolly and her colleagues develop epithelial ovarian cancer in both ovaries. This cancer arises in the surface, or epithelial, cells of the ovaries. The mouse model was made by introducing a genetically engineered DNA fragment into fertilized mouse eggs prior to their embryonic development. The fragment is a combination of a gene specific promoter and a potent oncogene. The oncogene, Simian virus 40 T antigen, triggers cancer development. The promoter is derived from a gene (Mullerian inhibitory substance type II receptor) that signals the expression of a specific protein found in cells covering the ovaries.

“It was critical to attach the oncogene to a regulator that would limit the cancer-causing gene’s expression to the ovary, including the epithelial ovarian cells,” explained Connolly. “Using this strategy, we have generated transgenic animals that develop epithelial ovarian cancer that spreads to the peritoneal organs, similar to human epithelial ovarian cancers.”

In humans, epithelial ovarian cancer is diagnosed in approximately 23,000 women each year. In 2003, it is estimated that 14,000 women will die of the disease, making it the fifth most common cancer in women in the United States.

Early detection of these tumors is challenging because there is no standard screening available for the disease. When ovarian cancer is diagnosed at early stages, the survival rate approaches 90 percent. However, the vast majority of cases of ovarian cancer are not identified until late stages, when the survival rate drops to only 30 to 40 percent.

“The development of mouse models of epithelial ovarian cancer may significantly facilitate advances in early detection and treatment of the disease,” said Thomas C. Hamilton, Ph.D., senior member of the medical science division at Fox Chase Cancer Center and leader of the ovarian cancer research program. “Models such as this are critical to cancer research because they will allow us to study the progression of ovarian cancer from the very earliest stages to advanced disease.

“The next step is to test chemotherapeutic and chemopreventive agents that we hope will translate into meaningful improvements in the prevention and treatment of ovarian cancer. We’ll also study the relevant oncogenes and tumor-suppressor genes for their ability to allow or trigger the cancer to develop,” Hamilton added.

Other contributing researchers include Rudi Bao, M.D., Kasie C. Stephens, Timothy W. Poole, Ph.D., Xiang Hua and Skye S. Harris of Fox Chase Cancer Center; Alexander Yu. Nikitin, M.D., Ph.D., of Cornell University; and Barbara C. Vanderhyden, Ph.D., of the University of Ottawa.

Funding for this research is provided in part by a grant from the National Cancer Institute’s Mouse Models of Human Cancers Consortium (MMHCC), of which Hamilton is a member. Mouse models that recapitulate many aspects of the genesis, progression and clinical course of human cancers are valuable resources to cancer researchers engaged in a variety of basic, translational, clinical and epidemiological investigations.

MMHCC is a collaborative program designed to derive and characterize mouse models and to generate resources, information and innovative approaches to the application of mouse models in cancer research.

Additional grants supporting Dr., Hamilton’s research were received from the National Institutes of Health, the National Cancer Institute Specialized Program of Research Excellence for ovarian cancer, the Commonwealth of Pennsylvania, Edgar Astrove, the Adler Foundation and the Evy Lessin Fund.

Fox Chase Cancer Center, one of the nation’s first comprehensive cancer centers designated by the National Cancer Institute in 1974, conducts basic and clinical 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 http://www.fccc.edu or call 1-888-FOX CHASE.