Mouse model for most common human cancer

ANN ARBOR—A new line of transgenic mice, created by researchers at the University of Michigan and the Hospital for Sick Children/University of Toronto, will help scientists understand genetic and biochemical changes that cause a common form of human skin cancer called basal cell carcinoma.

“More than one million skin cancers are diagnosed in the United States each year and the majority are basal cell carcinomas,” said Andrzej A. Dlugosz, M.D., associate professor of dermatology and scientific director of the Cutaneous Oncology Program at the U-M Comprehensive Cancer Center.

Previous studies revealed that a mutation in a gene called “patched” (PTCH) was associated with development of human basal cell carcinomas, but it is not known how this genetic change causes a normal skin cell to become a tumor cell. An initial study describing the new mouse model, published in the March 1 issue of Nature Genetics by Dlugosz and his co-investigators, strongly suggests that the protein Gli2 plays a key role in this process.

The research team created mice that produce abnormally large amounts of Gli2 in their skin. By three months of age, these animals spontaneously developed multiple skin tumors that appeared strikingly similar to human basal cell carcinomas. Mouse tumors also expressed the same protein and RNA markers found in human tumors.

“These mice will help us learn more about the biology of these common skin tumors,” Dlugosz said. Although basal cell carcinomas rarely metastasize and can be treated effectively with surgery, new forms of non-invasive therapy would be beneficial, especially for high-risk patients who develop multiple tumors. A practical mouse model “should be very useful in the search for new agents for treatment or prevention of basal cell carcinomas,” Dlugosz added.

While other mouse models for basal cell carcinoma exist, Dlugosz says the U-M/Toronto model has advantages for use in scientific research. Other mice either cannot reproduce or the offspring die at birth. U-M/Toronto mice are robust, healthy and producing offspring. Plus, they produce tumors spontaneously without radiation exposure.

First author of the Nature Genetics paper is Marina Grachtchouk, Ph.D., a research fellow in the U-M Medical School. Co-authors from the Hospital for Sick Children/University of Toronto are Rong Mo, Sandy Yu, Xiaoyun Zhang and Chi-Chung Hui. Hiroshi Sasaki of Osaka University also is a co-author.

The investigators have applied for a joint patent on the new mouse model. The study was funded by the U-M Comprehensive Cancer Center, the U-M Center for Organogenesis and the National Cancer Institute of Canada.

Hospital for Sick Children/University of TorontoAndrzej A. DlugoszNature GeneticsMedical SchoolU-M Center for Organogenesis