How Does Basal Cell Carcinoma Develop?
A New Mouse Model May Provide Answers

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

Marina Grachtchouk and Anrzej Dlugosz

"More than one million skin cancers are diagnosed in the U.S. each year and the majority are basal cell carcinomas," says 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, 2000, issue of Nature Genetics by Dlugosz and his co-investigators, strongly suggests that the protein Gli2 plays a key role in this process.

PTCH is an important component of a biochemical pathway, called the hedgehog pathway, which regulates embryonic development in organisms ranging from flies to humans. The hedgehog pathway is normally regulated in a very precise manner and is active only at certain times during development of different organs. Dlugosz explains that "when the PTCH gene is mutated, as in basal cell carcinomas, the hedgehog pathway is activated permanently."

In earlier studies, Dlugosz and coworkers studied the hedgehog pathway in normal skin as a foundation for understanding how basal cell carcinomas arise. They found that the hedgehog pathway controls hair follicle development through a protein called Gli2, suggesting that this molecule may also play an important role in basal cell carcinoma development when the hedgehog pathway is deregulated. To test this hypothesis, the research team created mice which 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 says. Basal cell carcinomas rarely metastasize and can be treated effectively with surgery, but the tumors can be disfiguring since they frequently occur on the face. New forms of non-invasive therapy would be beneficial, especially for high-risk patients who develop multiple tumors.

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 viable and produce offspring. Plus, they produce tumors spontaneously without radiation
exposure, which is commonly used to generate skin tumors in other mouse models.

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 at the 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.

Dlugosz can be reached at dlugosza@ umich.edu; Grachtchouk at marinagr@ umich.edu.