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| |  Researchers Develop First Mouse Model Of Most Common Human Cancer SAN FRANCISCO -- May 2, 1997 -- Researchers at Stanford University and UC San Francisco have developed genetically engineered mice that are prone to basal cell carcinoma, producing the first mouse model of this leading form of human cancer, the researchers report in the May 2 issue of the journal Science. The genetically altered mice developed signs of the skin cancer as a result of a single mutation, suggesting that this particular cancer may be somewhat easier to conquer than other forms of the disease, said Ervin Epstein, Jr., MD, UCSF professor of dermatology at the UCSF-affiliated San Francisco General Hospital and a senior author on the study. The mutation was located along the same biological pathway identified by the researchers last year as the genetic source of the disease. "This is another step in calling attention to this particular signaling pathway. I think it gives us further hope that it doesn't take a lot of mutations to cause basal cell carcinoma and gives us even more confidence that if we could manipulate this pathway, we could get rid of these tumors," Epstein said. In June 1996, the same two labs reported isolating the gene for basal cell carcinoma, which affects about 750,000 people in the United States a year. These tumors are not fatal and rarely spread throughout the body. They are generally treated with surgery or radiation. In the earlier study, the researchers identified the source of the cancer in a gene known as patched. Patched acts in opposition to another gene called Sonic Hedgehog, which controls cell growth and development. The Hedgehog signaling protein binds to the patched protein and inactivates it. The result is basal cell carcinoma. In the latest study, the researchers approached the issue further up this biological pathway by altering the Hedgehog gene so that it would produce too much of the Hedgehog protein. They reasoned that this change in Hedgehog would create the same effect as the inactivation of the patched gene and lead to basal cell carcinoma. Their experiments proved them right. The Stanford lab inserted the altered Hedgehog gene into the skin of otherwise normal mice, which then developed the characteristic signs of skin cancer. "When we constructed transgenic mice with an excess production of Hedgehog in the skin, what we saw were tumors that look a lot like basal cell carcinomas," said Matthew Scott, PhD, a professor of developmental biology and genetics at Stanford and a senior author of the study. Scott is also a Howard Hughes Medical Institute investigator at Stanford. The transgenic mice also developed symptoms of a related, inherited condition known as the basal cell nevus syndrome (BCNS). People with BCNS may develop hundreds of basal cell carcinomas and have other developmental and skeletal defects, such as extra fingers or abnormal ribs. The genetically altered mice suffered a similar fate: They had extra digits and multiple skeletal problems, including spina bifida (a condition where the spinal column is malformed). The mice were so profoundly affected, in fact, that many died at birth. With these results, Epstein's lab then launched a search for the Hedgehog mutation in humans. After studying 63 samples from different people with different kinds of tumors, they found the identical mutation in three different cancers: one basal cell carcinoma, one breast tumor and one medulloblastoma, a kind of brain tumor also found in higher incidence in BCNS. The researchers concluded that the Hedgehog gene is a likely candidate for a human oncogene, or cancer-causing gene, although its mutations are likely to be fairly rare, Epstein said. The researchers say they now hope the mouse model will prove useful in helping to develop therapies for treating human skin cancer. Though the transgenic mice die too early for prolonged study, it may be possible to modify them so that they survive long enough to be valuable research tools, Scott said. "This is not a perfect model, but it's the best yet. It shows that under the Right conditions, mice can be forced to develop basal cell carcinoma," said Anthony Oro, MD, PhD, a post-doctoral fellow at Stanford and the lead author of the report. "It also shows that these developmental abnormalities can be produced and studied. And our experimental prediction -- that an increase in Hedgehog would be equivalent to a decrease in patched -- was fulfilled." The co-authors on the study are: Kay Higgins, MS, Stanford research specialist; Zhilan Hu, MD, PhD, a visiting research associate in dermatology at UCSF; and Jeannette M. Bonifas, UCSF staff research associate. The research was partially supported by grants from the National Institute of Arthritis and Musculoskeletal and Skin Diseases, part of the National Institutes of Health.
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