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U. team zeroes in on childhood cancer

Mouse model to aid treatment of rare form of the disease

University of Utah researchers have successfully created a deadly fast-moving form of childhood cancer in mice — a step they hope will one day lead to effective treatments.

It's the first time a mouse model has been created for aveolar rhabdomyosarcoma, a deadly form of cancer that affects muscle and which few children survive.

Creating the model has reversed some of the thinking about how the disease occurs, said lead investigator Mario Capecchi, co-chairman of human genetics in the U. School of Medicine and an investigator with the Howard Hughes Medical Institute. Two new studies are being published back to back in the next issue of Genes and Development. The first shows what a fusion gene does and the second how to generate the tumor in mice.

Capecchi called the disease a "very mean form of cancer," despite aggressive treatment. While treatments for many other cancers have improved greatly, there has been little change in survival rates for children with this cancer over the past 30 years.

"Cancer is never the result of one event," said Capecchi. The U. researchers based their efforts on the realization that "most cancers don't originate at conception. You don't get them from your mother or father. They show up in somatic tissue, which is all tissue but germ cells, usually after birth."

Muscles form in two ways. In an embryo's early development there are cells that run up and down the body, creating the patterns the muscle will occupy in the adult. And after birth, muscles are also made from satellite cells, which are capable of dividing themselves and also of differentiating to form muscle. That's what adds bulk to muscle, he said. Those satellite cells also help replace muscle broken down by exercise, he said.

Scientists have suspected that those satellite stem cells that become new muscle lead to the disease. The U. research suggests instead that the cancer begins in more mature skeletal muscle fiber.

While childhood cancer is rare, the American Cancer Society says that 9,200 cases will be diagnosed in children under age 14 this year. Of those, 313 will be rhabdomyosarcomas, of which the aveolar variety is just one type.

Only 5 to 30 percent of children with that form of cancer survive five years.

It has already been shown that most children with the disease have a cancer-causing gene that is actually a fusion gene, created when two chromosomes each break into two parts and then fuse back together in a wrong combination. AA and BB become AB and BA. The fusion gene then has a piece of a gene that normally helps form muscle, the nervous system and the head, along with part of a gene that suppresses cell division and thus tumor growth. Researchers believe the new combination creates cancer by forming muscle inappropriately.

For the research, they created a version of the first gene that they could change into the recombined form, choosing where they wanted it and at what stage of development.

By analyzing the steps of tumor development, they hope to open doors to find treatments that can interfere with the process that creates the cancer.

The first study shows that introducing the fusion gene found in all human tumors does not by itself produce tumors. But if it is activated in differentiating muscle, tumors do form, which was a surprise to the scientists.

They also turn on a cell that makes itself green. That will allow researchers to see events that gave rise to the tumor. They can also "go to the tumor and ask what other genes are present that are not normally present," he said.

When the fusion gene is placed in differentiating muscle, tumors only form in 1 in about 200 mice. But if mutations are also added in either of the two genes, the frequency increases "enormously," Capecchi said.

Normally, the genes suppress cell division. So to create a tumor their action has to be disrupted.

"Now that we have a mouse model that closely reflects human tumor, we can learn about how tumor progression occurs and in detail the molecular events along the way," he said.

Lead author of the studies was Dr. Charles Keller, a pediatric cancer specialist at Huntsman Cancer Institute. Co-authors of the studies were U. undergraduate Mark Hansen; Cheryl Coffin, a physician in pediatric pathology; Benjamin Arenkiel, a graduate student in human genetics, and Harvard Medical School's Nabeel El-Bardeesy and Ronald DePinho.