Zebrafish aid in understanding the origins of rhabdomyosarcoma

BOSTON (ASRN.ORG) - Researchers from Children's Hospital Boston and the Dana-Farber Cancer Institute have identified the cancer stem cell for rhabdomyosarcoma, the most common soft-tissue sarcoma of childhood. They report their findings in the June 1 issue of Genes & Development.

Cancer stem cells make up only a small fraction of the overall number of cells in a tumor, but are capable of giving rise to other cancer cells, and thereby drive tumor growth and metastasis. The rhabdomyosarcoma stem cell is one of a handful of cancer stem cells identified to date, and the first to be identified by studying zebrafish.

"The zebrafish recapitulates human rhabdomyosarcoma very closely," says Leonard Zon, MD, Director of the Stem Cell Program at Children's Hospital Boston, Grousbeck Professor of Hematology/Oncology at Children's and the study's senior investigator. "Using zebrafish as a model, we identified a type of cell, called the cancer stem cell, that is capable of remaking the tumor. It is these cells that are retained after chemotherapy and cause patients to relapse. If one can target these rare cells for destruction, the hope is that tumors will not re-grow."

Rhabdomyosarcoma is an aggressive cancer that arises from a primitive skeletal muscle cell called a rhabdomyoblast. The most common subtype is embryonal rhabdomyosarcoma (ERMS), a devastating cancer usually found in children under 15, in the head and neck region and genitourinary tract.

Zon and colleagues were studying the RAS pathway, involved in about 30 percent of human cancers, and found that activating the RAS pathway in muscle efficiently induced ERMS in a strain of genetically engineered zebrafish. The animals developed visible tumors by 10 days of age. "We were modeling different kinds of cancer in zebrafish, to try to develop the quickest cancer model for research," says the study's first author, David Langenau, PhD, also of Children's Stem Cell Program and Division of Hematology/Oncology. "We were surprised to find that ERMS could be induced so quickly. This is the fastest cancer model known to date."

Through their model, the team identified a novel genetic signature, activated by the RAS pathway, that underlies ERMS progression in both zebrafish and human patients. Additional analysis revealed a second genetic signature in the cancer stem cells that is similar to that of normal muscle stem cells. The researchers speculate that normal muscle stem cells become cancer stem cells by simply getting stuck at an immature stage of development, retaining the ability to make many more copies of themselves.

The researchers now plan to use the zebrafish as a model in which to screen chemicals that might arrest ERMS stem cell activity. Because zebrafish produce large numbers of offspring each week, it will be possible to generate 300 to 400 zebrafish with tumors in a single day. Various chemicals can be tested simply by adding them to the fish water, and because the fish are so small, only minute amounts are needed. The work may also help tease out mechanisms of other cancers that involve the RAS pathway.

"The zebrafish is ideally suited for use in targeted chemical genetic approaches to specifically inactivate cancer pathways we have identified in our study," says Zon. "Identifying drugs that inactivate these pathways in the ERMS cancer stem cell may have far-reaching implications for treatment of patients with this disease."

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