Fishing for Answers... Zebra Fish: A Model System for Studying Neuroblastoma

At Dana Farber Cancer Institute, Drs. A. Thomas Look and Rodney A. Stewart are studying zebra fish models in hopes of identifying defective genes involved in neuroblastoma (NB), a very aggressive pediatric cancer that affects the nervous system. The investigation's innovative approach could have an enormous impact on the development of effective targeted therapies for this devastating disease.

In the first year of this HSK fellowship (generously underwritten by the Scotts Company), researchers have already identified five new suspicious gene mutations that cause changes in the normal development of the sympathetic nervous system in the embryos of zebra fish. These tiny striped fish, native to India and often popular in aquariums, offer a window to understanding the genetic basis of neuroblastoma and other human diseases.

"A zebra fish's nervous system is similar to that of humans. The same genes function in both species during the formation of the peripheral sympathetic nervous system (PSNS), and both develop similar tumors," explains Dr. Stewart. "Unlike mouse models, zebra fish are unique in the fact that they lay transparent eggs that develop externally. The formation of their PSNS can be directly observed."

Neuroblastoma is one of the most common solid tumors in children, and is the leading cause of cancer death in children under four years of age. Despite progressive efforts to treat NB, the long-term survival rate remains below 20- 30 percent in children with stage IV disease, which represents 70 percent of all patients. Innovative approaches are needed to better understand the genetic basis of this enigmatic disease before successful therapies can be developed.

Dr. Stewart says, "NB is an embryonic tumor of the sympathetic nervous system (SNS) whose normal development depends on the regulated activity of many genes. Mutations leading to the faulty regulation of some of these genes result in uncontrolled cell proliferation in the SNS, resulting in tumor formation and NB. These genetic abnormalities predict prognosis in neuroblastoma," he adds "Researchers have already discovered that the MYCN gene is inappropriately active in one third of all NB patients. However, additional genes also need to be mutated for childhood NB, but their identity is still unknown," he explains.

Dr. Stewart is hoping to identify these unknown genes. He has created a strain of zebra fish with an abnormal MYCN gene. Through genetic screening and fish-mating techniques, he hopes to determine what other defective genes are involved in the disease. The similar sympathetic nature between humans and zebra fish, combined with the unique transparency of zebra fish eggs and the fish's ability to reproduce up to 300 offspring per week, make the fish an excellent new animal model system to help clarify the cause of neuroblastoma.

"Every child should receive individualized treatment tailored to the special properties of his or her individual tumor cells," says Dr. Stewart. Before this can happen, more needs to be understood about the variety of genetic mutations that contribute to neuroblastoma. This study may ultimately provide this critical information and have an enormous impact on developing effective therapies for young patients facing the disease.

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