A Better Model for a Deadly Brain Cancer
April 26, 2006
Researchers have created a mouse model that closely mimics human medulloblastoma, the most common type of childhood brain tumor. The new model, which was created by knocking out a key component of the DNA repair machinery, will aid in exploring the genetic roots of this deadly brain cancer, and should also be useful in testing potential treatments.
The researchers, led by Frederick W. Alt, a Howard Hughes Medical Institute investigator at Children's Hospital Boston, published their findings the week of April 24, 2006, in the early online edition of the Proceedings of the National Academy of Sciences. Catherine Yan in Alt's laboratory was lead author of the article.
Although childhood cancers are rare, brain tumors are among the most common. About one out of five childhood brain tumors is medulloblastoma, an aggressive cancer of the cerebellum. Alt, Yan and colleagues produced the mouse model of medulloblastoma by knocking out a gene called XRCC4, which plays an important role in repairing chromosome breaks by joining the broken ends together. Chromosome breaks can occur in all cell types from exposure to radiation, chemicals, or other insults. When repair of these breaks goes awry, the result can be abnormal swapping of chromosomal regions, known as chromosomal translocation, that can contribute to cancer and other diseases.
In earlier studies, Alt and colleagues found that eliminating XRCC4 in mice led to widespread death of newly generated neurons (brain cells) and, ultimately, death of the embryo. Alt's team then eliminated a second gene, p53, which triggers the death of malfunctioning cells. With both p53 and XRCC4 missing, neurons survived and the mice lived into early adulthood, but then died of lymphomas caused by chromosomal translocations in the immune system. The researchers also noted that the mice were beginning to develop medulloblastoma.
This observation raised the possibility that deficiency of the XRCC4 protein might have a role in causing medulloblastoma. So Alt's team did new experiments, eliminating the XRCC4 gene, but only in the developing nervous system. "We wanted to know whether getting rid of both XRCC4 and p53 in the nervous system would predispose the animals to neuronal tumors, and whether or not those tumors would also be associated with particular chromosomal translocations," Alt explains.
Alt, Yan and colleagues engineered two strains of mice. One strain lacked only XRCC4 in its developing neural cells, and appeared to develop normally. But every mouse in the other strain -- lacking both XRCC4 and p53 -- died very early of medulloblastomas. "Those tumors strongly resembled human medulloblastoma," Alt adds.
Analyzing the tumors, Alt and his colleagues were intrigued to find recurrent chromosomal translocations that were often accompanied by alterations in specific genes--and the affected genes often were the same genes activated or inactivated in human medulloblastomas. Specifically, the tumors often showed amplifications of the genes N-myc and Cyclin D2, which are characteristic of medulloblastomas and many human brain tumors. The animals also lost one copy of a gene called patched, which is also characteristic of some human medulloblastomas.
While other groups have created mouse models of medulloblastoma by knocking out patched or other individual genes, "what we did was different," Alt says. "We created an environment in which chromosomal end-joining was defective, leading to instability of the genome, and let the biology of the cell sort out the consequences. And while in most other models not every mouse develops medulloblastoma, in our case every animal very reproducibly develops these tumors at a very young age."
The new mouse model will prove valuable in understanding why N-myc is so frequently amplified in human tumors, including neuroblastomas and medulloblastomas, and the consequences of that amplification, Alt says. The model also will enable the researchers to better explore causes of the chromosomal translocations, deletions, and amplifications in the nervous system.
Other laboratories have consulted Alt's team on the possibility of using its medulloblastoma mouse model for drug testing. "This model could be very useful, because every mouse gets tumors with an early onset and the tumors show activation or inactivation of a set of genes that is implicated in human tumors," Alt says. "So, if one wants to test therapies that interfere with pathways involved in human tumors, this should be a good model."
Other co-authors were from Brigham & Women's Hospital, CBR Institute of Biomedical Research, and the Dana-Farber Cancer Institute, all of Harvard Medical School.
Children's Hospital Boston is home to the world's largest research enterprise based at a pediatric medical center, where its discoveries have benefited both children and adults since 1869. More than 500 scientists, including eight members of the National Academy of Sciences, nine members of the Institute of Medicine and 11 members of the Howard Hughes Medical Institute comprise Children's research community. Founded as a 20-bed hospital for children, Children's Hospital Boston today is a 347-bed comprehensive center for pediatric and adolescent health care grounded in the values of excellence in patient care and sensitivity to the complex needs and diversity of children and families. Children's also is the primary pediatric teaching affiliate of Harvard Medical School. For more information about the hospital and its research visit: http://www.childrenshospital.org/research/.
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