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April 7, 2004
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Cross-species Comparison Reveals Shared Features Between Tumorigenesis and Organogenesis
A new study, published in the March 15th issue of Genes & Development, provides critical new insight into the shared mechanisms of normal organ development and solid tumor formation.
By studying the cerebellum (the structure in the brain largely responsible for coordinating motor activities) Drs. Alvin Kho and Isaac Kohane at Children's Hospital Boston, Dr. David Rowitch at Dana-Farber Cancer Institute, and their research colleagues in Boston have developed a novel method for comparing the genetic changes associated with normal development in mice with that of the most common malignancy of the pediatric nervous system, medulloblastoma.
"With information derived from the Human Genome Project we now have the ability to easily compare and identify meaningful patterns of gene expression between species such as mouse and human," said Kho, a postdoctoral fellow and the paper's lead author. Such cross-species comparison provides a powerful new tool for understanding the genetic changes associated with human tumor development.
In a developing organ, the pattern of gene expression changes as the individual cells commit to their own specialized functions. By analyzing the changing patterns of expression of more than 2,000 genes in the developing cerebellum in mice and comparing these to genes expressed in human medulloblastomas, the investigators were able to characterize the malignant cells from a developmental perspective.
The researchers found that different types of medulloblastomas share many common features with cerebellar cells at the very earliest stages of their development, further emphasizing that malignant cells have disrupted developmental programs.
''These findings have exploited our ability to analyze thousands of independently segregating genetic markers to confirm the classic theories by investigators such as Lobstein and Cohnheim in the 19th century that tumorigenesis recapitulates aspects of development,'' Rowitch said.
Kohane and Rowitch's research is important for two reasons. Firstly, this novel method provides a generalizable framework within which gene expression in development and tumorigenesis can be studied. This means the role of a particular gene in tumor progression can be better understood. Secondly, since this analysis is readily applicable to other tumor types it may be developed as a useful tool for both tumor diagnosis and prognosis.
Indeed, the investigators show that similar findings are obtained when a human squamous cell lung cancer is compared with the developing rodent lung.
''Much work remains to be done to determine whether the 'developmental perspective' can lead to clinically meaningful insights such as advances in diagnosis or our understanding of tumor behavior,'' Kohane said. ''This study provides a foundation to ask these questions and facilitate translation of a large basic science knowledge base into the clinical sphere.''
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 for over 100 years. More than 500 scientists, including seven members of the National Academy of Sciences, nine members of the Institute of Medicine and 10 members of the Howard Hughes Medical Institute comprise Children's research community. Founded in 1869 as a 20-bed hospital for children, Children's Hospital Boston today is a 300-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. It is also the primary pediatric teaching affiliate of Harvard Medical School. For more information about the hospital visit: www.childrenshospital.org.