XML Feed for RxPG News   Add RxPG News Headlines to My Yahoo!   Javascript Syndication for RxPG News

Research Health World General
 
  Home
 
   Health
 Aging
 Asian Health
 Events
 Fitness
 Food & Nutrition
 Happiness
 Men's Health
 Mental Health
 Occupational Health
 Parenting
 Public Health
 Sleep Hygiene
 Women's Health
 
   Healthcare
 Africa
 Australia
 Canada Healthcare
 China Healthcare
 India Healthcare
 New Zealand
 South Africa
 UK
 USA
 World Healthcare
 
   Latest Research
 Aging
 Alternative Medicine
 Anaethesia
 Biochemistry
 Biotechnology
 Cancer
  Bladder
  Blood
  Bone Cancer
  Brain
   Glioblastoma Multiforme
   Medulloblastoma
  Breast Cancer
  Carcinogens
  Cervical Cancer
  Colon
  Endometrial
  Esophageal
  Gastric Cancer
  Liver Cancer
  Lung
  Nerve Tissue
  Ovarian Cancer
  Pancreatic Cancer
  Prostate Cancer
  Rectal Cancer
  Renal Cell Carcinoma
  Risk Factors
  Skin
  Testicular Cancer
  Therapy
  Thyroid
 Cardiology
 Clinical Trials
 Cytology
 Dental
 Dermatology
 Embryology
 Endocrinology
 ENT
 Environment
 Epidemiology
 Gastroenterology
 Genetics
 Gynaecology
 Haematology
 Immunology
 Infectious Diseases
 Medicine
 Metabolism
 Microbiology
 Musculoskeletal
 Nephrology
 Neurosciences
 Obstetrics
 Ophthalmology
 Orthopedics
 Paediatrics
 Pathology
 Pharmacology
 Physiology
 Physiotherapy
 Psychiatry
 Radiology
 Rheumatology
 Sports Medicine
 Surgery
 Toxicology
 Urology
 
   Medical News
 Awards & Prizes
 Epidemics
 Launch
 Opinion
 Professionals
 
   Special Topics
 Ethics
 Euthanasia
 Evolution
 Feature
 Odd Medical News
 Climate
Search

Last Updated: Nov 18, 2006 - 1:55:25 PM

Medulloblastoma Channel
subscribe to Medulloblastoma newsletter

Latest Research : Cancer : Brain : Medulloblastoma

   DISCUSS   |   EMAIL   |   PRINT
New mouse model that closely mimics human medulloblastoma
Apr 28, 2006 - 1:38:00 AM, Reviewed by: Dr. Priya Saxena

“Only in our wildest dreams had we hoped to see these kinds of recurrent translocations. It's quite exciting to us that we'll be able to explore mechanistically why they happen when the basic process of end-joining is compromised.”

 
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.

The researchers, led by Howard Hughes Medical Institute investigator Frederick W. Alt, 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, who is in Alt's laboratory at Children's Hospital Boston, was lead author of the article. Other co-authors were from Brigham & Women's Hospital, CBR Institute of Biomedical Research, Children's Hospital and Dana-Farber Cancer Institute, all of Harvard Medical School.

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 and his colleagues produced the mouse model of medulloblastoma by knocking out a gene called XRCC4, which produces a protein that plays an important role in stitching together the ends of broken DNA. These breaks which can occur in all cell types from exposure to radiation, chemicals, or other insults, occur specifically in the immune system when genes are snipped and rearranged to produce a vast array of antibodies. The abnormal swapping of chromosomal regions that ensues when such repair goes awry--known as chromosomal translocations--is sometimes harmless, but can contribute to cancer and other diseases.

In earlier studies, Alt and his colleagues discovered that XRCC4 is a component of nonhomologous end-joining, a process that is essential for the repair of chromosome breaks. They found that knocking out this gene in mice led to widespread death of newly generated neurons and death late in embryonic development. The researchers then combined these experiments with the elimination of a gene for a sentinel protein called p53, which triggers the death of malfunctioning cells. With both p53 and XRCC4 missing, neurons survive and the mice live into early adulthood, but then die of lymphomas caused by translocations of antibody genes. The researchers noted that by this time, the mice were also beginning to develop medulloblastomas.

After they made that observation, Alt's team wanted to zero in on the possible role of XRCC4 deficiency in medulloblastomas. While their earlier studies involved knocking out the XRCC4 gene throughout the animals' bodies, now “the major goal was to eliminate this protein only in the developing nervous system, so we could specifically determine whether there was a role for nonhomologous end-joining in suppressing cancers of cells besides those of the immune system,” he said. “We also 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.”

So Yan and her colleagues engineered two strains of mice in which XRCC4 was knocked out only in neural progenitor cells in the developing nervous system. One strain had only the XRCC4 knockout, and the other also had a deficiency in both XRCC4 and p53. These mice appeared to develop normally without XRCC4, they found. But every mouse lacking both XRCC4 and p53 died very early of medulloblastomas. Furthermore, “those tumors strongly resembled human medulloblastomas,” said Alt.

Analyzing the tumors for genetic abnormalities, Alt and his colleagues found that specific genes were frequently altered in association with recurrent chromosomal translocations--and that affected genes often were those activated or inactivated in human medulloblastomas. Thus, the tumors often showed amplifications of two genes called N-myc and Cyclin D2, which are characteristic of many human neural tumors, including medulloblastomas. The animals also showed the loss of one copy of a gene called patched, which is also characteristic of some human medulloblastomas.

“Only in our wildest dreams had we hoped to see these kinds of recurrent translocations,” said Alt. “It's quite exciting to us that we'll be able to explore mechanistically why they happen when the basic process of end-joining is compromised.”

Other mouse models of medulloblastoma have been created by knocking out patched or other individual genes that have been implicated in the development of medulloblastoma. However, said Alt, “what we did was different. We created an environment in which end-joining was defective and let the biology of the cell sort out the consequences. And while in most other models not every mouse develops medulloblastomas, in our case every animal very reproducibly develops these tumors at a very young age. It's really quite intriguing, too, how this general genomic instability very specifically leads to the selection of tumor cells that have deregulated particular genes such as N-myc, patched and Cyclin D2.”

According to Alt, 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. The model also will enable the researchers to better explore causes of the chromosomal translocations, deletions, and amplifications in neuronal cells.

The mouse model should also be useful in testing potential treatments for medulloblastoma. Alt said that other laboratories have consulted them on the possibility of using the model for drug testing. “This model could be very useful for such a purpose 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,” he said. “So, if one wants to test therapies that interfere with pathways involved in human tumors, this should be a good model.”
 

- April 24, 2006, in the early online edition of the Proceedings of the National Academy of Sciences
 

www.hhmi.org

 
Subscribe to Medulloblastoma Newsletter
E-mail Address:

 



Related Medulloblastoma News
New mouse model that closely mimics human medulloblastoma


For any corrections of factual information, to contact the editors or to send any medical news or health news press releases, use feedback form

Top of Page

 

© Copyright 2004 onwards by RxPG Medical Solutions Private Limited
Contact Us