Scientists identify signalling system that inhibits growth of a childhood brain cancer

March 16th, 2008 - 1:41 pm ICT by admin  

Washington, Mar 16 (ANI): Scientists at St. Jude Childrens Research Hospital have taken a major step forward in the fight against medulloblastoma, a rare but often fatal childhood brain tumour, by discovering that one of the brains signalling pathways inhibits the growth of the highly aggressive cancer cells.

The researchers found that 3 proteins, namely, BMP2, BMP4 and BMP7, inhibit the growth of medulloblastoma tumours and induced the malignant cells to develop into normal neurons.

The study, led by Martine F. Roussel, Ph.D., a member of the St. Jude Department of Genetics and Tumour Cell Biology, may lead to better treatments for the cancer.

We think we have identified a pathway that can be used to prevent tumour formation and a potential target for therapy, said Roussel.

Medulloblastoma occurs in the cerebellum, located in the lower, rear part of the brain. Although there is an overall 5 -year survival rate of 70 percent, conventional therapies combining surgery, irradiation and chemotherapy frequently lead to permanent neurocognitive impairment.

Researchers hope to decipher the intricate signalling mechanisms governing the proliferation of cells called granule neuron progenitors (GNPs). Later, these cells develop into neurons in the cerebellum in the first year of life. But the disruption of this differentiation process can trigger medulloblastoma.

We were interested in whether there were signals that inhibited tumour formation. And if there were, which ones were they? Could they be used to identify new therapeutic targets? said Roussel.

Previous research had shown that spurring GNPs to differentiate into neurons requires that BMPs bind to a set of receptors on the cell surface. This binding results in blocking the activity of a signalling pathway triggered by another molecule called Sonic hedgehog.

What was not known, and what we now find, is that the effect of BMPs on normal GNP cells is almost exactly mimicked in GNP-like tumour cells, said Roussel.

Roussels group noticed that in cell culture experiments, BMPs rapidly cause the degradation of a protein called Math1, present in dividing GNPs, but not in non-proliferating neurons. However, after 12 hours of BMP treatment, researchers could not detect any Math1 causing the cell growth to be stopped soon.

Though the exact mechanism of Math1 remains unknown, in mice the protein is vital to the formation of a normal brain. Mice genetically altered for not carrying the gene for Math1 could not develop cerebellums.

The researchers also conducted gene transfer experiments in mice for testing BMPs as a possible medulloblastoma treatment. The scientists used a genetically altered virus to insert the BMP gene into the cancer cells and showed that the transfer not only halted tumour growth, but also induced the cancer cells to change into neurons.

However, BMPs are very expensive to purify but currently, the scientists are searching for tiny, less expensive biological molecules to copy the action of BMPs in medulloblastoma. It was also suggested that the ability of BMPs to transform medulloblastoma cells into normal neurons, coupled with a discovery made earlier at St. Jude, could offer a combination treatment for the cancer.

A report on this work appears in the recent issue of Genes & Development. (ANI)

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