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M. D. Anderson team identifies new oncogene for brain cancer

n indicator of poor prognosis for glioma patients. The PNAS paper takes it beyond this biomarker status.

Zhang, Fuller and colleagues employed a viral gene transfer delivery agent known as RCAS, which is loaded with the gene, or genes, of interest and injected into the mouse brain. The viral particles infect only glial cells, where the genes are expressed.

This system allows the researchers to observe whether a gene identified in a correlation study plays an active role in tumorigenesis. It also permits the delivery and study of combinations of genes.

They found that a combination of IGFBP2 and another known oncogene called K-Ras leads to development of astrocytomas a glioma named for the star-like shape of its constituent cells.

A combination of K-Ras and a third gene, Akt, previously had been shown to develop astrocytomas. Activation of Akt fuels cell growth and survival. None of the three genes caused brain cancer formation when delivered alone. The researchers tried a combination of Akt and IGFBP2 and no tumor formed, suggesting that the two genes lie in the same molecular pathway and have a similar effect.

For oligodendroglioma, the researchers found that IGFBP2 combined with platelet-derived growth factor beta (PDGFB) results in a higher-grade form of the cancer than that caused by PDGFB alone. The high-grade tumors formed by the combination were indistinguishable in their shape and brain-invasive behavior from human oligodendrogliomas.

The combination also activated the Akt pathway, which PDGFB does not induce by itself. Combined with their earlier findings, this led the team to hypothesize that IGFBP2 activates the Akt pathway, which they confirmed in subsequent lab experiments.

In a final experiment, they treated IGFBP2-PDGFB infected cells in culture with a known Akt inhibitor, which killed more of the combination cells than those infected only with platelet-derived growth fact
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Contact: Scott Merville
sdmervil@mdanderson.org
713-792-0661
University of Texas M. D. Anderson Cancer Center
2-Jul-2007


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