Aggressive brain tumors can originate from a range of nervous system cells

Glioblastoma multiforme (GBM) tumors can originate not only from the glial cells that make up the supportive tissue of the brain and from neural stem cells, but also from other types of differentiated cells in the nervous system, including cortical neurons. These research findings offer an explanation for the recurrence of GBM after treatment and suggest potential new targets to treat these deadly brain tumors.

GBM is one of the most devastating brain tumors that can affect humans. Despite progress in genetic analysis and classification, the prognosis of these tumors remains poor. Most patient die within 1 to 2 years after diagnosis.

“One of the reasons for the lack of clinical advances in GBMs has been the insufficient understanding of the underlying mechanisms by which these tumors originate and progress,” says Inder Verma, PhD, professor at the Salk Institute for Biological Studies. His research team used modified viruses, called lentiviruses, to disable powerful tumor suppressor genes that regulate the growth of cells and inhibit the development of tumors. Deactivating the tumor suppressors gave cancerous cells free rein to grow out of control. The researchers targeted the neurofibromatosis gene 1 (NF1) and p53 genes, which, when mutated, are implicated in severe gliomas like GBM.

The origin of glioblastomas from neurons has not been previously reported. This study provided further evidence that mature neurons can be transformed by these oncogenes by isolating critical neurons from genetically engineered mice and transducing them with one of the lentiviruses. The neurons that were transplanted back into the mice developed the same tumors as the ones in the laboratory.

Lead author and postdoctoral researcher Dinorah Friedmann-Morvinski, PhD, said, “Our findings suggest that, when two critical genes—NF-1 and p53—are disabled, mature, differentiated cells acquire the capacity to reprogram [dedifferentiate] to a neuroprogenitor cell-like state, which can not only maintain their plasticity, but also give rise to the variety of cells observed in malignant gliomas.”

Verma explained, “Our results offer an explanation of recurrence of gliomas following treatment, because any tumor cell that is not eradicated can continue to proliferate and induce tumor formation, thereby perpetuating the cycle of continuous cell replication to form malignant gliomas.”

This research was published in Science Express (2012; doi:10.1126/science.1226929).
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