Aggressive brain tumors can originate from a range of nervous system cells
Scientists have long believed that glioblastoma multiforme (GBM), the most aggressive type of primary brain tumors, begins in glial cells that make up supportive tissue in the brain or in neural stem cells. In a paper published in Science, however, Salk researchers reported that the tumors can originate from other types of differentiated cells in the nervous system, including cortical neurons.
"One of the reasons for the lack of clinical advances in GBM has been the insufficient understanding of the underlying mechanisms by which these tumors originate and progress," says Inder Verma, a professor in Salk's Laboratory of Genetics and the holder of the Irwin and Joan Jacobs Chair in Exemplary Life Science.
To better understand this process, Verma's team harnessed the power of modified viruses, called lentiviruses, to disable powerful tumor suppressor genes in mice that regulate the growth of cells and inhibit the development of tumors. With these tumor suppressors deactivated, cancerous cells are given free rein to grow out of control. The modified viruses target two genes—neurofibromatosis 1 (NF1) and p53—that, when mutated, are implicated in severe gliomas like GBM. Using sophisticated analytical techniques, they discovered that neurons genetically converted by the lentiviruses are capable of forming malignant gliomas.
"Our findings," says lead author Dinorah Friedmann-Morvinski, a postdoctoral researcher in the Laboratory of Genetics, "suggest that, when two critical genes—NF1 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."
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, with most patients dying within one to two years of diagnosis. The Salk researchers' findings suggest potential new targets to treat these deadly cancers.
"Our results offer an explanation of recurrence of gliomas following treatment," says Verma, "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."