Cell of origin for brain tumors may predict response to therapy

The finding is significant, the researchers say, because it gives cancer doctors and researchers new cellular pathways to target in developing therapies. It also updates current beliefs -- that brain tumors derive from neural stem cells -- with the indication that, since oligodendroglioma derives from progenitor cells, stem cell-specific therapies may not hold promise for treating those types of brain tumors.

Different life expectancies for two types of brain tumors were what first piqued the scientists' interest.

"With treatment, patients with oligodendroglioma can live many years longer than patients with gliobastoma multiforme. For two types of tumor that appear similar, the outcome is so different. We were interested in understanding this," said William A. Weiss, MD, PhD, corresponding author and professor in the Departments of Neurology, Pediatrics and Neurological Surgery.

"There has been a great deal of research into the molecular basis of glial tumors, but current therapies have not advanced much. Many remain ineffective and the majority of patients die from the disease, so fresh strategies are desperately needed. The ability we now have to sub-classify tumors and differentiate gliomas based on differences in cell of origin will be helpful in the search for more effective treatments," Weiss added.

Findings are described in the December 14 issue of the journal Cancer Cell.

Glioblastomas arise from the glial cells in the brain and are known to be highly aggressive, resulting in a life expectancy of just six to 12 months after diagnosis, according to the National Brain Tumor Society. Glial and neuronal cells both arise from progenitor cells, which in turn arise from neural stem cells. Oligodendrglial cells are a type of glial cell that supports neuronal cells, insulating them by producing myelin, a substance that promotes communication between neurons.

"Our study shows that tumors can arise from either neural stem cells or progenitor cells, which produce different types of brain cancers that exhibit different responses to therapy," Weiss said.

Using MRI and detailed analyses of both human and mouse tumors, the team discovered that tumor cells differentiate in the brain in two key ways, and the mode of differentiation impacts whether the tumor will be sensitive to therapy. Tumors that arise from neural stem cells such as astrocytomas (of which glioblastoma is the most common) are less sensitive to therapy because dormant stem cell-like tumor cells do not divide unless provoked by certain factors. Tumors that arise from progenitor cells, such as oligodendroglioma, are more sensitive to therapy because progenitor cells are actively dividing.

"These results suggest that oligodendroglioma tumor cells arise from normal oligodendrocyte progenitor cells, and that a progenitor rather than a neural stem cell origin underlies improved prognosis in patients with this tumor," said lead author Anders I. Persson, PhD, assistant professor of Neurology in UCSF's Helen Diller Family Comprehensive Cancer Center.

Since oligodendrogliomas are more sensitive to therapy, the team hypothesized that this sensitivity might be a property of the glial progenitors from which they arise. To test this, they treated stem cells, astrocytomas, progenitors and oligodendrogliomas with the chemotherapeutic used for glioma treatment, temozolomide. They found that stem cells and astrocytoma cells were largely resistant to the drug, but the growth of oligodendroglioma cells and of glial progenitors was vastly stalled.

"By studying the properties and behavior of the precursor cells, we have better clues about which cellular pathways could be effective for therapy, depending on the type of tumor," Persson said. "So for instance, now that we know to determine whether a brain tumor is a progenitor disease or stem cell disease, we could use MRI to make these diagnoses, resulting in faster, more effective treatment for glioma patients."

The study was supported by the Swedish Society for Medical Research, Swedish Medical Research Council, Hjarnfonden (the Swedish Brain Foundation), Sandler Postdoctoral Fellowship and the Joel A. Gingras Jr/American Brain Tumor Association Fellowship. Funding was also provided by a Sandler Opportunity Award in Basic Science, National Institutes of Health, Brain Tumor Society, UCSF Academic Senate, Accelerate Brain Cancer Cure and the Burroughs Wellcome Fund.

Additional UCSF authors include Claudia Petritsch, PhD; Fredrik J. Swartling, PhD; Melissa Itsara; David D. Goldenberg; Scott Vandenberg, MD, PhD; Kim N. Nguyen; Stanislava Yakovenko; Jennifer Ayers-Ringler; Mitchel S. Berger, MD; Gabriele Bergers, PhD; and Tracy R. McKnight, PhD.

Authors not affiliated with UCSF include Steven Goldman, MD, PhD, Frasier Sim, PhD and Romane Auvergne, PhD, from the University of Rochester; Akiko Nishiyama from the University of Connecticut; and William B. Stallcup, PhD, from Burnham Institute for Medical Research.

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