Researchers have found that abnormal stimulation of a cellular trigger that normally regulates replenishment of brain cells in adults causes invasive tumor-like growths in mice. Removing the abnormal stimulation causes the growths to regress--a finding the researchers said suggests a possible treatment for the lethal, aggressive brain tumors called malignant gliomas.
Arturo Alvarez-Buylla and Erica L. Jackson, of the University of California, San Francisco, and colleagues reported their findings in a paper in the July 20, 2006, Neuron, published by Cell Press. In their studies, they sought to discover whether neural stem cells in the brain called B cells carry a receptor--known as platelet-derived growth factor receptor á (PDGFRá)--for the signaling molecule PDGF.
Neural stem cells are immature cells that serve as the continual source of new brain cells in adults, and PDGF is known as an important regulator of such cells. Also, PDGF has been implicated as a key signaling molecule underlying the formation of brain tumors. PDGF triggers such cell response by plugging into the target receptor on the stem cell, like a key inserting into a lock.
There had been indirect evidence that neural stem cells give rise to brain tumors. "However, it has not been shown in vivo that tumor stem cells are derived from normal stem cells or that a specific population of cells with demonstrated stem cell properties is capable of initiating tumor formation," wrote the researchers.
Using tracers, the researchers discovered that PDGFRá is, indeed, found on the stem cells in both mouse and human brain tissue. They also found that the receptor is triggered by PDGF in the stem cells to regulate their production of mature brain cells. The researchers located the PDGFRá-containing cells in the subventricular zone (SVZ) of the brain, which is the center for production of new brain cells in adults.
The researchers also found that infusing PDGF into mouse brain caused abnormal growth--called hyperplasia--of tumor-like nodules that invaded surrounding brain tissue. Their analysis indicated that the PDGF infusion caused the stem cells to halt their normal production of mature brain cells and launch into the abnormal proliferation pathway. Importantly, the researchers found that stopping the PDGF infusion caused a complete regression of the nodules.
The researchers wrote that "these findings are significant due to our limited knowledge of surface markers for neural stem cells. Our data also provide evidence of a link between these PDGFRá B cells and the early changes associated with tumor initiation, suggesting they may be targets of neoplastic transformation. The regression of atypical hyperplasia after PDGF removal described here suggests that inhibition of PDGF signaling could provide a useful therapy for those gliomas in which the pathway is upregulated, especially given the recovery of the normal architecture after regression of the hyperplasia."
In a preview of the paper in the same issue of Neuron, Santosh Kesari and Charles D. Stiles wrote that the new findings "lend weight" to the argument that the stem cells identified by Alvarez-Buylla and his colleagues are the cells or origin for malignant gliomas. They wrote that such work offers "therapeutic opportunities," emphasizing that "the people that matter the most do not have the luxury of time to watch this work unfold. The median interval from diagnosis to death for patients with malignant glioma is currently only 14 months."
The researchers include Erica L. Jackson, Monica Roy, Scott VandenBerg, and Arturo Alvarez-Buylla of the University of California, San Francisco in San Francisco, California; Jose Manuel Garcia-Verdugo and Sara Gil-Perotin of the University of Valencia in Valencia, Spain; Alfredo Quinones-Hinojosa of the University of California, San Francisco and Johns Hopkins University in Baltimore, Maryland.
This work was supported by the Goldhirsh Foundation and NIH grant HD-32116. E.L.J. was supported by American Brain Tumor Association and American Cancer Society Fellowships. A.A.-B. holds the Heather and Melanie Muss Endowed Chair. The authors would also like to acknowledge John and Frances Bowes for their support of this research.
Jackson et al.: "PDGFRa-Positive B Cells Are Neural Stem Cells in the Adult SVZ that Form Glioma-like Growths in Response to Increased PDGF Signaling." Publishing in Neuron 51, 187-199, July 20, 2006 DOI 10.1016/j.neuron.2006.06.012 www.neuron.org
Related Preview by Kesari et al.: "The Bad Seed: PDGF Receptors Link Adult Neural Progenitors to Glioma Stem Cells."