Glioma, in all of its forms, is a primary brain tumor that routinely challenges the entire armamentarium available to the oncologist. Difficult to detect at early stages, difficult to treat once identified, it remains one of the more vexing cancers. A new study published in the July 8th 2011 issue of the journal Cell has identified a biochemical feature of glioma stem cells that may make them vulnerable to inhibitors targeting an enzyme involved in the production of nitric oxide.
Gliomas are one of the most difficult brain tumors to treat. The worst form of glioma, glioblastoma multiforme, is commonly fatal within 18 months of diagnosis. Current approaches to treatment can include surgical debulking or removal, use of chemotherapeutic agents, radiation therapy, and combinations of all three.
Cancer Stem Cells
Over the last 10 years, there has been a significant expansion in studies focused on what are believed to be tumor-specific cancer stem cells (CSCs). Numerous scientists believe that CSCs are a major contributor to both continued tumor growth and metastasis. Additionally, it appears that many of these cancer stem cells not only influence tumor growth and regrowth but are often resistant to standard anti-tumor treatment regimens. One of the key features of the new study was the researchers focus on the biology of what they believe to be glioma stem cells.
In the current study (Eyler), a collaborative group led by researchers at The Cleveland Clinic isolated glioma stem cells and determined that they utilized production of the molecule nitric oxide to positively influence their growth rate. Nitric oxide has been implicated in a number of normal physiological processes, but its role in tumors has not been clear.
Using cultures of glioma stem cells in tissue culture they found that these cells produced significantly more nitric oxide than non-stem cells. Using a molecular trick to restrict the levels of nitric oxide produced by the glioma stem cells, Eyler et al. were able to isolate glioma stem cells from primary gliomas and show that their growth was reduced if the nitric oxide production was reduced. Examining the expression of enzymes involved in the production of nitric oxide, they also found that the gene encoding nitric oxide synthase-2 (NOS2) was consistently more active in the glioma stem cells, perhaps explaining the increase in nitric oxide production by these cells.
Blocking Nitric Oxide Synthesis to Fight Tumors
In an important experiment using tumors engrafted into mice (tumor cell xenografting), Eyler et al. were able to show that blocking the activity of NOS2, using two already available chemical agents, was able to significantly delay the growth of these transplanted tumors. An important consideration was whether or not these compounds would also negatively impact on normal neural stem cells present in the brain, and the answer appears to be that they do not.
Using gene expression data collected from brain tumor patients that is available through the U.S. National Institutes of Health (NIH) in its Repository for Molecular Brain Neoplasia Data (REMBRANDT) database, Eyler et al. identified an intriguing correlate in human gliomas. They found that high levels of NOS2 expression correlated with poor patient outcomes, no matter the initial staging of the tumor. Perhaps the data revealed in this study identifies a potential mechanism being used by tumors to enhance their growth that could serve as a molecular target for future interventions in the treatment of glioma.
Source
Christine E. Eyler, Qiulian Wu, Kenneth Yan et al., Glioma Stem Cell Proliferation and Tumor Growth Are Promoted by Nitric Oxide Synthase-2. Cell: 146, 53–66, July 8, 2011
Kenneth Rosen - I am a medical research doctor with more than 20 years of experience studying how the nervous system and skeletal muscle develop and ...
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