Glioblastoma models reveal the connection between adult glial progenitors and the proneural phenotype |
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Authors: | Lei Liang Sonabend Adam M Guarnieri Paolo Soderquist Craig Ludwig Thomas Rosenfeld Steven Bruce Jeffrey N Canoll Peter |
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Institution: | Department of Pathology and Cell Biology, Columbia University, New York, New York, United States of America. |
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Abstract: | BackgroundTumor heterogeneity is a major obstacle for finding effective treatment of
Glioblastoma (GBM). Based on global expression analysis, GBM can be
classified into distinct subtypes: Proneural, Neural, Classical and
Mesenchymal. The signatures of these different tumor subtypes may reflect
the phenotypes of cells giving rise to them. However, the experimental
evidence connecting any specific subtype of GBM to particular cells of
origin is lacking. In addition, it is unclear how different genetic
alterations interact with cells of origin in determining tumor
heterogeneity. This issue cannot be addressed by studying end-stage human
tumors.Methodology/Principal FindingsTo address this issue, we used retroviruses to deliver transforming genetic
lesions to glial progenitors in adult mouse brain. We compared the resulting
tumors to human GBM. We found that different initiating genetic lesions gave
rise to tumors with different growth rates. However all mouse tumors closely
resembled the human Proneural GBM. Comparative analysis of these mouse
tumors allowed us to identify a set of genes whose expression in humans with
Proneural GBM correlates with survival.Conclusions/SignificanceThis study offers insights into the relationship between adult glial
progenitors and Proneural GBM, and allows us to identify molecular
alterations that lead to more aggressive tumor growth. In addition, we
present a new preclinical model that can be used to test treatments directed
at a specific type of GBM in future studies. |
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