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Researchers ID Gene Expression Signature in Aggressive Form of Glioblastoma

By a GenomeWeb staff reporter

NEW YORK (GenomeWeb News) – In a paper appearing online last night in the Proceedings of the National Academy of Sciences, researchers from Seattle and Illinois reported that they have tracked down a gene expression signature linked to an aggressive form of the brain cancer glioblastoma multiforme.

By comparing the gene expression patterns in GBM cells that are positive or negative for expression of CD133 — a transmembrane protein that has been used to identify putative cancer stem cell populations in other cancers — the team found a CD133-related gene expression profile resembling that of human embryonic stem cells. And, they say, because the CD133+ gene expression pattern often turns up in an aggressive form of GBM that affects relatively young patients, it may be possible to use this information for diagnosing and treating the disease.

"Our systematic analysis provides molecular and genetic support for the stem cell-like nature of CD133+ cells and an objective means for evaluating cancer aggressiveness," senior author Qiang Tian, a researcher affiliated with the Institute for Systems Biology and the University of Washington School of Medicine, and co-authors wrote.

With studies of leukemia and breast cancer turning up subsets of cancer cells with stem cell-like properties, the researchers explained, they decided to explore the possibility that cancer stem cells might contribute to other types of cancer as well — specifically GBM, a type of brain cancer with notoriously poor outcomes that typically involves both phenotypically and genetically diverse tumor cells.

To explore this possibility, the researchers first used immunostaining coupled with fluorescence activated cell sorting analysis to find cells that had elevated expression of CD133 — which has been detected in some brain cancer samples as well as cells with stem cell-like characteristics — in five fresh GBM tumor samples.

They then used microarray analyses to assess gene expression patterns in the CD133+ and CD133- cells and did subtractive analyses to track down differences in overall gene expression in each group, identifying 214 genes with expression differences in the cell populations. Of these, 89 transcripts showed elevated gene expression in the CD133+ cells, while 125 showed lower gene expression.

When they compared CD133+ and CD133- expression signatures in the tumors with published expression data and information from gene expression databases, the researchers found that the CD133+ expression profile not only resembled that found in GBM cells cultured in vitro, but was also surprisingly similar to that reported for human embryonic stem cells.

Moreover, the team explained, their subsequent analyses suggested that the CD133+ expression signature is more often found in younger patients and frequently coincides with particularly aggressive GBM cases with shorter survival times.

When they looked at data gathered through the Cancer Genome Atlas, meanwhile, the researchers found evidence that GBM samples expressing CD133 tend to have four times more mutations, on average, than CD133- samples.

Together, the team argued that the findings are not only consistent with the notion that cancer stem cells may contribute to GBM, but also point to a strategy for helping to characterize and treat GBM cases.

"By virtue of its similarity with stem cells and aggressive human cancers, the CD133 gene signature supports the stem-cell origin of CD133+ GBM cells," they concluded. "The aggressive molecular subtype of GBM identified in this study with the hyper-mutated genotype will be subjected to future clinical studies for developing targeted therapy."

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