Cell maturity pathway is deleted or weak in glioblastoma multiforme

Cell maturity pathway is deleted or weak in glioblastoma multiforme

A program that pushes immature cells to grow up and fulfill their destiny as useful, dedicated cells is short-circuited in the most common and deadly form of brain tumor, scientists say.

via ScienceDaily: Top Health News:

Aug. 7, 2013 — A program that pushes immature cells to grow up and fulfill their destiny as useful, dedicated cells is short-circuited in the most common and deadly form of brain tumor, scientists at The University of Texas MD Anderson Cancer Center report this week in the Early Edition of the Proceedings of the National Academy of Sciences (PNAS).Stuck in what amounts to cellular adolescence, these precursor cells accumulate, contributing to the variability among glioblastoma multiforme (GBM) cells that make it so difficult to treat, said first author Jian Hu, Ph.D., instructor of Genomic Medicine.”This arrested development is driven by the GBM cells’ plasticity — their stem-cell-like ability to produce many types of cells — and the breakdown of the cellular maturation process known as terminal differentiation,” said senior author and MD Anderson President Ronald DePinho, M.D.By searching for genes missing from GBM cells, rather than mutated, Hu and colleagues discovered a key differentiation pathway whose absence fuels tumor growth.”If glioblastoma cells were to undergo differentiation, the tumor would stop growing,” Hu said. “But we’ve shown that if the terminal differentiation circuitry is gone, they get stuck in the middle and produce many different cell types.”Such cellular diversity, or heterogeneity, is a hallmark of cancer that helps it survive and progress. The “multiforme” in glioblastoma multiforme reflects the heterogeneity among and inside tumors.Cancer stem cells: heterogeneity machines”When a normal neural stem cell divides, it makes one copy of itself and one copy of a precursor cell destined to differentiate into a neuron, an astrocyte or an oligodendrocyte,” Hu said.GBM cells appear locked in a stem-like state, which can lead to runaway division of undifferentiated cells.A microarray analysis of 71 human glioblastoma samples revealed high levels of stem cell and precursor cell markers for neurons and supportive cells. Fewer cells expressed markers of terminal differentiation. Overall, there were high levels of cellular heterogeneity dominated by immature cells. Higher-grade gliomas had greater heterogeneity.Sifting genes involved in nervous system developmentThe team then surveyed The Cancer Genome Atlas GBM database looking for genes that have a known role in nervous system development and are frequently deleted. Of 71 genes identified, A2BP1 caused a notable reduction in colony formation in a GBM cell line. A2BP1 is a gene-splicing factor active in neural development that has been implicated in developmental and psychiatric disorders when mutated.By profiling 430 TCGA GBM samples, the researchers found A2BP1 deleted in 10 percent of tumors. However, additional analysis showed that its protein is absent or steeply reduced in 90 percent of samples. …

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Cell maturity pathway is deleted or weak in glioblastoma multiforme

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