Researchers have identified a gene that is improperly silenced during the development of some neural stem-like cells in vitro, a finding which could help explain why similar cells may result in aggressive brain tumors in vivo. Further experiments in a human line derived from cells taken from glioblastoma multiforme patients showed that activating the silenced gene restores its normal developmental stages, suggesting a potential strategy for treating patients.

Tumor stem-like cells, like normal stem cells, can self-renew, but unlike stem cells, they fail to differentiate into normal cell types. Instead, they give rise to dysregulated cells, which may develop into a tumor.

This new research links changes in gene regulation to the survival of stem-like cells in culture and exposes a possible Achilles' heel.

Lead investigator Dr. Howard Fine of th National Cancer Institute's Center for Cancer Research is collaborating with drug developers to identify compounds that could activate the silenced gene in the subset of glioblastoma brain cancers with a similar flaw. The hope is that causing neural stem-like cells to mature could stop them from developing into brain tumors.

The silenced gene is the bone-morphogenetic protein receptor 1B (BMPR1B), which is involved in cell differentiation. The silencing occurs through an epigenetic change known as methylation in which the gene is chemically modified.

A surprise was that even though the brain cancer stem-like cells had genetic flaws as well as the epigenetic change, the single step of reactivating the BMPR1B receptor caused the cells to grow and differentiate normally. "We may be able to use a drug to differentiate these tumor stem cells without having to treat all the other genetic abnormalities," noted Dr. Fine. "One could argue that the stem-like cell pathways may trump the classic oncogenic pathways."

The findings also suggest that all cancer stem-like cells do not have the same flaws. Rather, to treat the disease it may be necessary to identify the specific pathways that are disrupted in individual cancer cells. The researchers estimate that the BMPR1B gene is silenced in 15 to 20 percent of glioblastoma cases.