Inflammatory protein converts glioblastoma cells into the most aggressive version

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A prominent protein activated by inflammation is the key instigator that converts glioblastoma multiforme cells to their most aggressive, untreatable form and promotes resistance to radiation therapy, reported an international research team.

This discovery points to new ways to increase radiation effectiveness and to potentially block or reverse progression of glioblastoma multiforme, which is the most common and lethal form of brain tumor. The research was published in Cancer Cell (2013; doi:10.1016/j.ccr.2013.08.001).

"We know that the mesenchymal (MES) subgroup of glioblastoma cells is the most aggressive subgroup clinically," said co–senior author Ken Aldape, MD, of The University of Texas MD Anderson Cancer Center in Houston. "This paper shows that the NF-kB pathway causes cells to change to that MES subgroup."

This conversion leads to radiation resistance.

"The pathway we identified serves as an escape mechanism for tumors," said lead author Krishna Bhat, PhD, also of MD Anderson. "In newly diagnosed patients, even before treatment, these cells already are poised to meet radiation therapy challenges."

NF-κB activation is stimulated by inflammation, which occurs in the tumor cell's microenvironment. Radiation resistance occurs as tumor cells shift to an MES type, which is a shift that is associated with invasion and new blood vessel formation.

Since 90% to 95% of glioblastoma is diagnosed without a prior history of a lower grade glioma, how glioblastoma progresses from its early stages is unknown. About half of newly diagnosed cases are in the MES subgroup. Glioblastomas with a proneural (PN) subtype have a much better prognosis, though after treatment they tend to recur as the aggressive MES subtype.

Two distinct cell types have been identified based on gene expression. The research team cultured 41 human glioblastoma samples and found that 33 developed into neurospheres. When 17 of the fastest-expanding cell cultures were analyzed by microarray, two distinct groups were found: one similar to MES and the other to PN.

When four genes common to each subtype were analyzed, all but two of the cell lines (70%) that originated from MES tumors lost their MES characteristics and acquired a PN signature. Bhat noted that these in vitro results do not match the human experience, where glioblastoma cells do not retreat from an aggressive to less aggressive state.

After the grafts from the cell cultures were implanted into mice and treated with radiation, survival increased for those with the PN type but was little affected for those with the MES type, which had an enhanced ability to repair damage caused by irradiation.

The Cancer Genome Atlas research on glioblastoma had previously found that genes in the TNFα receptor family and the NF-κB pathway are enriched in MES subclass tumors that also express high levels of the surface receptor CD44. This research team found that the exact same pathway had been turned on in the MES cells in their study.

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