Potentially lethal cancer stem cells — or tumour-initiating cells (TICs) — can divide indefinitely, just like normal stem cells. Speculating that this property might be due to an inability of TICs to differentiate, researchers led by Howard Fine of the US National Cancer Institute in Bethesda compared TICs from human brain tumours with normal neural stem cells from adult mice, mouse embryos and human fetal tissues. They found that a pathway active both in early embryogenesis and in neural stem cell differentiation is blocked in a subgroup of brain TICs. Restoring this pathway allowed the TICs to differentiate and rendered them less able to form tumours.

The researchers first showed that cells collected from samples of different human glioblastomas could cause tumours in mice. Treating the TICs with the signaling protein bone morphogenetic protein (BMP) caused TICs from several of the glioblastomas to differentiate, in the same way as late embryonic and adult neural stem cells under this treatment. In the TICs from one glioblastoma, however, BMP stimulated cell division but did not induce differentiation.

Further investigation showed that expression of the gene BMP receptor 1B (BMPR1B) in these TICs was much lower than in normal neural stem cells. The researchers did not find any DNA mutations in the BMPR1B gene in the TICs, however. Instead, the gene had been shut down, or 'silenced', by the methylation of certain nucleotides in the gene's promoter region. If expression of BMPR1B was increased, either by blocking methylation or by introducing an active copy of the gene into the TICs, these cells then differentiated in response to BMP.

In embryonic stem cells, BMPR1B is kept silent by the agency of a group of proteins known as the Polycomb repressor complex. When Fine and his colleagues silenced a component of this complex in TICs, BMPR1B was less methylated and more strongly expressed. This indicates that the mechanisms that prevent differentiation in TICs and in embryonic stem cells are similar.

These findings show that at least some TICs are cells trapped at an early developmental stage. It also points to a potential new way to treat glioblastoma. Small molecules that induce BMPR1B expression might cause TICs to differentiate rather than form tumours.