Aggressive and recurrent glioblastomas have been shown to contain a fraction of multipotent cells with extensive self-renewing properties that are likely to drive tumour growth. Angelo Vescovi and colleagues now show that bone morphogenetic proteins (BMPs) can block the growth of these brain-tumour-initiating cells (BTICs) and inhibit their ability to establish glioblastomas after transplantation.

BMPs direct normal brain stem cells towards an astroglial commitment, so the authors investigated whether they could also affect BTIC fate. They found that BMP4 and its cognate receptor are both expressed in glioblastoma cells, including the CD133+ subpopulation that is enriched in BTICs, and that the signalling pathway is functional, shown by the activation of the Smad signalling cascade. In vitro, BMP4 had a cytostatic effect on glioblastoma cells, reducing both their clonogenic index and growth rate, and inducing differentiation, as assessed by the detection of astroglial and neuronal markers. Remarkably, BMP4 reduced the subpopulation of glioblastoma cells that express CD133+ by almost 50%, indicating that it targets the BTIC compartment by inducing these cells to differentiate.

The authors then tested whether BMP4 could also affect the tumorigenic BTIC pool in vivo. They pre-treated CD133+ glioblastoma cells with BMP4 and injected them into immunodeficient mice. Strikingly, BMP4-treated cells did not form invasive tumours, but only small delimited lesions, whereas all mice injected with untreated cells developed large tumours and died after just a few months. BMP4 was also delivered either during or after the injection of glioblastoma cells, and in both cases it blocked tumour development and significantly increased survival compared with control mice.

Therefore, BMP4 is a promising candidate for new strategies against malignant glioblastomas — inducing differentiation rather than killing the tumour-initiating cells.