High-grade astrocytomas – tumours that arise in glial cells known as astrocytes – are the most common and most deadly type of brain tumour found in adults.

The median survival time for patients diagnosed with either Grade III or Grade IV astrocytoma (the latter being more widely known as glioblastoma multiforme) is less than two years, even with aggressive multi-modal therapy.

Neural stem cells and neuronal precursor cells (NPCs) are believed both to be the source of these tumours and to release compounds that suppress their growth.

Neuronal precursor cells are present in largest numbers, and are most active, in infancy, declining through childhood: thus, the prevalence of astrocytomas is inversely correlated with NPC activity.

A large, international team of researchers led by Rainer Glass from the University of Munich, Germany, has now shown that NPCs induce cell death in astrocytomas through the secretion of a group of fatty acids known as vanilloids and activation of a vanilloid receptor on the cell surface.

Glass and his co-workers first exposed a culture of high-grade astrocytoma (HGA) cells to medium that had been conditioned by NPCs.

Gene expression analysis, gene knockdown and inhibitor studies implicated the activity of the endovanilloids at the vanilloid receptor TRPV1, which is expressed strongly in HGA cells and much more weakly in healthy brain tissue, in inducing tumour cell death.

Next, they implanted human brain tumour cells into transgenic mice that had been modified to visualise NPCs using fluorescence, and found that these cells migrated to the site of the tumour implants.

Exposure of mouse tumours to factors secreted by these cells, but not to those secreted by any type of mature brain cell or by fibroblasts, caused the tumours to shrink through apoptosis.

The researchers analysed the compounds secreted by NPCs and found that these included a range of vanilloids and endocannabinoids and that this secretion was lost when the cells became differentiated.

HGA cell death could be greatly reduced if the binding of vanilloids to the TRPV1 receptor was blocked using selective antagonists. Endocannabinoids, however, did not stimulate the TRPV1 receptor and did not seem to mediate the loss of tumour cells.

The TRPV1 receptor is known to function as a non-selective cation channel. Glass and his co-workers investigated its mechanism further using a transgenic mouse model, Trpv1^-/-, in which this gene is deleted.

Whereas wild type mouse ganglions responded to signalling induced by both NPC-conditioned medium and known TRPV1 agonists, those in Trpv1^-/ mice rarely did so, indicating that this channel is necessary for a normal response to vanilloids. Further gene expression analysis showed that stimulation of TRPV1 induces cell death through an endoplasmic reticulum stress pathway that is controlled by a transcription factor known as ATF-3 (activating transcription factor 3). Expression of this gene was found to be both necessary and significant for vanilliods to induce astrocytoma cell death.

Finally, the researchers explored the age dependence of NPC-induced tumour suppression, also in a mouse model. In young (30 day old) but not adult mice, injected astrocytoma cells in which TRPV1 expression had been knocked down (TRPV1-KD cells) grew into significantly larger tumours than wild type astrocytoma cells.

Young mice implanted with wild type tumours also lived significantly longer than their adult counterplants; there was no difference in the survival time of older mice. However, administration of a synthetic vanilloid, arvanil, was able to lengthen the survival of older mice implanted with tumours with wild type TRPV1 expression.

Taken together, these results show that the neuronal precursor cells found in juvenile brains can protect against astrocytoma development by secreting vanilloids that act at the TRPV1 receptor. They further suggest that synthetic vanilloids can stimulate this pathway and that this might represent a promising new therapy for these intractable adult brain tumours.

Source: Stock, K., Kumar, J., Synowitz, M. and 20 others (2012). Neural precursor cells induce cell death of high-grade astrocytomas through stimulation of TRPV1. Nature Medicine, published online ahead of print 22 July 2012. doi:10.1038/nm.2827