by ecancer reported Clare Sansom

Malignant gliomas are the most deadly type of primary brain tumour; the 5-year survival for Grade IV glioma, which is also known as glioblastoma multiforme, is one of the lowest of all cancers at less than 5%.

The growth and maintenance of these tumours is thought to be driven by a few cells with stem-like properties termed brain tumour initiating cells (BTICs).

These cells are more resistant to radiation and to many chemotherapy drugs than other glioma cells.

Any successful strategy for the long-term treatment of malignant glioma must therefore involve either suppressing the stem cell-like properties of these cells or removing them completely.

Glioma cells in tumours are surrounded by several types of immune cells, particularly microglia that are native to the CNS and macrophages that infiltrate into the brain.

The function of these immune cells remains unclear; it is thought that in some circumstances they can prevent the growth and activity of gliomas, whereas in others their immune surveillance is suppressed by the tumour.

A large group of scientists led by V. Wee Yong of the University of Calgary, Canada has now investigated the complex interactions between glioma cells and the immune cells that surround them, focusing on the stem cell or BTIC component of the tumours.

Yong and his co-workers first isolated BTICs from patients with malignant glioma and grew them in suspension culture enriched with growth factors, forming spheres.

The cultured cells expressed elevated levels of proteins known to be stem cell markers, and formed tumours when implanted into the brains of immunosuppressed mice.

Microglia isolated from patients undergoing brain surgery for non-neoplastic conditions were cultured in a similar medium and then co-cultured with BTICs.

The researchers found that the microglia reduced the capacity of BTICs from several glioma cell lines bearing different mutations to form spheres.

Furthermore, the medium in which the microglia had been cultured (microglia conditioned medium or MCM) had a similar sphere-reducing effect to the microglia themselves, indicating that that effect arose through protein secretion.

Very similar effects were obtained using monocytes and macrophages that had been cultured from human blood.

However, human brain cells (astrocytes or neurons) did not secrete the proteins that suppressed BTIC growth.

BTIC sphere growth reduction appeared to be associated with a reduction in cellular proliferation and with increased differentiation rather than with apoptosis.

This was confirmed by microarray analysis, which showed that genes associated with decreasing cell growth and increasing differentiation were expressed more strongly in BTICs that had been treated with MCM than in those that had not.

Interleukin-8 and a chemokine, MCP-1, were among the proteins that were found to be at a particularly high concentration in MCM; both these proteins are known to promote the differentiation of at least one type of brain cell.

Yong and his co-workers tested a library of 1,040 compounds for their capacity to activate the BTIC-suppressing activity of microglia and macrophages, and identified a known anti-fungal drug, amphotericin B (AmpB) as a hit compound.

This compound increased the expression of TNF-α in macrophages and microglia and enhanced the ability of these cells to promote differentiation and reduce proliferation in BTICs.

Furthermore, AmpB reduced the tumourigenic properties of BTICs implanted into mouse brains.

BTICs exposed to AmpB without immune cells were unaffected, indicating that the compound acts only to stimulate these cells and not directly on the tumour cells.

However, macrophages and microglia derived from glioma patients were able to suppress BTICs only after they had been activated by AmpB.

Mice bearing gliomas that had been induced by BITC injection lived significantly longer if they were treated with a low daily dose of AmpB.

Taken together, these results suggest that chemical suppression of the stem-like properties of BTICs should be a useful strategy for the treatment of malignant glioma, and that amphotericin B, which is already on the market as an anti-fungal, is a potential candidate drug for this indication.

Reference

Sarkar, S., Döring, A., Zemp, F.J and 15 others (2013). Therapeutic activation of macrophages and microglia to suppress brain tumor-initiating cells. Nature Neuroscience, published ahead of print 8 December 2013. doi:10.1038/nn.3597