by ecancer reporter Clare Sansom

Glioblastoma multiforme, or Grade IV astrocytoma, is the most deadly type of brain tumour in adults.

Even with the best available treatment, the median survival time for patients diagnosed with this tumour is little more than a year, and fewer than 6% of patients survive for five years or more after diagnosis.

It is now known that glioblastomas vary considerably in genetics and morphology both within and between tumours, and this is thought to be one of the reasons why these tumours are so hard to treat.

This is one of the tumour types in which there is good evidence that tumours contain a small proportion of so-called tumour initiating cells, which express stem cell markers and are able both to renew themselves and to generate the cells that form the bulk of the tumour.

These brain tumour initiating cells (BTICs) are resistant to chemo- and radiotherapy, and any new drug that targets them specifically would be an important addition to the range of treatments for this condition.

Normal brain function requires an enormous amount of metabolic energy, which is mainly derived from glucose; neurons express a specific isoform of the glucose transporter, Glut3, which has a particularly high affinity for this nutrient.

Brain tumour cells also require large amounts of glucose, and there is some evidence that high glucose levels in the tumour correlate with poor survival.

Furthermore, glucose uptake and metabolism in brain tumour cells – particularly BTICs –is increased when glucose concentrations are low.

A team of researchers led by Jeremy Rich from Cleveland Clinic, Case Western Reserve University, Cleveland, OH, USA has now explored the effects of glucose restriction on glucose uptake and metabolism in BTICs.

Rich and his co-workers exposed samples of human GBM cells including a fraction of BTICs to standard and restricted glucose concentrations, and found that the BTIC population, as measured by stem cell marker expression, increased if glucose levels were restricted.

Glucose restriction also decreased the expression of proteins implicated in increasing cell differentiation.

The researchers investigated two hypotheses for the increase in BTIC numbers under low glucose concentrations by monitoring the numbers and ratios of the cell populations over time: namely, the preferential survival of BTICs and the transformation of other tumour cells into BTICs.

Cell death increased under low glucose conditions in both BTICs and non-BTIC tumour cells, but this increase was greater in non-BTICs, indicating that tumour initiating cells are better able to survive these conditions.

Over the same time period, non-BTIC tumour cells were also shown to adapt to these conditions by acquiring stem cell characteristics.

The researchers then exposed both types of tumour cells to a pulse of glucose after glucose starvation, and found glucose uptake to be greater in the BTICs.

The gene for the high-affinity glucose transporter GLUT3 was found to be highly expressed in BTICs, indicating that increased glucose uptake in these cells is driven by increased expression of the Glut3 protein.

Rich and his co-workers then used short hairpin RNA (shRNA) to knock down the expression of GLUT3 mRNA in glioblastoma cells and found that this reduced glucose uptake but only in BTICs.

Targeting GLUT3 expression using shRNA reduced tumour growth in immuno-compromised mice that had been injected with GBM cells.

Furthermore, analysis of expression data from glioblastoma patients indicated that high expression of GLUT3, but not of any other glucose transporter isoform, was correlated with poor 1-year survival; this trend was strongest in the proneural subtype of GBM.

Taken together, these results suggest that BTICs in glioblastomas take up glucose more effectively when nutrient levels are restricted through increasing GLUT3 expression, and that drugs that block glucose uptake through the Glut3 transporter might be useful in treating this intractable tumour.

Reference

Flavahan, W.A., Wu, Q., Hitomi, M. and 11 others (2013). Brain tumor initiating cells adapt to restricted nutrition through preferential glucose uptake. Nature Neuroscience, published online ahead of print 1 September 2013. doi:10.1038/nn.3510