CT brain scan of child with medulloblastoma and resulting hydrocephalus Wikimedia commons
For the last decade or so, scientists have been meticulously categorising the most common type of children’s brain tumour: medulloblastoma.
And in doing so, they’ve uncovered that the 60 cases diagnosed each year in the UK can actually be divided into different ‘types’.
Each of these develops from a different type of cell, responds differently to treatment and, perhaps most importantly, has a different outlook for the patient.
For three of the medulloblastoma subtypes this means that between 4 and 7 in 10 children diagnosed will not survive their disease.
This is partly because these tumours are less responsive to chemotherapy drugs – they just don’t work very well in these patients. The challenge is that researchers don’t know why.
In stark contrast to this, one of the subtypes – WNT-medulloblastoma – is extremely sensitive to chemotherapy. Patients respond well to chemotherapy and are often cured, even if the disease has spread to other parts of their body.
Until now, scientists haven’t known what sets these more sensitive tumours apart from the other subtypes.
Now they do.
A new study published today by a group of scientists – led by Professor Richard Gilbertson, director of the Cancer Research UK Cambridge Cancer Centre – could explain why there are such differences in survival between medulloblastoma patients. And, tantalisingly, the study – carried out at St Jude Children’s Research Hospital in Tennessee, USA – offers a possible way of making those harder to treat tumours more sensitive to chemotherapy.
Taking a different approach
Before beginning this research, Gilbertson and his team already knew that children with WNT-medulloblastomas do well following chemotherapy.
“Although they have this horrible cancerous tumour, they all do incredibly well,” he explains. “They respond well to treatment and are all cured.”
“What we don’t understand is the biology behind why these children are cured – why is chemotherapy so much more effective in this subtype than others?”
So they set about answering this question.
Generally, when researchers are trying to understand what makes cancer cells sensitive to treatments they crack open the cancer cells themselves and study how they work.
But Gilbertson and his team did something different – they looked at the cells surrounding the tumour instead.
Specifically, they studied the blood vessels – and the cells that line them – in four of the different types of medulloblastoma, to see if they differed.
Their rationale – blood vessels control what enters the brain.
Brains need a blood supply to grow. To make sure they have one, blood vessels grow around the brain – and brain tumours – that provide them with the oxygen and nutrients they need to survive.
But not everything should be granted access to the brain – that’s why it needs a blood brain barrier.
What’s a blood brain barrier then?
The phrase ‘blood brain barrier’ conjures up an image of a physical blockade that stands between the brain and blood.
It’s not quite that.
It’s a term used to describe healthy, intact blood vessels acting as a filter to control which substances and molecules enter the brain tissue.
It allows molecules like water and glucose – which are essential for normal brain function – to reach the brain cells, while keeping out unwanted, damaging things like bacteria and neurotoxins.
More often than not, chemotherapy drugs are too big to pass through the barrier. This means that, in brain tumour patients, chemotherapy drugs can’t reach the tumour to kill the cancer cells.
Needless to say, this isn’t ideal.
But if the blood brain barrier prevents chemotherapy drugs reaching brain tumours, why do WNT-medulloblastoma patients respond so well to chemotherapy?
It’s all about blood vessels
To answer this question, the team used a technique called immunohistochemistry to examine the blood vessels in non-cancerous brain samples from humans and mice to establish what a functional, intact barrier looks like.
Then they looked at the blood vessels in the brains of mice with different medulloblastoma subtypes, to see if they could spot any differences between the different tumours, and compared to healthy mouse brains.
Interestingly, the team found that three of the medulloblastoma subtypes they analysed which had poorer outlooks had blood vessels similar to healthy brains. They formed a functional, intact blood brain barrier, preventing large molecules from entering the brain tissue.
But WNT-medulloblastoma tumours were different. Their blood vessels weren’t the same as those in healthy brains – or the other subtypes.
Instead, they were highly branched and very ‘leaky’. And there were also lots of them.
The findings gave the researchers a possible explanation as to why WNT-medulloblastomas are so responsive to chemotherapy.
By having lots of leaky, branched blood vessels, the WNT-subtype creates a faulty blood brain barrier that doesn’t filter properly.
This suggests that large molecules like chemotherapy drugs might be able to pass through the barrier and into the brain tissue, where they can target and kill tumour cells.
Crucially, if this is the case, the findings could point to a way of making the other types of medulloblastoma more sensitive to chemotherapy.
Influencing the neighbours
To understand what makes WNT-medulloblastoma tumours develop abnormal, leaky blood vessels and a faulty blood brain barrier, the researchers next looked at how vessels develop.
In experiments carried out in mice, they saw that healthy brain cells – and cells from the three types of tumour with the poorest outlook – all produced molecules that encourage neighbouring cells to produce healthy blood vessels – and in turn an intact blood brain barrier.
But in WNT- medulloblastomas, the cancerous brain cells produced different molecules, which prevent nearby cells from making healthy intact vessels and a functional blood brain barrier.
This could explain why WNT-tumours respond so well to treatment.
These were exciting results.
The next step was to see if the blood brain barrier of mice with non-WNT-tumours can be manipulated to develop leakier, branched blood vessels, and if they allow chemotherapy drugs through the blood brain barrier.
Don’t be so manipulative….or do?
To answer the question, the researches modified mice with non-WNT-tumours so that their tumour cells produced the same molecules as WNT-tumours.
This meant they now made a non-functioning, non-filtering barrier, similar to that seen in WNT-tumours.
Now they needed to test whether this manipulation changed how well the mice responded to chemotherapy drugs. To do this they treated them with the chemotherapy drug vincristine.
Excitingly, they saw that these mice were now sensitive to vincristine – their blood vessels were now leaky enough to let the chemotherapy drug through the barrier and into the brain.
The techniques used in the lab to make non-leaky blood vessels leakier can’t currently be used in people.
Nevertheless, this exciting research improves scientists’ understanding of why some medulloblastoma tumours respond better to chemotherapy than others.
And according to Gilbertson: “It’s vital, fundamental research like this that lays the foundations for clinical trials that could improve treatments for patients in the future.”
The next step is to find out if scientists can safely and accurately carry out this cell manipulation in people. This will only be possible with more research and, in the future, clinical trials
As an organisation, Cancer Research UK is committed and determined to increase the amount of money spent on research into brain tumours and children’s cancers.
To help achieve this we have highlighted the need for more research into brain tumours as part of our research strategy. And we’ve established Cancer Research UK Kids and Teens, a dedicated campaign to raise money for research into cancers affecting people under 25.
These findings are a huge step forward in understanding why some patients with medulloblastoma do better than others. Now we need to make sure we bring the benefits of this research to patients as soon as we can.
T. N. Phoenix. (2016). Medulloblastoma Genotype Dictates Blood Brain Barrier Phenotype. Cancer Cell: 10.1016/j.ccell.2016.03.002
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