Glioblastoma is not only the most common form of brain cancer, it’s also the most deadly. It affects people from around 40 years of age, and most people live for less than 2 years after aggressive therapy. “This is a devastating disease,” says Simona Parrinello of the MRC’s Clinical Sciences Centre, who led the research.
New treatments are urgently needed, and in a study published today in eLife, the team shows that targetting just one protein has two effects, it both halts the division of the cancer cells, and stops these cells from spreading through normal tissue, a two-in-one approach.
“Current treatments often fail because the tumours spread throughout the brain, and so can’t be fully removed by surgery. If we can target this spread, it may be possible to make therapies more effective. When we target this one protein we block two key features of the tumour: its ability to divide and its ability to invade. It could be a combined therapy in one,” says Parrinello.
Scientists are not clear exactly how the cancer cells invade the brain in patients with this condition, though they know that one key route is through the space that surrounds blood vessels. It is also known that it’s a critical subset of cancer cells that appears to favour this route. These are called “glioblastoma stem-like cells”, or GSCs, because they behave in a similar way to stem cells in the developing and adult brain.
GSCs are particularly resistant to chemotherapy and radiotherapy. Scientists believe that this, and their ability to invade, could mean it’s these cells that are responsible for the regular recurrence of glioblastoma after initial treatment.
In this study, Parrinello’s team used a cutting-edge technique called intravital imaging, to watch GSC invasion within the normal brain in real time. Using this technique, the team discovered that when healthy cells first develop non-cancerous mutations, blood vessels within the brain keep them in a compartment so that they cannot spread and cause damage. They found that the vessels do this by producing a protein, called ephrin-B2, which appears to immobilise the cells and hold them in place. However, when cells become cancerous GSCs, they are able to override this anti-invasion signal, and escape the compartment. Crucially, Parrinello showed that the GSCs do this by producing their own ephrin-B2, which makes them insensitive to the ephrin-B2 already on the blood vessels.
The study also shows that a positive feedback effect comes into play along with the raised levels of ephrin-B2. At high levels, the protein appears to act as a signal, telling the GSCs to divide.
The team tried blocking ephrin-B2 using mouse models created with tumour cells from patients with the condition, a “gold standard” test for potential treatments in people. They found that the tumour cells were unable to divide and spread through the brain. This resulted in tumours shrinking in size and the mice outliving those that did not receive the treatment, with some tumours disappearing completely. Parrinello says it is exciting that one treatment targets two key traits of a tumour. “The ephrin-B2 system is complex, but in this case it works in our favour. By blocking one molecule we affect two key aspects of the tumour,” says Parrinello. “In addition, because ephrin-B2 levels are much higher in tumour cells relative to normal cells, blocking this protein should have minimal side-effects”.
Whilst an important discovery, the scientists expect that it will be many years before this treatment is ready to be tested in people. In this study, they explored one particular sub-type of glioblastoma. Parrinello now plans to investigate how other subtypes respond, and whether other signalling molecules play a similar role to ephrin-B2.
Earlier this year, Parrinello won a ‘Programme Foundation Award’ grant from Cancer Research UK worth £1.5 million. Her Cell Interactions and Cancer group has also been awarded a grant from MRC Technology, which will allow the team to explore how this treatment might be used alongside existing approaches such as chemotherapy and surgery.
In this study, the CSC scientists worked with colleague Vincenzo De Paola to set up the technique for intravital imaging of the tumour cells, with Steven Pollard from the MRC Centre for Regenerative Medicine in Edinburgh, who supplied patient cells, and with Jorge Martinez-Torrecuadrada from the Centro Nacional de Investigaciones Oncologicas in Madrid who developed the molecule that blocks ephrin-B2. Federico Roncaroli of the University of Manchester provided and analysed human tumour material. Paul Bertone from the European Bioinformatics Institute in Cambridge assisted with the bioinformatics analysis of the results.
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