Using human brain cells grown in dishes in the lab, the Cardiff-based scientists, have been the first to create a model of malignant glioma that mimics the molecular events thought to occur when people develop this type of tumour.
Malignant glioma is the most common brain cancer and is notoriously difficult to treat. But researchers believe the model, which provides a realistic view of what happens during glioma development, will speed up the search for new drugs to treat the disease.
Study author Prof David Wynford-Thomas, a Cancer Research UK scientist from the University of Wales College of Medicine in Cardiff says: “The development of brain cancer in humans is a very complex process but we’ve managed to recreate the key genetic steps in the lab to give us a unique insight into the disease.
“Our model allows us to study the underlying mechanisms that turn normal brain cells into cancer cells and provides us with a valuable tool with which to design and test new drugs.”
Brain cancer develops when genes that limit the number of times a cell can divide are faulty – allowing cells to multiply endlessly.
“Normal brain cells have built-in mechanisms which limit their lifespan and stop them developing into cancer. If we can design drugs to restore these in brain tumours that have lost them then we can slow down the growth of cancer cells and even kill them,” says Prof Wynford-Thomas.
Scientists already knew that three key genes – p53, p16 and HTERT – were faulty in brain cancer. Previous research found p53 disrupted in early stage tumours and p16 and HTERT in later stage, suggesting that the genes might be damaged in a particular sequence as the disease progresses.
In this study, researchers recreated the sequence in the lab by manipulating normal brain cells. They allowed normal cells to multiply until they hit their natural limit and stopped dividing. The team then added a faulty p53 gene to the cells and found that they started to divide again.
In most of these cells a second in-built barrier halted the renewed division. But researchers found some cells were able to overcome this limit and carry on dividing because they had lost the function of the p16 gene. When these cells hit a third growth barrier, scientists added a faulty version of the HTERT gene, which transformed the cells into immortal cancer cells that grow and divide endlessly.
“Our model mimics the sequence of gene damage that occurs in patients with malignant glioma and could allow us to identify key drug targets for the disease.
“If we can counteract the effect caused by genes damaged early on in brain cancer we can stop the disease from becoming aggressive,” says another of the study’s authors Professor David Kipling, from the University of Wales College of Medicine.
Cancer Research UK’s Director of Clinical Research, Professor Robert Souhami says: “The team in Cardiff have produced a lab model of brain cancer that closely resembles what happens in patients at a genetic level and this will be a very valuable tool in investigating the disease.
“Brain cancer does not generally respond well to radiotherapy or chemotherapy and currently the prognosis for patients is poor. So any discovery that can help towards generating new drug targets for the disease is very welcome.”
- Cancer Research63 (16)