Mouse models for tumour stem cells and anti-tumour efficacy studies

Brain cancer is a worldwide problem that is not well understood. For example, every year, approximately 6,000 cases of brain cancer are newly diagnosed in the UK alone and approximately 3,700 people die from this devastating disease.

The most aggressive brain tumour called Glioblastoma multiforme (GBM) is the most frequent primary brain tumour in adults and GBM patients have an extremely poor prognosis. Despite surgical removal of the tumour and chemo and irradiation therapy, the median patient survival time is only 12 - 17 months. Brain tumours are very difficult to treat due to their high complexity and research breakthroughs in recent years included the identification and characterisation of a subpopulation of therapy-evading tumour cells, termed brain tumour stem cells (BTSCs). Unlike differentiated cells of the tumour bulk, BTSCs possess the ability to reproduce themselves (self-renewal capacity), hence enabling tumour relapse. Therapeutic options against BTSCs, including new combination therapies, are urgently needed. This approach requires pre-clinical research models that mimic BTSC growth and tumour invasion of healthy brain tissue in humans. 

To this end, we inject patient-derived BTSCs directly into the mouse brain and closely monitor the progression and development of the resulting cancer using imaging and histological techniques. The surgical procedures are carried out using a stereotaxic apparatus (allowing for precise cell delivery) under general anaesthesia and pain killers are administered to minimize surgery-related pain. Few mice show any adverse effects after surgery and the animals are closely monitored throughout the experiments. To reduce the number of mice that is required for scientifically sound results, we use imaging techniques in live animals and statistical analysis tools. We carry out the vast majority of our experiments in cell culture, hence gaining substantial information on how a new potential anti-cancer agent works in cancer compared with ‘normal’ cells, before using animals/pre-clinical research models. These models allow us to test the effect of potential anti-tumour substances in an organism, and thus may inform future clinical research (involving human subjects). For example, we can assess the ability of potential anti-cancer agents to cross the blood brain barrier, a major obstacle for the treatment of brain diseases. As a comparison, we may test substances on cancer cells that were injected under the skin (lacking the restriction of the blood brain barrier). Overall, the so-called tumour xenograft models that we use in our research, together with patient-derived cell models, provide new insight into improved treatment options for malignant brain tumours.

Non-technical summary 

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