Dirk Sieger: In Vivo Studies of Microglia-glioma Interactions

Cancer Research Programme

Gliomas are the commonest type of malignant brain tumour. Due to complex morphologic and genetic characteristics they resist even multimodal therapies and patients show significant mortality within the first 2 years after diagnosis. Gliomas show a topographically diffuse appearance and although the migration of glioma cells away from the main tumour mass through the brain parenchyma was described already in 1940, the underlying mechanisms are still not understood. Recent studies suggest that high levels of macrophages/microglia within the glioma are positively correlated with glioma grade and invasiveness.

Microglia are the resident macrophages of our brain. During glioma growth, microglia and infiltrating macrophages are attracted to and colonize the tumour. However, instead of an expected anti-tumoural activity they display pro-tumoural functions and promote tumour growth. The underlying mechanisms of this behaviour are not understood.

Given the ineffectiveness of standard therapies to cure gliomas and the role of macrophages/microglia in tumour growth, it is of particular importance to understand the signalling mechanisms that regulate these cells within the tumour environment.

We use the zebrafish larva to study the interactions of macrophages/microglia and glioma in the living brain in real time. In particular the opportunity to image cellular interactions at high temporal and spatial resolution in the living brain, combined with the possibility of intervening genetically and pharmacologically, make the zebrafish an excellent model. To induce glioma growth we are following a dual strategy, the overexpression of oncogenes and the xenotransplantation of human glioblastoma cells into the zebrafish brain.

Using this model we address the following questions:

• When and how do resident microglia respond to tumour growth in vivo? Which circumstances lead to an additional infiltration by macrophages?
• What are the initial signalling mechanisms that attract macrophages/microglia to the tumour? Are they related to those that attract these cells to wounds and infections?
• How is the activity of the macrophage/microglia altered upon contact to the tumour?
• Is there an anti-tumoural activity and how can this be induced in vivo?

Answering these questions will lead to a more comprehensive understanding of macrophage/microglia biology and help to understand the behaviour of these cells within gliomas. This is the necessary first step to develop strategies to interfere with their functions, which might be a way to inhibit glioma growth.