Glioblastoma multiforme is the most common and deadliest form of brain cancer. Gliomas are highly infiltrated by microglia and macrophages, which have been shown to promote tumour growth and invasion. However, due to... [ view full abstract ]
Glioblastoma multiforme is the most common and deadliest form of brain cancer. Gliomas are highly infiltrated by microglia and macrophages, which have been shown to promote tumour growth and invasion. However, due to limitations of existing models it is unclear when exactly microglia respond to gliomas and which signalling mechanism are controlling these early events.
We have established a zebrafish in vivo model to study the interactions of macrophages/microglia and early tumours 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 tumour growth we followed a dual strategy, the overexpression of human oncogenes and the xenotransplantation of human glioblastoma cells into the zebrafish brain.
The overexpression of human oncogenes led to malignant transformations and glioblastoma growth in the larval zebrafish brain. Importantly, we detected an immediate reaction of the microglial network during the earliest stages of malignant transformations. This response was characterised by increased microglial numbers and a change of their activation status. In vivo imaging revealed intimate interactions between macrophages/microglia and oncogenic cells. This model will allow us to understand the signalling mechanisms underlying the earliest responses of microglia to glioma growth.
Transplantation of human glioblastoma cells into larval zebrafish brains showed engraftment and growth of the human cells accompanied by distinct microglial interactions. Importantly, these interactions turned out to be pro-tumoural and transplantation of glioblastoma cells into a zebrafish mutant devoid of microglia showed impaired survival of the human glioblastoma cells.
In summary, our data proof the suitability of the zebrafish to study the interplay between microglia and glioma cells. Understanding these interactions on the molecular level is the first step to develop new therapies.
