Endogenous neural precursor cells display extensive tropism for experimental glioblastomas and improve survival in an animal model

Gliomas are the major tumour entity of the central nervous system. The term glioma implies that these cells may originate from glial cells, although this has not been proven. Recent evidence indicates an interaction and interrelationship of glioma cells with stem cells. Neural stem cells generate all neurons, astrocytes and oligodendrocytes of the developing brain. They persist through adulthood in two specialized stem cell niches. A number of recent studies suggest that altered proliferation and differentiation of neural stem and precursor cells could be the primary source for glioma. Previously, it was demonstrated that cultured, immortalised neural precursors display tropism for gliomas, and that such precursors exert an anti-tumourigenic effect on glioma.

In a murine experimental glioma model we show that endogenous neural precursors migrate from the subventricular zone towards the tumor and surround it. The association of endogenous precursors with syngenic tumor grafts was observed, after injecting DsRed-labeled G261 cells into the caudate putamen of transgenic mice, which express green fluorescent protein under a promoter for nestin (nestin-GFP). 14 days after inoculation the nestin-GFP cells surrounded the tumors in several cell layers and expressed markers of early, non-committed and of committed precursors. Nestin-GFP cells were further identified by a characteristic membrane current pattern as recorded in acute brain slices. BrdU labeling and dye tracing experiments revealed, that the tumor associated precursors originated from the subventricular zone. Moreover, in cultured explants from the subventricular zone the neural precursors showed extensive tropism for gliomas. Tumor-induced endogenous precursor cell accumulation decreased with age of the recipient, this correlated with increased tumor size and shorter survival times in aged mice. Coinjection of glioma cells with neural precursors improved the survival time of old mice to a similar level as in young mice. Co-culture experiments showed that neural precursors suppress the rapid increase in tumor cell number, which is characteristic of glioma, and induced glioma cell apoptosis. Our results indicate that tumor cells attract endogenous precursor cells, that the presence of precursor cells is anti-tumorigenic and that this cellular interaction decreases with ageing.