Neural Progenitor Cells in malignancy and injury of the brain. A Trojan Horse fro gliomas?

Abstract: Gliomas are neoplasms arising in the central nervous system (CNS), and constitute the most common primary brain tumor. They are classified depending on the grade and morphology, from grade I, pilocytic astrocytoma, to grade IV, glioblastoma multiforme (GBM). Glioblastomas constitute a great challenge in treatment due to their disseminating nature. Classical treatments such as surgery, radiation therapy and chemotherapy still offer a poor prognosis for the patient, depending on the location and grade of the tumor. Patients with high grade gliomas have rapid deterioration and a predicted survival time of approximately 12 months with current treatment modalities. Pre-clinical research for treating gliomas has, during the last years, tried to develop neural progenitor cells as delivery vehicles for therapeutic genes. This is based on the fact that neural progenitor cells (NPC) have a great migratory potential and have been shown to specifically migrate to tumor cells. In this thesis we have tried to address the novel approach of using NPC to target malignant gliomas in rodents. This was done to increase the understanding of tumor progression and to investigate the impact of tumor growth on surrounding cells and their interaction with NPC. When the work on this thesis was started, novel findings of NPC with the ability to specifically home to gliomas in the brain were revolutionizing the notion of targeting disseminating single tumor cells. We wanted to investigate the potential of using NPC as specific delivery vehicles or a ?Trojan horse? for delivering harmful substances or molecules to tumor cells. We made the spectacular finding that certain NPC could prolong the lifespan of animals with gliomas and even cure 25% of the animals. This showed that some NPC themselves displayed antitumor properties. We focused our work towards understanding the underlying mechanism of this and the interaction of NPC and glioma cells in the brain. It appeared that the NPC acted as a true ?Trojan horse? bearing within them the ability to reduce tumor burden as well as tumor invasion in the animals. We have so far investigated and shown that there is a mutual responsiveness between tumor cells and embryonic NPC, which seem to be lacking in the adult brain, at least in response to the syngeneic glioma N29. The NPC can specifically migrate to tumor cells if transplanted at a distance. Upon tumor encounter they change phenotype to express the marker vimentin and can reduce the tumor volume with 67% during the first two weeks. However, no endogenous neuroblast activation, from the subventricular zone, towards a glioma was seen. This was in contrast to the extensive neuroblast activation observed to an excitotoxic lesion, as reported previously. Characterization of the tumor cells and NPC show that there is a genetical difference between NPC which display antitumor effects compared to NPC which do not. Genetical and protein screenings revealed candidate proteins, expressed by the NPC, which could be able to target glioma outgrowth in the brain either through direct toxicity or more likely secondary effects on the tumor microenvironment.