Stem cell based therapy of malignant brain tumors
Abstract: Malignant brain tumor is a highly invasive and vascularized cancer. Current forms of therapy are not curative and can, at best, prolong survival for patients with this disease. The mean survival is only around 15 months. The aims of the present thesis have been to develop and explore a stem cell based vector system for delivery of therapeutic transgenes to experimental gliomas. First, we investigated the frequency and properties of cancer stem cell (CSC)-like cells in the rat glioma models used in the present thesis. Virtually all cells within both glioma models concomitantly express CD133, nestin as well as the neural lineage markers glial fibrillary acidic protein, ?III-tubulin and CNPase in vitro and in vivo. Unsorted tumor cells displayed very high clonogenic capacity in vitro and robust tumorigenicity in vivo. Thus, CSC-like cells do not reside within a rare sub-population of cells in these glioma models but constitute most, or all, cells. We next examined the subventricular zone (SVZ) response to growth of malignant glioma. Tumor growth resulted in decreased numbers of SVZ proliferating cells, increased SVZ neuroblast immunoreactivity, and migration of striatal neuroblasts from the SVZ toward glioma. Although endogenous neuroblast migration toward gliomas was of moderate magnitude, this indicates a region specific reparative mechanism in response to tumor growth. We continued by implanting rat SVZ-derived neural precursor cells (NPCs) and rat multipotent mesenchymal stroma cells (MSCs) into gliomas. Intratumorally implanted NPCs and MSCs migrated specifically within gliomas and largely avoided normal brain tissue. Importantly, implanted NPCs and MSCs did not proliferate within tumors. This indicates a low risk of development of secondary malignancies. A comparative analysis revealed higher survival and better intratumoral migratory capacity of implanted MSCs, compared to NPCs. Intratumorally implanted MSCs migrated to the majority of the invasive glioma extensions and to a substantial fraction of distant tumor microsatellites. Furthermore, implanted MSCs integrated into tumor blood vessel walls and expressed pericyte markers but not endothelial cell markers. The pericyte marker expression profile and perivascular location of implanted MSCs indicate that these cells act as pericytes within tumors. MSC implantation did not, however, affect tumor microvessel density or the survival of glioma-bearing animals. In summary, gliomas can attract endogenous striatal neuroblasts from the SVZ. However, intratumoral implantation of NPCs and MSCs yields a much more powerful, and tumor-specific, infiltration within gliomas. In particular, pericyte-like MSCs represent a well suited vector system for the delivery of therapeutic transgenes to vascularized and invasive gliomas.
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