Mesenchymal stromal cells in malignant glioma - Functions and therapeutic potential

Abstract: The most common malignant brain tumor in adults is a glioma called glioblastoma multiforme (GBM). About 300 persons are diagnosed with GBM every year in Sweden. Unfortunately, it is also the most aggressive brain tumor and as of today, it is not possible to cure it. Despite treating the patients with surgery, radiation and chemotherapy, the median survival is only 15 months. The main problem with GBM is its infiltrative growth. As the tumor cells leave the tumor bulk and migrate into the normal brain parenchyma, it is impossible to reach them with the current standard treatments. Hence, even after treatment, some tumor cells will remain in the brain and eventually give rise to a new tumor. To be able to reach the migrating cells, new treatment strategies need to be developed. One such strategy is to use stem cells as drug delivery vehicles. It has been shown that mesenchymal stromal cells (MSCs) derived from the bone marrow (BM) have the ability to specifically migrate throughout a glioma. Upon intratumoral transplantation, they spread within the tumor, along its extensions and toward migrating tumor cells that has left the main tumor bulk, making BM-MSCs ideal as transporters of anti-tumoral substances. However, several safety concerns have been raised as MSCs also have shown to mediate tumor growth by acting immunosuppressive and contribute to the tumor stroma and vascularization. This thesis will discuss 1) the role of endogenous MSCs in malignant glioma and 2) the use of transplanted BM-MSCs as glioma treatment. We have shown that human malignant gliomas harbor two distinct cell populations that resemble BM-MSCs. We have characterized the cells and conclude that they most likely play an important role in tumor angiogenesis and immunosuppression. Further on, we have seen that MSC-like pericytes within the normal mouse brain are activated by, and migrate into, an orthotopic glioma model. The cells align perivascularly and contribute the majority of all pericytes within the tumor. To evaluate their tumor-tropism, MSCs were derived from rat bone marrow and transplanted into, and adjacent to, orthotopic rat gliomas. We conclude that even though they show strong tumor-tropic migration capabilities upon intratumoral transplantation they do not migrate when transplanted into the normal brain of tumor bearing animals. We also report that intratumorally transplanted BM-MSCs potentiate the effect of peripheral immunotherapy against malignant gliomas, demonstrating their use in a therapeutic setting.