The dual role of mesenchymal stem cells in gliomas: new therapies and therapeutic targets.
Prof. Dr. Rainer Glaß, Leiter der Neurochirurgischen Forschung, Klinik für Neurochirurgie, Klinikum der Universität München, Marchioninistr. 15, 81377 München. Email: firstname.lastname@example.org
Report-period: 1 / 2016 until 12 / 2016
Glioblastomas (GBM) are treated by multi-modal therapy comprising surgery, irradiation and chemotherapy. Nevertheless the outlook for GBM patients is grim as these tumours almost invariably relapse. Recurrent GBM can often arise in an area neighbouring with the resection cavity that was generated after front-line neurosurgical treatment. This suggests that some invasive GBM cells may be spared from resection, have the capacity to resist radiation-treatment and do not undergo cell-death after application of alkylating agents (like Temozolomide, which is the standard of care for chemotherapy of GBM patients). In our preclinical research project we investigate the mechanisms that enable GBM to endure this stringent treatment-strategy and the signalling cues supporting GBM cell-invasion. The strong support by the Anni-Hofmann Foundation as well as the regular and stimulating intellectual exchange with our partners in the Anni-Hofmann Foundation enabled us to address this important pathological question. We observed that cells of the brain-tumour microenvironment have a fundamental role in supporting GBM cells. In particular we found that tissue-resident stem cells named mesenchymal stem cells (MSC), which support tissue-remodelling and healing processes in aging and pathological insults, play a major role in therapeutic resistance of GBM. Initially we established that MSC are triggered towards different (tumour-supportive or tumour suppressive) traits when they are exposed to blood-serum or are in a blood-serum free environment. This is in line with the physiological role of MSC e.g. in injury when MSC are initially activated and expand and then have to support tissue regeneration during the wound-healing process. In agreement with previous reports on the attraction of MSC towards GBM we suggest that MSC are initiated (from peripheral organs) to home to GBM via the blood-stream. In the CNS MSC will then experience a blood-serum free habitat and may exert regenerative / supportive functions. This culminates in supporting the growth, invasion and chemo-resistance of GBM. In order to inhibit this protumorigenic process we have studied the molecular pathways of MSC to GBM communication and we discovered that MSC-derived membraneous vesicles (so-called exosomes) mediate one major tumour-supportive effect. The MSC-secreted exosomes carry the genetic information (messenger RNA) for the expression of signalling-molecules, these exosomes are then internalised by GBM and the genetic information (originating from MSC) is expressed by GBM. This signal transduction pathway promotes GBM cell-invasion and can be blocked pharmacologically. However, we also observed that MSC likely mediate their pathological effect in an early GBM-recurrence situation, when a small number of GBM cells is modulated by tumour-associated MSC (thereby accelerating GBM relapse). This situation could so far not be recapitulated in preclinical models and hence little cell-biological information is available on this point. With generous support by the Anni-Hofmann-Foundation we are now generating a preclinical model to recapitulate the moment of GBM recurrence. In our last meeting with the board of the Anni-Hofmann-Foundation we could present our advances on this model, which will help to find new clinical approaches to suppress GBM-relapse.