Current Research

Hematopoietic stem cells as vehicles for a gliomasdirected therapy

This project aims at elucidating the molecular mechanisms of lesiontropism of hematopoietic stem cells (Tabatabai et al. 2005 & 2006). Independent subprojects in this project are:
• mechanism of endothelial transvasation of hematopoietic stem cells
• comparison of hematopoietic and mesenchymal stem cells for the delivery of therapeutic molecules
• development of a cell-based antiangiogenic therapy for malignant gliomas
• optimization of an anti-transforming growth factor (TGF)-β therapy with stem cells

Functional characterization of invasion-related proteins induced by chronic non-lethal hypoxia

Malignant gliomas are hypoxic tumors and this contributes to the resistance to therapy and putatively also to the invasive phenotype. In a proteome study several proteins have been identified to be differentially expressed under hypoxic treatment compared to normoxic conditions and could be confirmed by orthogonal methods. Of these candidates N-myc downstream regulated gene 1 protein (NDRG1) and neuroenolase (ENO2) will be analysed. Silencing of the corresponding candidate genes and reexposing these cells to hypoxia in the invasion/apoptosis and angiogenesis paradigms will underscore the functional relevance of the candidates for the induction of an invasive phenotype or gliomas angiogenesis. Applying proteomics techniques, additionally involved proteins are looked for in cells harboring the silenced candidate gene to find downstream molecules that potentially serve as therapeutic targets for an anti-angiogenic therapy.

Novel functions of BCL-2 family proteins in glioblastomas - invasiveness and autophagy

Since this subproject focuses on invasion analyses, apoptotic and non-apoptotic cell death mechanisms, and orthotopic glioma animal models. In glioblastomas, the BCL-2 and BCL-xL proteins contribute to an overall resistance to apoptosis which correlates with the clinically relevant chemo- and radioresistance. Our recent data demonstrate that BCL-xL specifically promotes the invasiveness of glioma cells in vitro and in vivo (Weiler et al. 2006). This novel BCL-xL function is mediated by altered gene expression and does not depend on the direct anti-apoptotic effect of BCL-xL through sequestering pro-apoptotic BCL-2 family members. Moreover, BCL-2 and BCL-xL were recently described to be major regulators of autophagic cell death (type II cell death). There is increasing evidence that autophagy plays a crucial role in the tumorigenesis and therapy resistance of glioblastoma
• Development of a protein kinase C inhibitor for the therapy of malignant gliomas (Tabatabai et al. 2007) and experimental autoimmune encephalomyelitis.
• Evaluation of anti-glioma vaccination.
• Description and functional characterization of gliomasinitiating cells.

Wick Fig1
Fig 1: Adult hematopoietic stem cell exhibit a TGF-β CXCL-12-dependent tropism for gliomas in vitro and in vivo. Images 1 - 3 depict an experimental LNT-229 intracranial glioma (nuclei DAPI stained (1-2) or H&E staining (3)) invaded by hematopoietic stem cells (PKH26). Image 4 shows that there are no stem cells in the non-tumor hemisphere

 

Wick Fig2
Fig 2: Free floating human glioblastoma tumor spheres of the tumors 323 and 325 cultured in NSC-M after excision and homogenisation and respective adherent non-sphereforming cells
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Latest Revision: 2012-08-20
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