Glioma

STEM CELLS AND CANCER-GLIOMA

In recent years, evidence has mounted suggesting that the clinical properties of tumors are largely determined by a small subpopulation of cancer cells that can continuously self-renew and regenerate the tumor. In brain cancers, it was shown that only a minor population of tumor cells, characterized by their expression of specific cell-surface markers, has the potential to form new tumors in xenograft models. Current treatment strategies, however, are designed to target the bulk tumor mass and potentially fail to account for the different molecular and clinical properties of cancer stem cells. Therefore, it is imperative to characterize the biology of cancer stem cells and develop new therapeutic approaches that directly target this clinically most relevant subpopulation of cancer cell. In cooperation with department of neurosurgery at Heidelberg University, we are isolating and characterizing CD133-positive tumor-initiating cells from glioblastoma, one of the most devastating brain tumors in adults.

In NOD/SCID mouse xenograft experiments, these cells are highly tumorigenic, producing highly invasive tumors closely resembling the phenotype of the patient tumor. After concluding array-based analyses of DNA-copy number, DNA-methylation, and gene expression we now are performing functional analyses of putative cancer- and stem-cell relevant genes. To explore novel therapeutic options, we are exposing the glioblastoma-initiating cells to retinoic acid, leading to down-regulation of the stem cell marker CD133, partial differentiation, and a dramatic loss of tumorigenicity. We are currently analyzing genetic and epigenetic molecular mechanisms that might be responsible for these clinically relevant phenotypic changes. Current data suggest a differential regulatory role of several miRNA clusters in normal and neoplastic differentiation.

PD. Dr. Cristel Herold-Mende, Department of Neurosurgery, University of Heidelberg
Prof. Guido Reifenberger, Department of Neuropathology, Heinrich-Heine University, Düsseldorf
Prof. Dr. Ruthild Weber, Department of Human Genetics, University of Bonn