The stem cell connection of primary brain tumors

Gliomas account for more than half of adult primary intracranial tumors, with anaplastic astrocytomas and glioblastoma multiforme (also known as malignant gliomas) being the most common. Plethora of evidence supports the notion that malignant glioma and other types of primary brain tumors arise from cells with stem cell/progenitor cell properties. To designate this cellular population a novel term has been introduced: glioma stem cells. These cells form a small subset of all cancer cells and share some features of normal stem cells, e.g. a capacity for self-renewal, multipotency and relative quiescence. These chemo- and radiation resistant cells are mainly responsible for maintaining tumor volume leading to therapy failure and recurrence. This review summarizes new findings on the interaction between the glioma stem cells, the tumor micro-environment, and specific cancer-causing genetic changes in the evolution of primary central nervous system tumors.Biomedical Reviews 2009; 20: 31-39

Redox metals and oxidative abnormalities in human prion diseases

Prion diseases are characterized by the accumulation of diffuse and aggregated plaques of protease-resistant prion protein (PrP) in the brains of affected individuals and animals. Whereas prion diseases in animals appear to be almost exclusively transmitted by infection, human prion diseases most often occur sporadically and, to a lesser extent, by inheritance or infection. In the sporadic cases (sporadic Creutzfeld-Jakob disease, sCJD), PrP-containing plaques are infrequent, whereas in transmitted (variant CJD) and inherited (Gerstmann-Straussler-Scheinker Syndrome) cases, plaques are a usual feature. In the current study, representative cases from each of the classes of human prion disease were analyzed for the presence of markers of oxidative damage that have been found in other neurodegenerative diseases. Interestingly, we found that the pattern of deposition of PrP, amyloid-ß, and redox active metals was distinct for the various prion diseases. Whereas 8-hydroxyguanosine has been shown to be increased in sCJD, and inducible NOS is increased in scrapie-infected mice, well-studied markers of oxidative damage that accumulate in the lesions of other neurodegenerative diseases (such as Alzheimer’s disease, progressive supranuclear palsy, and Parkinson’s disease), such as heme oxygenase-1 and lipid peroxidation, were not found around PrP deposits or in vulnerable neurons. These findings suggest an important distinction in prion-related oxidative stress, indicating that different neurodegenerative pathways are involved in different prion diseases

An Enzyme- and Serum-free Neural Stem Cell Culture Model for EMT Investigation Suited for Drug Discovery

Epithelial to mesenchymal transition (EMT) describes the process of epithelium transdifferentiating into mesenchyme. EMT is a fundamental process during embryonic development that also commonly occurs in glioblastoma, the most frequent malignant brain tumor. EMT has also been observed in multiple carcinomas outside the brain including breast cancer, lung cancer, colon cancer, gastric cancer. EMT is centrally linked to malignancy by promoting migration, invasion and metastasis formation. The mechanisms of EMT induction are not fully understood. Here we describe an in vitro system for standardized isolation of cortical neural stem cells (NSCs) and subsequent EMT-induction. This system provides the flexibility to use either single cells or explant culture. In this system, rat or mouse embryonic forebrain NSCs are cultured in a defined medium, devoid of serum and enzymes. The NSCs expressed Olig2 and Sox10, two transcription factors observed in oligodendrocyte precursor cells (OPCs). Using this system, interactions between FGF-, BMP- and TGFbeta-signaling involving Zeb1, Zeb2, and Twist2 were observed where TGFbeta-activation significantly enhanced cell migration, suggesting a synergistic BMP-/TGFbeta-interaction. The results point to a network of FGF-, BMP- and TGFbeta-signaling to be involved in EMT induction and maintenance. This model system is relevant to investigate EMT in vitro. It is cost-efficient and shows high reproducibility. It also allows for the comparison of different compounds with respect to their migration responses (quantitative distance measurement), and high-throughput screening of compounds to inhibit or enhance EMT (qualitative measurement). The model is therefore well suited to test drug libraries for substances affecting EMT