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Glioblastoma multiforme (GBM) is the most common and deadliest form of primary brain tumor. Despite treatment with surgery, radiotherapy, and chemotherapy with the drug temozolomide, the expected survival after diagnosis remains low. The median survival is only 14.6 months and the two-year survival is a mere 30%. One reason for this is the heterogeneity of GBM including the presence of glioblastoma cancer stem cells (GSCs). GSCs are a subset of cells with the unique ability to proliferate, differentiate, and create tumors. GSCs are resistant to chemotherapy and radiation and thought to play an important role in recurrence. In order to effectively treat GBM, a drug must be identified that can kill GSCs. The ionophore salinomycin has been shown to kill cancer stem cells and is therefore a promising future treatment for GBM. This study focuses on salinomycin's potential to treat GBM including its ability to reduce the CSC population, its toxicity to normal brain cells, its mechanism of action, and its potential for combination treatment.

Metastasis is the leading cause of cancer deaths due to the spread of cancer cells through the blood vessels and the subsequent formation of secondary tumors. Metastasizing cancer cells in the human vasculature are called circulating tumor cells (CTCs) and are characterized to express the epithelial cell adhesion molecule (EpCAM). They are further known to survive physiological fluid shear stress (FSS) conditions. However, the effect of FSS on CTC molecular phenotype, such as the epithelial to mesenchymal transition (EMT) and cancer stem cell (CSC) expression, has not been extensively studied. Here, CTCs in FSS are evaluated in an in vitro model system. MCF7 and MDA-MB-231 breast cancer cell lines were grown in adherent and suspension culture media. The cell lines were tested for EMT and CSC genetic and protein markers using qRT-PCR and flow cytometry, respectively. Suspension cells showed a significantly increased EMT signature compared to adherent cells (p0.05), suggesting that they model cells detaching from primary tumors in vivo. Upon application of FSS, MCF7 and MDA-MB-231 cells did not show a significant change in EMT expression (p0.05), but there was a statistically significant increase of the CSC population in MCF7 suspension cultures (p0.05). These results with MCF7 suggest that CTCs can be modeled in vitro as non-adherent cancer cells in FSS and that they show an increased CSC-like signature during circulation, providing new insights to the importance of CSC-targeting strategies when treating metastatic patients.

A set of proteins reflecting the prognosis of patients have clinical significance since they could be utilized as predictive biomarkers and/or potential therapeutic targets. With the aim of finding novel diagnostic and prognostic markers for glioblastoma (GBM), a tissue microarray (TMA) library consisting of 62 GBMs and 28 GBM-associated normal spots was constructed. Immunohistochemistry against 78 GBM-associated proteins was performed. Expression levels of each protein for each patient were analyzed using an image analysis program and converted to H-score [summation of the intensity grade of staining (0-3) multiplied by the percentage of positive cells corresponding to each grade]. Based on H-score and hierarchical clustering methods, we divided the GBMs into two groups (n=19 and 37) that had significantly different survival lengths (p0.05). In the two groups, expression of nine proteins (survivin, cyclin E, DCC, TGF-β, CDC25B, histone H1, p-EGFR, p-VEGFR2/3, p16) was significantly changed (q0.05). Prognosis-predicting potential of these proteins were validated with another independent library of 82 GBM TMAs and a public GBM DNA microarray dataset. In addition, we determined 32 aberrant or mislocalized subcellular protein expression patterns in GBMs compared with relatively normal brain tissues, which could be useful for diagnostic biomarkers of GBM. We therefore suggest that these proteins can be used as predictive biomarkers and/or potential therapeutic targets for GBM.