Gliomas are a group of primary brain neoplasms classified mainly on the basis of their morphological resemblance to glial cells. Their most malignant form, grade IV glioma or glioblastoma multiforme, continues to remain lethal, partly due to a pronounced intratumoral heterogeneity which prevents effective therapeutic targeting. The heterogeneity seen in glioblastomas ranges from multiple genetic and epigenetic alterations to a cellular diversity that has recently been traced to the existence of tumor stem cells.Glioma stem cells, like other types of cancer stem cells, have the ability to self-renew and differentiate into multiple tissue-specific lineages. They can therefore maintain and propagate the tumor by continuously giving rise to a variety of malignant offspring and also initiate tumor recurrence from a very small number of cells. Furthermore, they are also considered to be the cells most likely to survive even multi-modality treatments, due to characteristics such as slow cycling or quiescence, high drug efflux capacity and strong antioxidant and immune defense systems.With the addition of each new research finding, the concept of glioma stem cell itself continues to evolve. However, many aspects of glioma stem cell biology are still insufficiently understood. It is not known which cells they originate from, what their relationship to normal tissue stem cells is and what mechanisms or events underlie their malignant transformation. Furthermore, whether the answers to these questions are the same for all glioma stem cells is also a matter that requires further investigation.This review focuses on our current understanding of glioma stem cells, the signaling pathways behind their pathogenic features and their role in glioma biology. We also discuss possible answers to the questions mentioned above, in the context of knowledge obtained from the study of tumor stem cells of several other types of malignancies. Finally, we review the importance of glioma stem cells in treatment resistance in glioblastoma and the implications of stem cell-specific targeting strategies.
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