Glioma Stem Cells

Abstract

Gliomas are the most frequent primary brain tumors and are classified as grade I to IV according to their degree of malignancy (Daumas-Duport et al., 1988). Grade I and II gliomas are clinically benign or semi-benign with relatively long-term survival, while grade III and IV are malignant and lethal within several years. In particular, glioblastoma multiforme (GBM), the most malignant glioma as grade IV often relapse even after radical surgical resection and standard chemo/radiation therapies, because of their diffuse infiltration into the surrounding brain parenchyma and high degree of chemo/radioresistance. Despite extensive efforts, the overall survival of GBM patients remains still short and has not yet been dramatically improved for more than several decades. GBMs are often composed of various types of cells with distinct morphology and clinical phenotypes. Their histological and biological multiformity has been classically explained by the stochastic clonal evolution model (Nowell, 1976). According to this model, all tumor cells should have low but inheritable ability to form tumors. However, recent evidence has suggested another concept, the cancer stem cell (CSC) hierarchy model, which shows that only a rare stem cell population has high ability to proliferate (Jordan et al., 2006). CSCs have similar characters to normal stem cells in the way of having high ability to self-renew and differentiate into multiple types of progenies to organize tissue architectures. Exclusively, CSCs can proliferate uncontrollably to propagate tumor cells. CSC model have direct relevance with tumor replenishment, disease recurrence and metastatic activity, suggesting that CSCs should be the target to eradicate the tumors. The aim of this chapter is to provide our insights into how CSCs in human glioma; i.e. glioma stem cells (GSCs) should be attacked. In the first parts, we summarize the general basis of CSC concept inclusive of the current knowledge on how a CSC is defined, how CSCs should be technically prepared and modeled, and what characteristics CSCs possess. In the following part, we highlight what abnormal signaling pathways regulate CSCs as the potential therapeutic targets. Understanding the framework of a GSC research field could help us to think of novel treatment strategy. Most importantly, however, CSCs have enhanced resistance to conventional chemotherapies. Considering this fact, we finally propose that it could be most promising strategy to disrupt the extracellular environments