br Introduction Glioblastoma is one

Introduction Glioblastoma is one of the deadliest among human cancers with highly dismal prognosis (Stupp et al., 2005; Tabatabai and Weller, 2011). Even with seemingly successful initial treatment, recurrence is inevitable and almost always fatal in the majority of glioblastoma cases, which implies that the control of recurrence is key to realizing long-term survival of glioblastoma patients (Cheng et al., 2010; Neman and Jandial, 2010). A growing body of evidence now suggests that glioblastomas contain a small subpopulation of immature, undifferentiated tumor naltrexone hcl with tumor-initiating capacity, which is lost once they undergo differentiation (Binello and Germano, 2011; Cheng et al., 2010; Tabatabai and Weller, 2011). Such cells are called glioma stem cells (or alternatively, stem-like glioma cells, glioma-initiating cells [GICs], glioma-propagating cells), and due to their inherent therapy resistance, are now deemed a possible culprit of glioblastoma recurrence (Binda et al., 2012). Elucidation of the molecular mechanisms underlying the maintenance of the immature, stem cell state of glioma stem cells as well as the process of their differentiation, therefore, is expected to lead to the identification of novel targets of therapeutic intervention to prevent recurrence and thus could contribute to better clinical management of this devastating disease. Currently, with the dramatic expansion of research in the field of glioma stem cells, an increasing number of molecules/pathways involved in their maintenance and differentiation, e.g., bone morphogenetic proteins and transforming growth factor β, are being identified (Binello and Germano, 2011). However, the role of reactive oxygen species (ROS) in cancer stem cells, including glioma stem cells, has been poorly characterized with only limited information published to date (Kobayashi and Suda, 2012), in contrast to their well-documented, pleiotropic roles in cancer cell biology in general (Pan et al., 2009). In particular, although previous studies implicated ROS in the radioresistance of breast cancer stem cells (Diehn et al., 2009; Phillips et al., 2006), the role of ROS in the control of stem cell state/differentiation of cancer stem cells remains largely undetermined (Shi et al., 2012).
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Discussion Despite the wealth of studies investigating the role of ROS in cancer cell biology (Pan et al., 2009), surprisingly little is known about its specific role in cancer stem cells (Kobayashi and Suda, 2012; Shi et al., 2012). In particular, control of the cellular fate of cancer stem cells, i.e., to remain in the stem cell state and continue self-renewal or to undergo differentiation into specific lineages, is one of the most important issues to be addressed and elucidated in the field of cancer stem cell biology. However, the role of ROS in the control of this critical cellular decision process remains largely unexplored (Kobayashi and Suda, 2012; Shi et al., 2012). With respect to normal stem cells such as hematopoietic stem cells and neural stem cells, there are a number of studies that examined the role of ROS in their biology. However, most of the studies are focused on the role of ROS in the control of their proliferation and self-renewal, and few address the role of ROS in the process of differentiation (Ito et al., 2004, 2006; Kim and Wong, 2009; Le Belle et al., 2011; Smith et al., 2000). Furthermore, the results of the studies indicate that the role of ROS in the control of stem cell self-renewal, for example, may be context-dependent, lending support to both ideas that ROS promote and inhibit self-renewal of stem cells (Ito et al., 2004, 2006; Kim and Wong, 2009; Le Belle et al., 2011; Smith et al., 2000; Yang et al., 2012). Thus, the role of ROS in the control of self-renewal and differentiation of cancer stem cells is not only unknown but is even unpredictable from current literature, warranting and underscoring the necessity of investigating their role in stem cells of each cancer type.