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  • ruthenium red Supplier Our results suggest several open ques


    Our results suggest several open questions that will require further investigation. Although evidence suggests that eradication of cancer stem ruthenium red Supplier appears to be beneficial for curing cancers, recent studies also suggest that noncancer stem cells acquire a cancer stem cell phenotype ruthenium red Supplier when challenged by stressors such as glucose deprivation (Flavahan et al., 2013). Thus, eradication of the existing cancer stem cells may not be sufficient, and instead a therapeutic combination targeting noncancer stem cells in addition to cancer stem cells may be mandatory. The IR-induced increases in MELK and EZH2 may be due to (1) the preferential eradication of nonstem tumor cells and subsequent enrichment of GSCs after treatment (i.e., selection of a therapy-resistant tumor cell population) or (2) IR-induced phenotypic changes of the treated GBM sphere cells, resulting in increased MELK and subsequently EZH2 through modulation of stress-induced enzymes (plasticity of GSCs and non-GSCs). It is also possible that both explanations are true. Future studies will address this issue. Another open question is, which GBM subtypes and GSC subtypes are dependent on the MELK-FOXM1-EZH2 signaling axis? Thus far, recent genome-wide transcriptome and methylome analyses support the existence of three to six GBM subtypes (Phillips et al., 2006; Sturm et al., 2012; Verhaak et al., 2010) and two GSC subtypes (Bhat et al., 2013; Mao et al., 2013). It is not entirely clear whether any of the GBM/GSC subtypes are more preferentially dependent on the MELK-FOXM1-EZH2 axis or all subtypes rely equally on this signaling axis. Future studies will address this question. In conclusion, in this study, we identified a signaling pathway for EZH2 upregulation in GSCs that plays a critical role in GBM tumor propagation and radioresistance. Identification of the MELK/FOXM1 protein complex as the predominant regulator for the EZH2 gene in GSCs highlights a possible therapeutic target for the devastating disease GBM.
    Experimental Procedures
    Author Contributions
    Introduction Understanding the cell of origin of cancer is pivotal for a better prevention and more efficient cure of the disease. Some examples of cancers arising from the transformation of stem cells have been shown, but in most cases, the cell of origin remains unknown. In healthy tissue, the microenvironment (niche) governs the fate of stem cells by balancing their self-renewal and differentiation through the regulation of the availability of soluble molecules, cell-cell contact, cell-matrix interactions, and physical constraints (Maguer-Satta, 2011). Increasing evidence indicates that the microenvironment plays an active role in cancer, such as alterations of mesenchymal stem cells that promote the proliferation and dissemination of cancer cells (McLean et al., 2011). However, the role of the microenvironment in the initial steps of cell transformation remains unexplored. The niche can affect normal stem cells and their malignant counterparts through soluble signals that create a carcinogenic microenvironment (Li et al., 2012). Among the soluble signals, inflammatory cytokines such as interleukin-6 (IL-6) play an important role in cancer (Iliopoulos et al., 2011; Vendramini-Costa and Carvalho, 2012). Abnormalities in bone morphogenetic protein (BMP) expression and their signaling pathway have also been reported in many systems (Davies et al., 2008; Thawani et al., 2010). BMP proteins are soluble members of the transforming growth factor β (TGF-β) superfamily that govern stem cell regulation in embryonic development, hematopoietic, neural, and epithelial systems, including the mammary gland (Alarmo et al., 2013; Forsman et al., 2013; Jeanpierre et al., 2008; Rendl et al., 2008). BMP signaling affects the stem cell niche both directly and indirectly (Zhang et al., 2003). Within this family, BMP2 and BMP4 are important regulators of both normal and cancer stem cells (Laperrousaz et al., 2013; Sagorny et al., 2012). In breast cancer, BMP2 and BMP4 have both protumor and antitumor functions (Balboni et al., 2013; Clement et al., 2005), but alterations of BMP receptors and their intracellular signal transducers SMAD1/5/8 clearly contribute to cancer progression and metastasis (Helms et al., 2005; Katsuno et al., 2008). Multiple abnormalities of BMP signaling have been reported in breast cancer, but available data only document a role in advanced disease, while effects on early transforming events remain to be identified.