The existing clinical and preclinical findings show that, as well as the conventional pathological and clinical indicators which have a prognostic value in radiation oncology, the amount of cancer stem cells (CSCs) and their inherent radioresistance are essential parameters for regional control after radiotherapy. concentrations of ROS scavengers and neutralize Methoxsalen (Oxsoralen) radiation-induced ROS [89]. As well as the known proteins with ROS scavenger function, the multifunctional proteins apurine/apirimidine endonuclease/redox effector element (Ape1/Ref-1) can be increasingly indicated in CSCs. Among additional functions, Ape1/Ref-1 can be part of the DNA repair complex base excision repair (BER), so that Ape1/Ref-1 can reduce both intracellular ROS and increase DNA repair [68]. Radioresistance in mesenchymal CSCs indirectly influencing DNA repair capacity could also be Methoxsalen (Oxsoralen) due to nicotinamide and after gemcitabine in pancreatic cancer [75] or a stronger activation of ATR/Chk1 in colon carcinoma after treatment with DNA interstrand-crosslinking (ICL) agents was shown [83]. Zhang and colleagues even went so far as to postulate a direct dependence of the DNA signaling cascade and stem-cell characteristics. They observed an ATM-mediated stabilization of zinc finger E-box binding homeobox 1 (ZEB1) leading to an enhanced Chk1-dependent DNA damage response in previously epithelial breast cells [104]. This direct dependence on stem cell character and HR or S-phase DNA repair was also observed for breast epithelial cells. Depletion of and led to reprogramming in breast epithelial cells to mesenchymal phenotype [105]. 4. CSC Heterogeneity and Plasticity Tumor tissues constitute a heterogeneous population of cancer cells. Among them are CSCs with distinct clinically relevant properties, such as tumor-initiating capacity, therapy resistance, dormancy, and increased metastatic potential. Different models were generated to describe this intratumoral heterogeneity. Clonal evolution is a nonhierarchical model characterized by acquisition of mutations that allow emergence and expansion of a dominant clone by a growth advantage that increases frequency of this clone over time. The classical CSC model is hierarchical and Methoxsalen (Oxsoralen) hypothesizes an asymmetric division of a CSC, resulting in a stable number of CSCs. Finally, strong experimental evidence is accumulating to support CSC plasticity; a conversion of a CSC into a non-CSC phenotype can be reversed as a result of genetic mutations, epigenetic alterations, or microenvironmental changes. All these cues not only impact the fundamental CSC properties such as their capacity to self-renew and to differentiate, Grem1 but also affect the proliferative potential, therapy resistance, and metastatic capacity of CSCs and their progenies [13,23,106]. Because no model can clarify the difficulty and behavior of the tumor completely, chances are that these systems donate to heterogeneity in parallel. Dick and Kreso combined these choices towards the united style of clonal advancement [13]. 4.1. CSC and EMT Phenotype Even though percentage of CSCs inside a tumor is normally low, the CSC inhabitants can be divergent itself because of acquisition of different mutational lots, epigenetic adjustments, or mobile plasticity. Many of these elements may be affected by environmental elements like hypoxia, launch of development cytokines and elements, or relationship of CSCs with stroma and extracellular matrix. Actually, even ionizing rays (IR) itself can induce adjustments in CSCs. For instance, IR can induce metastasis and EMT, which are features associated with a CSC phenotype [107 carefully,108,109,110]. If EMT is connected with CSCs continues to be heavily debated currently. However, a increasing body of proof supports the theory that EMT a minimum of in part plays a part in top features of CSCs [111,112,113]. Consistent with this, main transcription factors of the EMT signaling cascade like Snail family transcriptional repressor (Snail), ZEB1, or Twist family BHLH transcription factor 1 (Twist1) were shown to promote stemness properties [114,115]. In this context, Snail not only plays a crucial role in IR-mediated activation of EMT, migration, and invasion [116], but it also confers resistance to radiotherapy in colorectal cancer cells [117]. ZEB1, on the other hand, represses microRNAs like miR-183, miR200c, and miR203, which are known to inhibit stemness. The repression of these microRNAs essentially leads to upregulation of stem-cell factors SRY-box 2 (Sox2) and Kruppel-like factor 4 (Klf4) [118]. Finally, Twist1 positively regulates BMI1 proto-oncogene (Bmi-1), thereby inducing EMT and stemness [119]. Notably, ZEB1 and Twist1 were recently identified as downstream targets of fibroblast growth factor receptor 1 (FGFR1)/forkhead box M1 (FOXM1) in glioblastoma, and their expression is usually highly associated with resistance to radiotherapy [120]. Moreover, purified breast CSCs were shown to be more radioresistant when treated with transforming growth factor beta 1(TGF-1) compared to their parental counterparts [121]. It was shown that IR itself can contribute to enhanced TGF-1 release involving transcription factor activator protein 1 (AP-1) [122]. Secreted TGF-1 remains inactive upon binding as homodimer to the latent TGF- binding protein, but can be activated by IR-induced ROS [123]. The active form of TGF-1 promoted stemness in breast and lung cancer cells by upregulating stem cell factors octamer binding.