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C cells into induced pluripotent stem cells by the transduction of C cells into induced pluripotent stem cells by the transduction of only 4 transcription variables [72]. Having said that, it has been identified for a lot of years that reprogramming/dedifferentiation of differentiated cells in vivo can occur spontaneously inside the absence of exogenous reprogramming things beneath the proper micro-environmental conditions, as summarized inside a recent assessment [96]. Regular tissue non-stem cells, and their malignant counterparts, have the ability to spontaneously convert into a standard tissue stem cell or CSC state [97]. These observations suggest that the method of differentiation isn't unidirectional. A recent report demonstrated the conversion of differentiated broncheo-alveolar epithelial cells into epithelial stem cells upon viral infection or chemical injury in vivo [98]. Additionally, Shaykhiev et al. reported an embryonic stem cell gene expression signature for lung stem/progenitor cells in healthier smokers, which suggests the possibility that acquisition of genetic mutations cooperate having a stress-induced stem cell state to initiate malignant growth [99]. The tumor microenvironment is composed of a variety of cell varieties, which includes cancer connected fibroblasts (CAFs), immune cells, endothelial cells lining the tumor vasculatureSemin Cancer Biol. Author manuscript; obtainable in PMC 2016 April 01.Vlashi and PajonkPageand extracellular matrix components, among other people [100]. For most solid cancers, the CSC niche is at the moment undefined plus the supporting signals for a multi-potent CSC state haven't but been unveiled. Having said that, in brain cancers it has been shown that CSCs preferentially reside in relatively well-oxygenated perivascular niches inside the tumor [101]. Interestingly, endothelial cells express both, CXCL12/SDF1 [102] and Notch ligands [103], which trigger chemotaxis towards tumor blood vessels and promote self-renewal in glioma [104], which may possibly hold a druggable target against CSCs. A second, hypoxic niche for glioma cells was described by Jeremy Rich's laboratory [105]. Importantly, hypoxic situations resulted in reprogramming of CD133-negative glioma cells into CD133-positive cells using a CSC phenotype. These reprogramming events coincided with elevated Oct4, Nanog, and cMyc expression [105]. The same group later reported that exposure of non-stem glioma cells to low pH, frequently identified in hypoxic tumors also mediated the acquisition of a CSC phenotype [106]. The above studies demonstrate an apparent preference for localization of CSCs within the tumor microenvironment, therefore defining a CSC pseudo-niche. Alternatively, these observations could suggest that the CSC state is not a cell autonomous procedure, but rather dictated by the tumor microenvironment. In some sophisticated research Vermeulen et al. demonstrated that the CSC state of Wnt-activated colon cancer cells was dependent on activation by stromal-derived hepatocyte growth element (HGF) present inside the tumor microenvironment [107]. In a unique study Giannoni et al. uncovered the importance of IL-6 in activating tumor-associated fibroblasts, which in turn induced EMT and stemness in prostate cancer cells [108]. In help of these research, Iliopoulos et al. identified IL-6 as the mediator responsible for converting non-stem cancer cells into CSCs in patient-derived breast cancer specimen and breast and prostate cancer cell lines [109]. A dynamic equilibrium was observed between CSCs and their progeny, resulting inside a constant ratio amongst both cell populations o.