Transduction by oncogenic Cre-inducible lentiviruses in the cortex of synapsinI-Cre or GFAP-Cre transgenic mice, which drive the expression of Cre specifically in neurons and glial cells, respectively, induced the formation of gliomas. and how this may pose a risk to the application of this new technology in regenerative medicine. by transplanting the nuclei of embryo (blastula) cells. Later, similar experiments were carried out with eggs of the South African frog using nuclei from fully differentiated cells [6]. Collectively, these results challenged the unidirectional developmental model: Cells now can go back in time, dedifferentiate by changes in nuclear gene expression while maintaining their genome intact. Somatic cell nuclear transfer (SCNT), or nuclear reprogramming, is the technology by which the nucleus of the donor somatic cell is usually removed and transferred into an enucleated oocyte, where undefined factors in the cytoplasm of this oocyte are able to reprogram the somatic donor nucleus to a pluripotent state. In a remarkable experiment, Takahashi and Yamanaka [3] exhibited that introduction of mere four genes (refers to the molecular differences that occur between tumors initiated in the same organ, which allows the classification of these tumors in different subtypes and may even represent biologically unique disease entities [18]. Malignancy stem cell can be defined as the cells within a tumor that possess the capacity to self-renew and to STING ligand-1 cause the heterogeneous lineages of malignancy cells that comprise the tumor. CSCs are thus a biologically unique subpopulation of cells that can perpetuate indefinitely as STING ligand-1 oppose to the bulk of cells that reside in the tumor, and are mostly insensitive to currently used malignancy therapies. The CSC model assumes that this unique subpopulation of cells sustain malignant growth NOTCH1 by means of their ability to self-renew and the possibility to give rise to progeny with self-limited proliferative capacity. This suggests a hierarchical business where CSCs are responsible for the generation of the heterogeneity found within tumors. Although CSCs exhibit the stem cell properties of self-renewal and differentiation, they do not necessarily originate from the transformation of normal tissue stem cells [18]. Several recent studies now suggest that not all cancers purely conform to the unidirectional hierarchical CSC model, and entertain the possibility of tumor cell plasticity, where non-CSC can dedifferentiate and acquire CSC-like properties under certain conditions as exhibited by examples below: Glioblastoma (GBM), the most common and aggressive subtype of the malignant gliomas, is usually characterized by intense proliferation, invasion, and intratumor heterogeneity. A decade ago, STING ligand-1 Ronald DePinho’s group exhibited that the combined loss of p16INK4a and p19ARF enables mature astrocyte dedifferentiation in response to EGFR activation [19]. Moreover, transduction of Ink4a/Arf(?/?) neural stem cells (NSCs) or astrocytes with constitutively active EGFR induces a common high-grade glioma phenotype. These findings identify neural stem cells and astrocytes as equally permissive compartments for gliomagenesis. The identification of TUJ1-positive neurons in the tumors originating from the transformed astrocytes suggested that dedifferentiation may STING ligand-1 be so complete as to generate a pluripotent cell with the potential to make neurons as well as glia. More recently, our group showed that GBM can originate from a variety of cells in the brain, including terminally differentiated cortical astrocytes and neurons [20]. Transduction by oncogenic Cre-inducible lentiviruses in the cortex of synapsinI-Cre or GFAP-Cre transgenic mice, which drive the expression of Cre specifically in neurons and glial cells, respectively, induced the formation of gliomas. Interestingly, these tumors mostly expressed markers of progenitor/neural stem cells, nestin and Sox2. In a STING ligand-1 study aimed to follow the kinetic expression of some of these markers during tumor development, we observed that at early stages, differentiation markers are progressively diminished, while nestin, a marker of NSC, undetectable a few days after transduction, increased significantly with tumor progression (Fig?1). We proposed that oncogenic-induced dedifferentiation of mature cells in the brain to a stem-/progenitor-like state leads to heterogeneous glioma tumors (Fig?2). The genetically acquired plasticity of these cells allows progression and maintenance of this aggressive tumor and even formation of its own blood vessels by transdifferentiation [21]. These data also supported the view originally proposed by Ronald DePinho and his group [19] that dysregulation of specific genetic pathways, rather than cell of origin, dictates the emergence and.