Module Map of Stem Cell Genes Guides Creation of Epithelial Cancer Stem Cells
ABSTRACT Self-renewal is a hallmark of stem cells and cancer, but existence of a shared stemness program remains controversial. Here, we construct a gene module map to systematically relate transcriptional programs in embryonic stem cells (ESCs), adult tissue stem cells, and human cancers. This map reveals two predominant gene modules that distinguish ESCs and adult tissue stem cells. The ESC-like transcriptional program is activated in diverse human epithelial cancers and strongly predicts metastasis and death. c-Myc, but not other oncogenes, is sufficient to reactivate the ESC-like program in normal and cancer cells. In primary human keratinocytes transformed by Ras and I kappa B alpha, c-Myc increases the fraction of tumor-initiating cells by 150-fold, enabling tumor formation and serial propagation with as few as 500 cells. c-Myc-enhanced tumor initiation is cell-autonomous and independent of genomic instability. Thus, activation of an ESC-like transcriptional program in differentiated adult cells may induce pathologic self-renewal characteristic of cancer stem cells.
Full-textDOI: · Available from: David S Cassarino, Aug 12, 2015
- SourceAvailable from: Shima Tavakol
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- "Cancer cells overexpress higher level of Nanog and Oct4 as compared to normal cells and lower than induced pluripotent cells (iPS). However, up-regulation of Nanog and Oct4 are in good agreement with tumorogensis, malignancy and metastasis in poorly undifferentiated tumors       . Thus, cancer is an obvious case of pathological reprogramming  . "
ABSTRACT: Eelier studies demonstrated the up-regulation of some transcriptional factors such as Oct4, Nanog, Sox2 in undifferentiated cancer cells. These transcriptional regulators are up-regulated in pluripotent cells, as well and are responsible for cell reprogramming in normal cells. It might be said that normal cells adjacent tumor site are undergone of failed cell reprogramming.Medical Hypotheses 10/2014; 83(6). DOI:10.1016/j.mehy.2014.09.014
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- "Gene expression analysis has recently been utilized to identify the re-activation of pluripotency-related markers in different human tumors. These studies have shown that similar global gene expression patterns in tumors and ES cells correlates with poorly differentiated and more aggressive tumors (Ben-Porath et al., 2008; Wong et al., 2008). Expression of pluripotency-related transcription factors such as Oct4 and Nanog has been associated with tumorigenesis in many reports, but the exact functional involvement of these factors in tumor progression and/or development has been controversial. "
ABSTRACT: Though expression of the homeobox transcription factor Nanog is generally restricted to pluripotent cells and early germ cells, many contradictory reports about Nanog’s involvement in tumorigenesis exist. To address this, a modified Tet-On system was utilized to generate Nanog-inducible mice. Following prolonged Nanog expression, phenotypic alterations were found to be restricted to the intestinal tract, leaving other major organs unaffected. Intestinal and colonic epithelium hyperplasia was observed—intestinal villi had doubled in length and hyperplastic epithelium outgrowths were seen after 7 days. Increased proliferation of crypt cells and downregulation of the tumor suppressors Cdx2 and Klf4 was detected. ChIP analysis showed physical interaction of Nanog with the Cdx2 and Klf4 promoters, indicating a regulatory conservation from embryonic development. Despite downregulation of tumor suppressors and increased proliferation, ectopic Nanog expression did not lead to tumor formation. We conclude that unlike other pluripotency-related transcription factors, Nanog cannot be considered an oncogene.Stem Cell Research 09/2014; 13(2). DOI:10.1016/j.scr.2014.08.001
- "This involves the gene expression signature of ESCs being dissected into three major functional modules (Core, Polycomb, and Myc). Of note, the Myc module is closely related to the core ESC-like module identified by Wong et al. (2008) but is distinct from the Core module that comprises genes regulated by core pluripotency factors such as Oct3/4 and Nanog. We monitored alterations of Myc and Core module activities by GSEA during loss of Max gene expression (Figure 2C). "