Module Map of Stem Cell Genes Guides Creation of Epithelial Cancer Stem Cells

Program in Epithelial Biology, Stanford University, Stanford, CA 94305, USA.
Cell stem cell (Impact Factor: 22.27). 05/2008; 2(4):333-44. DOI: 10.1016/j.stem.2008.02.009
Source: PubMed


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.

Download full-text


Available from: David S Cassarino,
  • Source
    • "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 [7] [8] [9] [10] [11] [12] [13]. Thus, cancer is an obvious case of pathological reprogramming [14] [15]. "
    [Show abstract] [Hide abstract]
    ABSTRACT: Background: 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. Presentation of the hypothesis: Extracellular pH of cancer cell is acidic and recent studies reveal the role of acidic environment in cell reprogramming of normal cells. This hypothesis deals with the potential role of acidic pH in malignant tumor development through normal cells adjacent cancer cells. It seems that cancer cells are more intelligent and acid release from these cells is not just a by-product but also and more important reason, is a tool to up-regulate cell reprogramming markers, induce epigenetic modification and tumor progress in normal cells adjacent cancer cells. If this is correct, then it could be expected that with alkaline targeting of tumor environment, failed cell reprogramming, aberrant epigenetic modification will decrease in normal cells adjacent cancer cells and afterward metastasis will decrease. Testing the hypothesis: It is proposed to investigate altered genetic and epigenetic modification (DNA methylation, histone modification) in cancer, early cancer and cells in vicinity of cancer cells at different pH range of 5.8-7.8. This study is performed to determine whether acidic pH induces reprogramming, global hypomethylation and promoter hypermethylation in cancer cells and cells in vicinity of cancer cells at different pH values. Implications of the hypothesis: This hypothesis deal with the ability of acidic pH to convert normal cells adjacent cancer cells to cancerous cells and its inductive potential on genetic and epigenetic modification of normal cells adjacent cancer cells and will further emphasize the important of extracellular acidic targeting in cancer therapy.
    Medical Hypotheses 10/2014; 83(6). DOI:10.1016/j.mehy.2014.09.014 · 1.07 Impact Factor
  • Source
    • "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. "
    [Show abstract] [Hide abstract]
    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 · 3.69 Impact Factor
  • Source
    • "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). "

Show more