EMT-Induced Stemness and Tumorigenicity Are Fueled by the EGFR/Ras Pathway
Open Access
- 12 August 2013
- journal article
- research article
- Published by Public Library of Science (PLoS) in PLOS ONE
- Vol. 8 (8), e70427
- https://doi.org/10.1371/journal.pone.0070427
Abstract
Recent studies have revealed that differentiated epithelial cells would acquire stem cell-like and tumorigenic properties following an Epithelial-Mesenchymal Transition (EMT). However, the signaling pathways that participate in this novel mechanism of tumorigenesis have not been fully characterized. In Runx3−/−p53−/− murine gastric epithelial (GIF-14) cells, EMT-induced plasticity is reflected in the expression of the embryonal proto-oncogene Hmga2 and Lgr5, an exclusive gastrointestinal stem cell marker. Here, we report the concurrent activation of an EGFR/Ras gene expression signature during TGF-β1-induced EMT in GIF-14 cells. Amongst the altered genes was the induction of Egfr, which corresponded with a delayed sensitization to EGF treatment in GIF-14. Co-treatment with TGF-β1 and EGF or the expression of exogenous KRas led to increased Hmga2 or Lgr5 expression, sphere initiation and colony formation in soft agar assay. Interestingly, the gain in cellular plasticity/tumorigenicity was not accompanied by increased EMT. This uncoupling of EMT and the induction of plasticity reveals an involvement of distinct signaling cues, whereby the EGFR/Ras pathway specifically promotes stemness and tumorigenicity in EMT-altered GIF-14 cells. These data show that the EGFR/Ras pathway requisite for the sustenance of gastric stem cells in vivo and in vitro is involved in the genesis and promotion of EMT-induced tumor-initiating cells.Keywords
This publication has 45 references indexed in Scilit:
- The Pan-ErbB Negative Regulator Lrig1 Is an Intestinal Stem Cell Marker that Functions as a Tumor SuppressorCell, 2012
- EMT and Dissemination Precede Pancreatic Tumor FormationCell, 2012
- Paracrine and Autocrine Signals Induce and Maintain Mesenchymal and Stem Cell States in the BreastCell, 2011
- EGFR/Ras/MAPK Signaling Mediates Adult Midgut Epithelial Homeostasis and Regeneration in DrosophilaCell Stem Cell, 2010
- Epithelial-Mesenchymal Transitions in Development and DiseaseCell, 2009
- Cancer stem cells: mirage or reality?Nature Medicine, 2009
- Deconstructing Stem Cell Tumorigenicity: A Roadmap to Safe Regenerative MedicineThe International Journal of Cell Cloning, 2009
- The Epithelial-Mesenchymal Transition Generates Cells with Properties of Stem CellsCell, 2008
- Gene set enrichment analysis: A knowledge-based approach for interpreting genome-wide expression profilesProceedings of the National Academy of Sciences of the United States of America, 2005
- Significance analysis of microarrays applied to the ionizing radiation responseProceedings of the National Academy of Sciences of the United States of America, 2001