Rubio, D; Garcia, S; Paz, MF; De la Cueva, T; Lopez-Fernandez, LA; Lloyd, AC; ... Bernad, A; + view all Rubio, D; Garcia, S; Paz, MF; De la Cueva, T; Lopez-Fernandez, LA; Lloyd, AC; Garcia-Castro, J; Bernad, A; - view fewer (2008) Molecular Characterization of Spontaneous Mesenchymal Stem Cell Transformation. PLOS ONE , 3 (1) , Article e1398. 10.1371/journal.pone.0001398.
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Background. We previously reported the in vitro spontaneous transformation of human mesenchymal stem cells (MSC) generating a population with tumorigenic potential, that we termed transformed mesenchymal cells (TMC). Methodology/Principal Findings. Here we have characterized the molecular changes associated with TMC generation. Using microarrays techniques we identified a set of altered pathways and a greater number of downregulated than upregulated genes during MSC transformation, in part due to the expression of many untranslated RNAs in MSC. Microarray results were validated by qRT-PCR and protein detection. Conclusions/Significance. In our model, the transformation process takes place through two sequential steps; first MSC bypass senescence by upregulating c-myc and repressing p16 levels. The cells then bypass cell crisis with acquisition of telomerase activity, Ink4a/Arf locus deletion and Rb hyperphosphorylation. Other transformation-associated changes include modulation of mitochondrial metabolism, DNA damage-repair proteins and cell cycle regulators. In this work we have characterized the molecular mechanisms implicated in TMC generation and we propose a two-stage model by which a human MSC becomes a tumor cell.
|Title:||Molecular Characterization of Spontaneous Mesenchymal Stem Cell Transformation|
|Open access status:||An open access version is available from UCL Discovery|
|Additional information:||© 2008 Rubio et al. This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited. DR and SG received predoctoral fellowships from the Spanish Ministry of Education and Science, JG-C and L L-F received postdoctoral fellowships from the Ministry of Science and Technology and the Ministerio de Sanidad y Consumo (FIS; CP03/0031 and CP06/0267). This work was partially supported by Spanish Ministry of Science and Technology (CICYT) grants SAF2001-2262, SAF2005-0864 and GEN2001-4856-C13-02 to AB. The Department of Immunology and Oncology was founded and is supported by the Spanish National Research Council (CSIC) and by Pfizer.|
|Keywords:||ACUTE MYELOID-LEUKEMIA, NEOPLASTIC TRANSFORMATION, C-MYC, CANCER, TELOMERASE, GENE, IMMORTALIZATION, METHYLATION, P16(INK4A), LOCUS|
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