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- Title
The differentiation stage of p53-Rb-deficient bone marrow mesenchymal stem cells imposes the phenotype of in vivo sarcoma development.
- Authors
Rubio, R; Gutierrez-Aranda, I; Sáez-Castillo, A I; Labarga, A; Rosu-Myles, M; Gonzalez-Garcia, S; Toribio, M L; Menendez, P; Rodriguez, R
- Abstract
Increasing evidence suggests that mesenchymal stem/stromal cells (MSCs) carrying specific mutations are at the origin of some sarcomas. We have reported that the deficiency of p53 alone or in combination with Rb (Rb−/− p53−/−) in adipose-derived MSCs (ASCs) promotes leiomyosarcoma-like tumors in vivo. Here, we hypothesized that the source of MSCs and/or the cell differentiation stage could determine the phenotype of sarcoma development. To investigate whether there is a link between the source of MSCs and sarcoma phenotype, we generated p53−/− and Rb−/−p53−/− MSCs from bone marrow (BM-MSCs). Both genotypes of BM-MSCs initiated leiomyosarcoma formation similar to p53−/− and Rb−/−p53−/− ASCs. In addition, gene expression profiling revealed transcriptome similarities between p53- or Rb-p53-deficient BM-MSCs/ASCs and muscle-associated sarcomagenesis. These data suggest that the tissue source of MSC does not seem to determine the development of a particular sarcoma phenotype. To analyze whether the differentiation stage defines the sarcoma phenotype, BM-MSCs and ASCs were induced to differentiate toward the osteogenic lineage, and both p53 and Rb were excised using Cre-expressing adenovectors at different stages along osteogenic differentiation. Regardless the level of osteogenic commitment, the inactivation of Rb and p53 in BM-MSC-derived, but not in ASC-derived, osteogenic progenitors gave rise to osteosarcoma-like tumors, which could be serially transplanted. This indicates that the osteogenic differentiation stage of BM-MSCs imposes the phenotype of in vivo sarcoma development, and that BM-MSC-derived osteogenic progenitors rather than undifferentiated BM-MSCs, undifferentiated ASCs or ASC-derived osteogenic progenitors, represent the cell of origin for osteosarcoma development.
- Subjects
MESENCHYMAL stem cells; BONE marrow; CELL differentiation; P53 antioncogene; SARCOMA; LEIOMYOSARCOMA; GENE expression; OSTEOSARCOMA; TRANSPLANTATION immunology
- Publication
Oncogene, 2013, Vol 32, Issue 41, p4970
- ISSN
0950-9232
- Publication type
Article
- DOI
10.1038/onc.2012.507