Journal
ONCOGENE
Volume 32, Issue 41, Pages 4970-4980Publisher
NATURE PUBLISHING GROUP
DOI: 10.1038/onc.2012.507
Keywords
mesenchymal stem cells; leiomyosarcoma; osteosarcoma; osteogenic differentiation; p53; Rb
Funding
- Instituto de Salud Carlos III/FEDER [PI10/00449, CP11/00024, RD12/0036/0015]
- Junta de Andalucia/FEDER [P08-CTS-3678]
- MINECO
- Spanish Association Against Cancer (Junta Provincial de Albacete) [CI110023]
- Health Canada [H4084-112281]
- ISCIII/FEDER
- [PLE-2009-0111]
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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.
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