title: The differentiation stage of p53-Rb-deficient bone marrow mesenchymal stem cells imposes the phenotype of in vivo sarcoma development.
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.
authors.affiliation: GENYO. Centre for Genomics and Oncological Research: Pfizer/University of Granada/Andalusian Regional Government, Granada, Spain.
authors.forename: R
authors.initials: R
authors.lastname: Rubio
authors.forename: I
authors.initials: I
authors.lastname: Gutierrez-Aranda
authors.forename: A I
authors.initials: AI
authors.lastname: Sáez-Castillo
authors.forename: A
authors.initials: A
authors.lastname: Labarga
authors.forename: M
authors.initials: M
authors.lastname: Rosu-Myles
authors.forename: S
authors.initials: S
authors.lastname: Gonzalez-Garcia
authors.forename: M L
authors.initials: ML
authors.lastname: Toribio
authors.forename: P
authors.initials: P
authors.lastname: Menendez
authors.forename: R
authors.initials: R
authors.lastname: Rodriguez
mesh_terms: D000273:Adipose Tissue / Q000473:pathology; D000818:Animals; D001854:Bone Marrow Cells / Q000473:pathology; D063646:Carcinogenesis; D002453:Cell Cycle; D002454:Cell Differentiation; D017353:Gene Deletion; D015972:Gene Expression Regulation, Neoplastic; D007890:Leiomyosarcoma / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D059630:Mesenchymal Stem Cells / Q000473:pathology*; D051379:Mice; D010012:Osteogenesis; D012516:Osteosarcoma / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D010641:Phenotype; D016160:Retinoblastoma Protein / Q000172:deficiency* / Q000235:genetics; D012509:Sarcoma / Q000235:genetics / Q000378:metabolism / Q000473:pathology*; D016159:Tumor Suppressor Protein p53 / Q000172:deficiency* / Q000235:genetics
chemical_list: D016160:Retinoblastoma Protein; D016159:Tumor Suppressor Protein p53