Deficiency in p53 but not Retinoblastoma Induces the Transformation of Mesenchymal Stem Cells In vitro and Initiates Leiomyosarcoma In vivo
- 12 May 2010
- journal article
- Published by American Association for Cancer Research (AACR) in Cancer Research
- Vol. 70 (10), 4185-4194
- https://doi.org/10.1158/0008-5472.can-09-4640
Abstract
Sarcomas have been modeled in mice by the expression of specific fusion genes in mesenchymal stem cells (MSC), supporting the concept that MSCs might be the target initiating cell in sarcoma. In this study, we evaluated the potential oncogenic effects of p53 and/or retinoblastoma (Rb) deficiency in MSC transformation and sarcomagenesis. We derived wild-type, p53−/−, Rb−/−, and p53−/−Rb−/− MSC cultures and fully characterized their in vitro growth properties and in vivo tumorigenesis capabilities. In contrast with wild-type MSCs, Rb−/−, p53−/−, and p53−/−Rb−/− MSCs underwent in vitro transformation and showed severe alterations in culture homeostasis. More importantly, p53−/− and p53−/−Rb−/− MSCs, but not Rb−/− MSCs, were capable of tumor development in vivo after injection into immunodeficient mice. p53−/− or p53−/−Rb−/− MSCs originated leiomyosarcoma-like tumors, linking this type of smooth muscle sarcoma to p53 deficiency in fat tissue–derived MSCs. Sca1+ and Sca1 low/− cell populations isolated from ex vivo–established, transformed MSC lines from p53−/−Rb−/− tumors showed identical sarcomagenesis potential, with 100% tumor penetrance and identical latency, tumor weight, and histologic profile. Our findings define the differential roles of p53 and Rb in MSC transformation and offer proof-of-principle that MSCs could provide useful tools to dissect the sarcoma pathogenesis. Cancer Res; 70(10); 4185–94. ©2010 AACR.Keywords
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This publication has 48 references indexed in Scilit:
- Stem cell concepts renew cancer researchBlood, 2008
- Mesenchymal stem cells and their use as cell replacement therapy and disease modelling toolJournal of Cellular and Molecular Medicine, 2008
- Cancer stem cells in solid tumours: accumulating evidence and unresolved questionsNature Reviews Cancer, 2008
- Mesenchymal stem cell-natural killer cell interactions: evidence that activated NK cells are capable of killing MSCs, whereas MSCs can inhibit IL-2-induced NK-cell proliferationBlood, 2006
- Stem-Like Cells in Bone Sarcomas: Implications for TumorigenesisNeoplasia, 2005
- Cancer stem cells: lessons from leukemiaTrends in Cell Biology, 2005
- Bone marrow mesenchymal stem cells induce division arrest anergy of activated T cellsBlood, 2005
- Mesenchymal stem cells: clinical applications and biological characterizationThe International Journal of Biochemistry & Cell Biology, 2004
- Pluripotency of mesenchymal stem cells derived from adult marrowNature, 2002
- Multilineage Potential of Adult Human Mesenchymal Stem CellsScience, 1999