期刊
CANCER RESEARCH
卷 70, 期 10, 页码 4185-4194出版社
AMER ASSOC CANCER RESEARCH
DOI: 10.1158/0008-5472.CAN-09-4640
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资金
- CSJA [0030/2006, 0108/2007]
- CICE, de la Junta de Andalucia [P08-CTS-3678]
- The Spanish Ministry of Health [PI070026, PI080029]
- MICINN [PLE-2009-0111, SAF2008-00121]
- Asociacion Espanola Contra el Cancer
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. (C) 2010 AACR.
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