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.
Highlights
Mesenchymal stem cells (MSC) are multipotent stem cells present in several tissues including bone marrow, cord blood, placenta, and fat tissue among others [1, 2]
Recent evidence suggests that MSCs might constitute a target cell for transforming mutations responsible for the formation of sarcomas [14,15,16,17,18]
Little is known about the mechanistic basis of MSC transformation, which has often been linked to the accumulation of chromosome instability [23,24,25,26,27]
Summary
Mesenchymal stem cells (MSC) are multipotent stem cells present in several tissues including bone marrow, cord blood, placenta, and fat tissue among others [1, 2]. They differentiate in vitro and in vivo into multiple mesodermal tissues [2,3,4]. Rubio designed and performed experiments, analyzed the data, and wrote the manuscript; J. García-Castro conceived the study and performed research; I. Menendez analyzed the data and interpreted the results, supervised the study, and wrote the paper; R. Rodríguez conceived and supervised the study, wrote the paper, analyzed the data, and interpreted the results.
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