Deficiency in p53 but not Retinoblastoma Induces the Transformation of Mesenchymal Stem Cells In vitro and Initiates Leiomyosarcoma In vivo

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 andidentical 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.