Carcinogenesis Advance Access originally published online on July 27, 2009
Carcinogenesis 2009 30(10):1789-1795; doi:10.1093/carcin/bgp180
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Targeted mutation of p53 and Rb in mesenchymal cells of the limb bud produces sarcomas in mice
Department of Orthopaedic Oncology
1 Department of Pathology, The University of Texas M.D. Anderson Cancer Center, Houston, TX 77230-1402, USA
2 Department of Orthopaedic Surgery, Graduate School of Medicine, Kyoto University, Kyoto, Japan 606-8507
3 Department of Genetics, The University of Texas M.D. Anderson Cancer Center, Houston, TX 77230-1402, USA
* To whom correspondence should be addressed: Department of Orthopaedic Oncology, Unit 408, The University of Texas M.D. Anderson Cancer Center, 1400 Holcombe Boulevard, Houston, TX 77030-1402, USA. Tel: +1 713 745 0088; Fax: +1 713 792 8448; Email: plin{at}mdanderson.org
Mice bearing germ line mutations of p53 develop sarcomas at a significant rate. Since they are susceptible to a variety of other malignancies, they are not ideally suited to the study of sarcomas. To test the possibility that targeted mutation of tumor suppressor genes in early mesenchymal cells would induce formation of sarcomas, the Prx1-cre transgenic mouse was crossed to mice-bearing floxed alleles of p53 and Rb. Mice with homozygous deletion of p53 (Prx1-cre p53lox/lox) developed sarcomas in the extremities at a mean time of 50 weeks. Osteosarcomas (OS) were the most common type of sarcoma (61%) followed by poorly differentiated soft tissue sarcomas (PDSTS) (32%). Homozygous deletion of p53 produced sarcomas significantly more rapidly than heterozygous deletion, which resulted in sarcoma formation after a mean of 96 weeks. Mice with homozygous Rb mutation (Prx1-cre Rblox/lox) developed normally and had no ostensible defects in the limbs. In contrast to p53, targeted deletion of Rb did not produce sarcomas in the limbs. However, simultaneous deletion of Rb and p53 accelerated the time to sarcoma formation, and a greater percentage of PDSTS were found. Deletion of p53 in committed osteoblasts by the Col1a1-cre transgenic mouse bearing an osteoblast-specific enhancer resulted in a high percentage of OS. These findings suggest that deletion of p53 in mesenchymal cells that give rise to osteoblasts is a powerful initiator of OS. Deletion of Rb does not initiate sarcoma formation in mice, but it accelerates formation of both soft tissue sarcomas and OS.
Abbreviations: OS, osteosarcomas
Received May 11, 2009; revised June 23, 2009; accepted July 18, 2009.