Lin Patrick P, Pandey Manoj K, Jin Fenghua, Raymond A Kevin, Akiyama Haruhiko, Lozano Guillermina
Department of Orthopaedic Oncology, The University of Texas M.D. Anderson Cancer Center, Houston, TX 77230-1402, USA.
Carcinogenesis. 2009 Oct;30(10):1789-95. doi: 10.1093/carcin/bgp180. Epub 2009 Jul 27.
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 p53(lox/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 Rb(lox/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.
携带p53生殖系突变的小鼠会以较高的发生率患上肉瘤。由于它们易患多种其他恶性肿瘤，所以并不非常适合用于肉瘤的研究。为了测试早期间充质细胞中肿瘤抑制基因的靶向突变是否会诱导肉瘤形成，将Prx1-cre转基因小鼠与携带p53和Rb的floxed等位基因的小鼠进行杂交。p53纯合缺失的小鼠（Prx1-cre p53(lox/lox)）在平均50周时在四肢患上肉瘤。骨肉瘤（OS）是最常见的肉瘤类型（61%），其次是低分化软组织肉瘤（PDSTS）（32%）。p53纯合缺失比杂合缺失产生肉瘤的速度明显更快，杂合缺失导致肉瘤形成的平均时间为96周。Rb纯合突变的小鼠（Prx1-cre Rb(lox/lox)）发育正常，四肢没有明显缺陷。与p53不同，Rb的靶向缺失并未在四肢产生肉瘤。然而，同时缺失Rb和p53会加速肉瘤形成的时间，并且发现PDSTS的比例更高。通过携带成骨细胞特异性增强子的Col1a1-cre转基因小鼠在已分化的成骨细胞中缺失p53会导致高比例的OS。这些发现表明，在产生成骨细胞的间充质细胞中缺失p53是OS的有力启动因素。Rb的缺失不会在小鼠中引发肉瘤形成，但会加速软组织肉瘤和OS的形成。
