Hosur Vishnu, Kavirayani Anoop, Riefler Jennifer, Carney Lisa M B, Lyons Bonnie, Gott Bruce, Cox Gregory A, Shultz Leonard D
The Jackson Laboratory, Bar Harbor, ME, USA.
Cancer Genet. 2012 May;205(5):232-41. doi: 10.1016/j.cancergen.2012.03.005.
Although researchers have yet to establish a link between muscular dystrophy (MD) and sarcomas in human patients, literature suggests that the MD genes dystrophin and dysferlin act as tumor suppressor genes in mouse models of MD. For instance, dystrophin-deficient mdx and dysferlin-deficient A/J mice, models of human Duchenne MD and limb-girdle MD type 2B, respectively, develop mixed sarcomas with variable penetrance and latency. To further establish the correlation between MD and sarcoma development, and to test whether a combined deletion of dystrophin and dysferlin exacerbates MD and augments the incidence of sarcomas, we generated dystrophin and dysferlin double mutant mice (STOCK-Dysf(prmd)Dmd(mdx-5Cv)). Not surprisingly, the double mutant mice develop severe MD symptoms and, moreover, develop rhabdomyosarcoma (RMS) at an average age of 12 months, with an incidence of >90%. Histological and immunohistochemical analyses, using a panel of antibodies against skeletal muscle cell proteins, electron microscopy, cytogenetics, and molecular analysis reveal that the double mutant mice develop RMS. The present finding bolsters the correlation between MD and sarcomas, and provides a model not only to examine the cellular origins but also to identify mechanisms and signal transduction pathways triggering development of RMS.
尽管研究人员尚未在人类患者中建立肌肉萎缩症（MD）与肉瘤之间的联系，但文献表明，MD相关基因肌营养不良蛋白和肌膜蛋白在MD小鼠模型中起到肿瘤抑制基因的作用。例如，分别作为人类杜氏肌营养不良症和2B型肢带型肌营养不良症模型的肌营养不良蛋白缺陷型mdx小鼠和肌膜蛋白缺陷型A/J小鼠，会发展出具有不同外显率和潜伏期的混合肉瘤。为了进一步确定MD与肉瘤发生之间的相关性，并测试肌营养不良蛋白和肌膜蛋白的联合缺失是否会加剧MD并增加肉瘤的发生率，我们培育了肌营养不良蛋白和肌膜蛋白双突变小鼠（STOCK-Dysf(prmd)Dmd(mdx-5Cv)）。不出所料，双突变小鼠出现了严重的MD症状，此外，在平均12个月大时发生横纹肌肉瘤（RMS），发病率超过90%。使用一组针对骨骼肌细胞蛋白的抗体进行组织学和免疫组织化学分析、电子显微镜检查、细胞遗传学分析和分子分析表明，双突变小鼠发生了RMS。目前的发现支持了MD与肉瘤之间的相关性，并提供了一个模型，不仅可以研究细胞起源，还可以识别触发RMS发生的机制和信号转导途径。
