Transgenic mouse model of cardiac rhabdomyosarcoma formation

Abstract

Cardiac rhabdomyosarcomas are rare and the pathogenesis of this detrimental disease is widely unknown. Most data are obtained from case reports or small series and models for systematic pathogenetic studies are lacking. Here we present a new transgenic mouse model of cardiac rhabdomyosarcoma formation. Standard techniques were used to construct a minigene comprised of the 5' region of the 1.4 kb SM22alpha gene and the 2.7 kb SV40 T antigen (TAg) early region. This TAg fragment includes the coding sequences for the binding sites of p53 and the proteins of the pRb-family. Transgenic mice were studied at the age of 8–12 weeks. Cardiac tumors were found of variable size in the left or right heart and were associated with TAg expression. Histologic analysis revealed a 3.1-fold enhanced cell density, infiltrative growth, enlarged cell nuclei and a 3.4-fold enhanced DNA content. Phenotypic characterization of cardiac tumors resulted in positive staining for desmin, smooth-muscle alpha-actin, troponin c and Myo D1, which met the criteria for rhabdomyosarcomas. According to the specificity of the promoter, transgene expression was also found in vascular and genitourinary smooth muscle but was less pronounced and lacked tumor formation in non-cardiac tissues. To the best of our knowledge, the present study is the first description of a mouse model of cardiac rhabdomyosarcoma formation based on genetic modulation. Our model will be a valuable tool for illuminating the pathogenesis of cardiac rhabdomyosarcomas and will allow the testing of new therapeutic approaches to fight this dreadful disease.