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. 2011;6(8):e23498.
doi: 10.1371/journal.pone.0023498. Epub 2011 Aug 10.

Rhabdomyosarcomas in Aging A/J Mice

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Free PMC article

Rhabdomyosarcomas in Aging A/J Mice

Roger B Sher et al. PLoS One. .
Free PMC article

Abstract

Rhabdomyosarcomas (RSCs) are skeletal muscle neoplasms found in humans and domestic mammals. The A/J inbred strain developed a high frequency (between 70-80%) of adult pleomorphic type (APT) RSC at >20 months of age while BALB/cByJ also develop RSC but less frequently. These neoplasms invaded skeletal muscle surrounding either the axial or proximal appendicular skeleton and were characterized by pleomorphic cells with abundant eosinophilic cytoplasm, multiple nuclei, and cross striations. The diagnosis was confirmed by detection of alpha-sarcomeric actin and myogenin in the neoplastic cells using immunocytochemistry. The A/J strain, but not the related BALB/c substrains, is also characterised by a progressive muscular dystrophy homologous to limb-girdle muscular dystrophy type 2B. The association between the development of RSC in similar muscle groups to those most severely affected by the progressive muscular dystrophy suggested that these neoplasms developed from abnormal regeneration of the skeletal muscle exacerbated by the dysferlin mutation. Transcriptome analyses of RSCs revealed marked downregulation of genes in muscular development and function signaling networks. Non-synonymous coding SNPs were found in Myl1, Abra, Sgca, Ttn, and Kcnj12 suggesting these may be important in the pathogenesis of RSC. These studies suggest that A strains of mice can be useful models for dissecting the molecular genetic basis for development, progression, and ultimately for testing novel anticancer therapeutic agents dealing with rhabdomyosarcoma.

Conflict of interest statement

Competing Interests: The authors have declared that no competing interests exist.

Figures

Figure 1
Figure 1. Rhabdomyosarcoma in A/J mice >500d.
(A) A large, pale, irregular mass in the lumbar region was firmly attached to the underlying muscle in this moribund A/J mouse. (B) Neoplastic cells were small, round cells with a single nucleus or elongated strap-like cells with regimented clusters of nuclei (H&E). (C) Cross striations were evident in the strap-like cells when sections were stained with phosphotungstic acid hematoyxlin. (D) Bones and normal skeletal muscle were infiltrated by the neoplastic cells above the vertebrae and spinal cord, destroying the normal architecture. (E) Higher magnification of A demonstrated the pleomorphic phenotype of the APT RSC. (F) Higher magnification of the boxed area in E illustrated strap-like, spindle-shaped, and single round cells with abundant brightly eosinophilic cytoplasm (H&E). (G) APT RSC invaded locally through the bone and compressed the spinal cord. (H) Higher magnification of boxed area illustrated the poorly differentiated multinucleated giant cells (arrows) and a bizarre mitotic figure (boxed area; H&E).
Figure 2
Figure 2. Protein expression in mouse rhabdomyosarcomas and Ingenuity Pathway Analysis of Illumina microarray data.
(A–D) Immunohistochemistry confirmed the tumor cells contained sarcomeric actin and myogenin but not smooth muscle actin, thereby confirming the diagnosis of rhabdomyosarcoma. A–D, 20x; A’–D’ boxed areas from A–D at 63x. Red = anti-sarcomeric actin, Green = anti-smooth muscle actin, Blue = anti-myogenin. (E) Signalling pathways of the most significantly dysregulated networks when a 10 fold or greater change was used as a cutoff. (F) Most of the genes in this network were significantly downregulated (green).

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